Intelligent polymeric micelles: development and application as drug delivery for docetaxel.

PubMed

Li, Yimu; Zhang, Hui; Zhai, Guang-Xi

2017-04-01

Recent years, docetaxel (DTX)-loaded intelligent polymeric micelles have been regarded as a promising vehicle for DTX for the reason that compared with conventional DTX-loaded micelles, DTX-loaded intelligent micelles not only preserve the basic functions of micelles such as DTX solubilization, enhanced accumulation in tumor tissue, and improved bioavailability and biocompatibility of DTX, but also possess other new properties, for instance, tumor-specific DTX delivery and series of responses to endogenous or exogenous stimulations. In this paper, basic theories and action mechanism of intelligent polymeric micelles are discussed in detail, especially the related theories of DTX-loaded stimuli-responsive micelles. The relevant examples of stimuli-responsive DTX-loaded micelles are also provided in this paper to sufficiently illustrate the advantages of relevant technology for the clinical application of anticancer drug, especially for the medical application of DTX.

Polymeric Micelles: Recent Advancements in the Delivery of Anticancer Drugs.

PubMed

Gothwal, Avinash; Khan, Iliyas; Gupta, Umesh

2016-01-01

Nanotechnology, in health and medicine, extensively improves the safety and efficacy of different therapeutic agents, particularly the aspects related to drug delivery and targeting. Among various nano-carriers, polymer based macromolecular approaches have resulted in improved drug delivery for the diseases like cancers, diabetes, autoimmune disorders and many more. Polymeric micelles consisting of hydrophilic exterior and hydrophobic core have established a record of anticancer drug delivery from the laboratory to commercial reality. The nanometric size, tailor made functionality, multiple choices of polymeric micelle synthesis and stability are the unique properties, which have attracted scientists and researchers around the world to work upon in this opportunistic drug carrier. The capability of polymeric micelles as nano-carriers are nowhere less significant than nanoparticles, liposomes and other nanocarriers, as per as the commercial feasibility and presence is concerned. In fact polymeric micelles are among the most extensively studied delivery platforms for the effective treatment of different cancers as well as non-cancerous disorders. The present review highlights the sequential and recent developments in the design, synthesis, characterization and evaluation of polymeric micelles to achieve the effective anticancer drug delivery. The future possibilities and clinical outcome have also been discussed, briefly.

Physico-chemical characterization of polymeric micelles loaded with platinum derivatives by capillary electrophoresis and related methods.

PubMed

Oukacine, Farid; Bernard, Stephane; Bobe, Iulian; Cottet, Hervé

2014-12-28

(1,2-diamino-cyclohexane)Platinum(II) ((DACH)Pt) loaded polymeric micelles of poly(ethylene glycol-b-sodium glutamate) (PEG-b-PGlu) are currently studied as a potential candidate to replace oxaliplatin in the treatment of cancers with the aim to reduce side effects like cumulative peripheral distal neurotoxicity and acute dysesthesias. As for all synthetic polymeric drug delivery systems, the characterization of the (co)polymer precursors and of the final drug delivery system (polymeric micelles) is crucial to control the repeatability of the different batches and to get correlation between physico-chemical structure and biological activity. In this work, the use of capillary electrophoresis (CE) and related methods for the characterization of (DACH)Pt-loaded polymeric micelles and their precursor (PEG-b-PGlu copolymer) has been investigated in detail. The separation and quantification of residual PGlu homopolymer in the PEG-b-PGlu sample were performed by free solution capillary zone electrophoresis mode. This mode brought also information on the PEG-b-PGlu copolymer composition and polydispersity. It also permitted to monitor the decomposition of polymeric micelles in the presence of NaCl at room temperature. Interactions between PEG-b-PGlu unimers, on one hand, and polymeric micelles or surfactants, on the other hand, were studied by using the Micellar Electrokinetic Chromatography and Frontal Analysis Capillary Electrophoresis modes. Finally, weight-average hydrodynamic radii of the loaded polymeric micelles and of the PEG-b-PGlu unimers were determined by Taylor Dispersion Analysis (an absolute size determination method that can be easily implemented on CE apparatus). Copyright © 2014 Elsevier B.V. All rights reserved.

Polymeric micelles in mucosal drug delivery: Challenges towards clinical translation.

PubMed

Sosnik, Alejandro; Menaker Raskin, Maya

2015-11-01

Polymeric micelles are nanostructures formed by the self-aggregation of copolymeric amphiphiles above the critical micellar concentration. Due to the flexibility to tailor different molecular features, they have been exploited to encapsulate motley poorly-water soluble therapeutic agents. Moreover, the possibility to combine different amphiphiles in one single aggregate and produce mixed micelles that capitalize on the features of the different components substantially expands the therapeutic potential of these nanocarriers. Despite their proven versatility, polymeric micelles remain elusive to the market and only a few products are currently undergoing advanced clinical trials or reached clinical application, all of them for the therapy of different types of cancer and administration by the intravenous route. At the same time, they emerge as a nanotechnology platform with great potential for non-parenteral mucosal administration. However, for this, the interaction of polymeric micelles with mucus needs to be strengthened. The present review describes the different attempts to develop mucoadhesive polymeric micelles and discusses the challenges faced in the near future for a successful bench-to-bedside translation. Copyright © 2015 Elsevier Inc. All rights reserved.

Multifunctional polymeric micelles for delivery of drugs and siRNA

PubMed Central

Jhaveri, Aditi M.; Torchilin, Vladimir P.

2014-01-01

Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers with a core-shell structure have been used as versatile carriers for delivery of drugs as well as nucleic acids. They have gained immense popularity owing to a host of favorable properties including their capacity to effectively solubilize a variety of poorly soluble pharmaceutical agents, biocompatibility, longevity, high stability in vitro and in vivo and the ability to accumulate in pathological areas with compromised vasculature. Moreover, additional functions can be imparted to these micelles by engineering their surface with various ligands and cell-penetrating moieties to allow for specific targeting and intracellular accumulation, respectively, to load them with contrast agents to confer imaging capabilities, and incorporating stimuli-sensitive groups that allow drug release in response to small changes in the environment. Recently, there has been an increasing trend toward designing polymeric micelles which integrate a number of the above functions into a single carrier to give rise to “smart,” multifunctional polymeric micelles. Such multifunctional micelles can be envisaged as key to improving the efficacy of current treatments which have seen a steady increase not only in hydrophobic small molecules, but also in biologics including therapeutic genes, antibodies and small interfering RNA (siRNA). The purpose of this review is to highlight recent advances in the development of multifunctional polymeric micelles specifically for delivery of drugs and siRNA. In spite of the tremendous potential of siRNA, its translation into clinics has been a significant challenge because of physiological barriers to its effective delivery and the lack of safe, effective and clinically suitable vehicles. To that end, we also discuss the potential and suitability of multifunctional polymeric micelles, including lipid-based micelles, as promising vehicles for both siRNA and drugs. PMID:24795633

Redox and pH Dual-Responsive Polymeric Micelles with Aggregation-Induced Emission Feature for Cellular Imaging and Chemotherapy.

PubMed

Zhuang, Weihua; Xu, Yangyang; Li, Gaocan; Hu, Jun; Ma, Boxuan; Yu, Tao; Su, Xin; Wang, Yunbing

2018-05-21

Intelligent polymeric micelles for antitumor drug delivery and tumor bioimaging have drawn a broad attention because of their reduced systemic toxicity, enhanced efficacy of drugs, and potential application of tumor diagnosis. Herein, we developed a multifunctional polymeric micelle system based on a pH and redox dual-responsive mPEG-P(TPE- co-AEMA) copolymer for stimuli-triggered drug release and aggregation-induced emission (AIE) active imaging. These mPEG-P(TPE- co-AEMA)-based micelles showed excellent biocompatibility and emission property, exhibiting great potential application for cellular imaging. Furthermore, the antitumor drug doxorubicin (DOX) could be encapsulated during self-assembly process with high loading efficiency, and a DOX-loaded micelle system with a size of 68.2 nm and narrow size distribution could be obtained. DOX-loaded micelles demonstrated great tumor suppression ability in vitro, and the dual-responsive triggered intracellular drug release could be further traced. Moreover, DOX-loaded micelles could efficiently accumulate at the tumor site because of enhanced permeability and retention effect and long circulation of micelles. Compared with free DOX, DOX-loaded micelles exhibited better antitumor effect and significantly reduced adverse effects. Given the efficient accumulation targeting to tumor tissue, dual-responsive drug release, and excellent AIE property, this polymeric micelle would be a potential candidate for cancer therapy and diagnosis.

Thermally stable nanoparticles on supports

DOEpatents

Roldan Cuenya, Beatriz; Naitabdi, Ahmed R.; Behafarid, Farzad

2012-11-13

An inverse micelle-based method for forming nanoparticles on supports includes dissolving a polymeric material in a solvent to provide a micelle solution. A nanoparticle source is dissolved in the micelle solution. A plurality of micelles having a nanoparticle in their core and an outer polymeric coating layer are formed in the micelle solution. The micelles are applied to a support. The polymeric coating layer is then removed from the micelles to expose the nanoparticles. A supported catalyst includes a nanocrystalline powder, thin film, or single crystal support. Metal nanoparticles having a median size from 0.5 nm to 25 nm, a size distribution having a standard deviation .ltoreq.0.1 of their median size are on or embedded in the support. The plurality of metal nanoparticles are dispersed and in a periodic arrangement. The metal nanoparticles maintain their periodic arrangement and size distribution following heat treatments of at least 1,000.degree. C.

Fluorescent polymeric micelles with aggregation-induced emission properties for monitoring the encapsulation of doxorubicin.

PubMed

Chen, Jen-Ing; Wu, Wen-Chung

2013-05-01

A new type of fluorescent polymeric micelles is developed by self-assembly from a series of amphiphilic block copolymers, poly(ethylene glycol)-b-poly[styrene-co-(2-(1,2,3,4,5-pentaphenyl-1H-silol-1-yloxy)ethyl methacrylate)] [PEG-b-P(S-co-PPSEMA)]. Their capability of loading doxorubicin (DOX) is investigated by monitoring the loading content, encapsulation efficiency, and photophysical properties of micelles. Förster resonance energy transfer from PPSEMA to DOX is observed in DOX-loaded micelles, which can serve as an indication of successful encapsulation of DOX in these micelles. The application of this new type of fluorescent polymeric micelles as a fluorescent probe and an anticancer drug carrier simultaneously is explored by studying the intracellular uptake of DOX-loaded micelles. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Method for forming thermally stable nanoparticles on supports

DOEpatents

Roldan Cuenya, Beatriz; Naitabdi, Ahmed R.; Behafarid, Farzad

2013-08-20

An inverse micelle-based method for forming nanoparticles on supports includes dissolving a polymeric material in a solvent to provide a micelle solution. A nanoparticle source is dissolved in the micelle solution. A plurality of micelles having a nanoparticle in their core and an outer polymeric coating layer are formed in the micelle solution. The micelles are applied to a support. The polymeric coating layer is then removed from the micelles to expose the nanoparticles. A supported catalyst includes a nanocrystalline powder, thin film, or single crystal support. Metal nanoparticles having a median size from 0.5 nm to 25 nm, a size distribution having a standard deviation .ltoreq.0.1 of their median size are on or embedded in the support. The plurality of metal nanoparticles are dispersed and in a periodic arrangement. The metal nanoparticles maintain their periodic arrangement and size distribution following heat treatments of at least 1,000.degree. C.

Polymeric micelles: nanocarriers for cancer-targeted drug delivery.

PubMed

Zhang, Yifei; Huang, Yixian; Li, Song

2014-08-01

Polymeric micelles represent an effective delivery system for poorly water-soluble anticancer drugs. With small size (10-100 nm) and hydrophilic shell of PEG, polymeric micelles exhibit prolonged circulation time in the blood and enhanced tumor accumulation. In this review, the importance of rational design was highlighted by summarizing the recent progress on the development of micellar formulations. Emphasis is placed on the new strategies to enhance the drug/carrier interaction for improved drug-loading capacity. In addition, the micelle-forming drug-polymer conjugates are also discussed which have both drug-loading function and antitumor activity.

Redox-Responsive Biomimetic Polymeric Micelle for Simultaneous Anticancer Drug Delivery and Aggregation-Induced Emission Active Imaging.

PubMed

Hu, Jun; Zhuang, Weihua; Ma, Boxuan; Su, Xin; Yu, Tao; Li, Gaocan; Hu, Yanfei; Wang, Yunbing

2018-05-10

Intelligent polymeric micelles have been developed as potential nanoplatforms for efficient drug delivery and diagnosis. Herein, we successfully prepared redox-sensitive polymeric micelles combined aggregation-induced emission (AIE) imaging as an outstanding anticancer drug carrier system for simultaneous chemotherapy and bioimaging. The amphiphilic copolymer TPE-SS-PLAsp- b-PMPC could self-assemble into spherical micelles, and these biomimetic micelles exhibited great biocompatibility and remarkable ability in antiprotein adsorption, showing great potential for biomedical application. Anticancer drug doxorubicin (DOX) could be encapsulated during the self-assembly process, and these drug-loaded micelles showed intelligent drug release and improved antitumor efficacy due to the quick disassembly in response to high levels of glutathione (GSH) in the environment. Moreover, the intracellular DOX release could be traced through the fluorescent imaging of these AIE micelles. As expected, the in vivo antitumor study exhibited that these DOX-carried micelles showed better antitumor efficacy and less adverse effects than that of free DOX. These results strongly indicated that this smart biomimetic micelle system would be a prominent candidate for chemotherapy and bioimaging.

Conjugation of arginine-glycine-aspartic acid peptides to poly(ethylene oxide)-b-poly(epsilon-caprolactone) micelles for enhanced intracellular drug delivery to metastatic tumor cells.

PubMed

Xiong, Xiao-Bing; Mahmud, Abdullah; Uludağ, Hasan; Lavasanifar, Afsaneh

2007-03-01

An arginine-glycine-aspartic acid (RGD) containing model peptide was conjugated to the surface of poly(ethylene oxide)-block-poly(epsilon-caprolactone) (PEO-b-PCL) micelles as a ligand that can recognize adhesion molecules overexpressed on the surface of metastatic cancer cells, that is, integrins, and that can enhance the micellar delivery of encapsulated hydrophobic drug into a tumor cell. Toward this goal, PEO-b-PCL copolymers bearing acetal groups on the PEO end were synthesized, characterized, and assembled to polymeric micelles. The acetal group on the surface of the PEO-b-PCL micelles was converted to reactive aldehyde under acidic condition at room temperature. An RGD-containing linear peptide, GRGDS, was conjugated on the surface of the aldehyde-decorated PEO-b-PCL micelles by incubation at room temperature. A hydrophobic fluorescent probe, that is, DiI, was physically loaded in prepared polymeric micelles to imitate hydrophobic drugs loaded in micellar carrier. The cellular uptake of DiI loaded GRGDS-modified micelles by melanoma B16-F10 cells was investigated at 4 and 37 degrees C by fluorescent spectroscopy and confocal microscopy techniques and was compared to the uptake of DiI loaded valine-PEO-b-PCL micelles (as the irrelevant ligand decorated micelles) and free DiI. GRGDS conjugation to polymeric micelles significantly facilitated the cellular uptake of encapsulated hydrophobic DiI most probably by intergrin-mediated cell attachment and endocytosis. The results indicate that acetal-terminated PEO-b-PCL micelles are amenable for introducing targeting moieties on the surface of polymeric micelles and that RGD-peptide conjugated PEO-b-PCL micelles are promising ligand-targeted carriers for enhanced drug delivery to metastatic tumor cells.

Amphiphilic polymeric micelles as the nanocarrier for peroral delivery of poorly soluble anticancer drugs.

PubMed

Tian, Ye; Mao, Shirui

2012-06-01

Many amphiphilic copolymers have recently been synthesized as novel promising micellar carriers for the delivery of poorly water-soluble anticancer drugs. Studies on the formulation and oral delivery of such micelles have demonstrated their efficacy in enhancing drug uptake and absorption, and exhibit prolonged circulation time in vitro and in vivo. In this review, literature on hydrophobic modifications of several hydrophilic polymers, including polyethylene glycol, chitosan, hyaluronic acid, pluronic and tocopheryl polyethylene glycol succinate, is summarized. Parameters influencing the properties of polymeric micelles for oral chemotherapy are discussed and strategies to overcome main barriers for polymeric micelles peroral absorption are proposed. During the design of polymeric micelles for peroral chemotherapy, selecting or synthesizing copolymers with good compatibility with the drug is an effective strategy to increase drug loading and encapsulation efficiency. Stability of the micelles can be improved in different ways. It is recommended to take permeability, mucoadhesion, sustained release, and P-glycoprotein inhibition into consideration during copolymer preparation or to consider adding some excipients in the formulation. Furthermore, both the copolymer structure and drug loading methods should be controlled in order to get micelles with appropriate particle size for better absorption.

Polymeric Micelles and Alternative Nanonized Delivery Vehicles for Poorly Soluble Drugs

PubMed Central

Lu, Ying; Park, Kinam

2013-01-01

Poorly soluble drugs often encounter low bioavailability and erratic absorption patterns in the clinical setting. Due to the rising number of compounds having solubility issues, finding ways to enhance the solubility of drugs is one of the major challenges in the pharmaceutical industry today. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as solubilizing agents for delivery of poorly soluble drugs. This manuscript examines the fundamentals of polymeric micelles through reviews of representative literature and demonstrates possible applications through recent examples of clinical trial developments. In particular, the potential of polymeric micelles for delivery of poorly water-soluble drugs, especially in the areas of oral delivery and in cancer therapy, is discussed. Key considerations in utilizing polymeric micelles’ advantages and overcoming potential disadvantages have been highlighted. Lastly, other possible strategies related to particle size reduction for enhancing solubilization of poorly water-soluble drugs are introduced. PMID:22944304

A pH and redox dual stimuli-responsive poly(amino acid) derivative for controlled drug release.

PubMed

Gong, Chu; Shan, Meng; Li, Bingqiang; Wu, Guolin

2016-10-01

A pH and redox dual stimuli-responsive poly(aspartic acid) derivative for controlled drug release was successfully developed through progressive ring-opening reactions of polysuccinimide (PSI). Polyethylene glycol (PEG) chains were grafted onto the polyaspartamide backbone via redox-responsive disulfide linkages, providing a sheddable shell for the polymeric micelles in a reductive environment. Phenyl groups were introduced into the polyaspartamide backbone via the aminolysis reaction of PSI to serve as the hydrophobic segment of micelles. The polyaspartamide scaffold was also functionalized with N-(3-aminopropyl)-imidazole to obtain the pH-responsiveness manifesting as a swelling of the core of micelles at a low pH. The polymeric micelles with a core-shell nanostructure forming in neutral media exhibited both pH and redox responsive characteristics. Doxorubicin (DOX) as a model drug was encapsulated into the core of micelles through both hydrophobic and π-π interactions between aromatic rings and the DOX-loaded polymeric micelles exhibited accelerated drug release behaviors in an acidic and reductive environment due to the swelling of hydrophobic cores and the shedding of PEG shells. Furthermore, the cytocompability of the polymer and the cytotoxicity of DOX-loaded micelles towards Hela cells under corresponding conditions were evaluated, and the endocytosis of DOX-loaded polymeric micelles and the intracellular drug release from micelles were observed. All obtained data indicated that the micelle was a promising candidate for controlled drug release. Copyright © 2016 Elsevier B.V. All rights reserved.

Synthesis of Cross-Linked Polymeric Micelle pH Nanosensors: An Investigation of Design Flexibility.

PubMed

Kumar, E K Pramod; Jølck, Rasmus I; Andresen, Thomas L

2015-09-01

The design flexibility that polymeric micelles offer in the fabrication of optical nanosensors for ratiometric pH measurements is investigated. pH nanosensors based on polymeric micelles are synthesized either by a mixed-micellization approach or by a postmicelle modification strategy. In the mixed-micellization approach, self-assembly of functionalized unimers followed by shell cross-linking by copper-catalyzed azide-alkyne cycloaddition (CuAAC) results in stabilized cRGD-functionalized micelle pH nanosensors. In the postmicelle modification strategy, simultaneous cross-linking and fluorophore conjugation at the micelle shell using CuAAC results in a stabilized micelle pH nanosensor. Compared to the postmicelle modification strategy, the mixed-micellization approach increases the control of the overall composition of the nanosensors. Both approaches provide stable nanosensors with similar pKa profiles and thereby nanosensors with similar pH sensitivity. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Complex and hierarchical micelle architectures from diblock copolymers using living, crystallization-driven polymerizations.

PubMed

Gädt, Torben; Ieong, Nga Sze; Cambridge, Graeme; Winnik, Mitchell A; Manners, Ian

2009-02-01

Block copolymers consist of two or more chemically distinct polymer segments, or blocks, connected by a covalent link. In a selective solvent for one of the blocks, core-corona micelle structures are formed. We demonstrate that living polymerizations driven by the epitaxial crystallization of a core-forming metalloblock represent a synthetic tool that can be used to generate complex and hierarchical micelle architectures from diblock copolymers. The use of platelet micelles as initiators enables the formation of scarf-like architectures in which cylindrical micelle tassels of controlled length are grown from specific crystal faces. A similar process enables the fabrication of brushes of cylindrical micelles on a crystalline homopolymer substrate. Living polymerizations driven by heteroepitaxial growth can also be accomplished and are illustrated by the formation of tri- and pentablock and scarf architectures with cylinder-cylinder and platelet-cylinder connections, respectively, that involve different core-forming metalloblocks.

Polymeric micelles for ocular drug delivery: From structural frameworks to recent preclinical studies.

PubMed

Mandal, Abhirup; Bisht, Rohit; Rupenthal, Ilva D; Mitra, Ashim K

2017-02-28

Effective intraocular drug delivery poses a major challenge due to the presence of various elimination mechanisms and physiological barriers that result in low ocular bioavailability after topical application. Over the past decades, polymeric micelles have emerged as one of the most promising drug delivery platforms for the management of ocular diseases affecting the anterior (dry eye syndrome) and posterior (age-related macular degeneration, diabetic retinopathy and glaucoma) segments of the eye. Promising preclinical efficacy results from both in-vitro and in-vivo animal studies have led to their steady progression through clinical trials. The mucoadhesive nature of these polymeric micelles results in enhanced contact with the ocular surface while their small size allows better tissue penetration. Most importantly, being highly water soluble, these polymeric micelles generate clear aqueous solutions which allows easy application in the form of eye drops without any vision interference. Enhanced stability, larger cargo capacity, non-toxicity, ease of surface modification and controlled drug release are additional advantages with polymeric micelles. Finally, simple and cost effective fabrication techniques render their industrial acceptance relatively high. This review summarizes structural frameworks, methods of preparation, physicochemical properties, patented inventions and recent advances of these micelles as effective carriers for ocular drug delivery highlighting their performance in preclinical studies. Copyright © 2017 Elsevier B.V. All rights reserved.

Camptothecin prodrug nanomicelle based on a boronate ester-linked diblock copolymer as the carrier of doxorubicin with enhanced cellular uptake.

PubMed

Gao, Ya; Xiao, Yi; Liu, Shiyuan; Yu, Jiahui

2018-02-01

A novel pH-sensitive polymeric prodrug of camptothecin (CPT) by polymerizing γ-camptothecin-glutamate N-carboxyanhydride (Glu (CPT)-NCA) on boronate ester-linked poly (ethyleneglycol) (PEG) directly via the amine-initiated ring open polymerization (ROP) has been developed. The resulting amphiphilic prodrug (mPEG-BC-PGluCPT) could self-assemble into nanoparticles and encapsulate doxorubicin (Dox) simultaneously in aqueous solution for dual-drug delivery. The formation of polymeric prodrug micelles (mPEG-BC@PGluCPT) was confirmed by the measurements of critical aggregation concentration (CAC), particle size, and morphology observations. The mPEG-BC@PGluCPT micelles were colloidally stable in solutions for two weeks. Polymeric prodrug micelles mPEG-BC@PGluCPT and Dox-loaded micelles mPEG-BC@PGluCPT⋅Dox showed sustained drug release profiles over 48 h. As expected, drug release was accelerated by the decreasement of pH value from 7.4 to 6.0, which demonstrated pH-dependent manner of drug release. Additionally, it was found that cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles on HepG2 cells was higher than that on HL-7702 cells, especially in culture medium at pH 6.0. The enhanced cellular uptake of mPEG-BC@PGluCPT⋅Dox micelles under acidic condition on HepG2 cells resulted in the higher cytotoxicity of mPEG-BC@PGluCPT⋅Dox micelles at acidic pH than that at pH 7.4.

Amphiphilic polymeric micelle as pseudostationary phase in electrokinetic chromatography for analysis of eight corticosteroids in cosmetics.

PubMed

Xu, Xiaojin; Ni, Xinjiong; Cao, Yuhua; Zhuo, Xiaolu; Yang, Xiaoxiao; Cao, Guangqun

2014-03-01

Amphiphilic polymeric micelle, as a novel pseudostationary phase in EKC was used to determine eight kinds of corticosteroids namely hydrocortisone, prednisolone, hydrocortisone acetate, prednisone, cortisone acetate, prednisolone acetate, dexamethasone, and triamcinolone acetonide in cosmetics. Amphiphilic random copolymer poly(methyl methacrylate-co-methacrylic acid) (P(MMA-co-MAA)) was micellizated via neutralization in alkaline aqueous solution. The influences of the molar ratio of monomer MMA to MAA, the concentration of polymer and pH on the polymeric micelle microstructure and EKC performances were investigated. As molar ratio of MMA to MAA in P(MMA-co-MAA) increased, both CMC and environmental polarity of the inner core in polymeric micelle decreased dramatically. With increasing monomer ratio, the size of polymeric micelles increased firstly, and then decreased, finally increased again. ζ potential of the micelle had a slight decline trend. As increment of polymer concentration, the size of the polymeric micelle increased steadily. By optimizing the monomer ratio, the polymer concentration, and pH of the running buffer, as well as operation conditions such as separation voltage and temperature, the eight analytes could be separated within 16.5 min using 7.5 mg/mL polymer with the monomer ratio of 7:3 dissolved in pH 9.2 borax buffer as the running buffer. The method has been used for analysis of corticosteroids in cosmetic samples with simple extraction; the recoveries for eight analytes were between 85.9 and 106%. This method was of accuracy, repeatability, pretreatment simplicity, and could be applied to the quality control of cosmetics. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Supramolecular "Step Polymerization" of Preassembled Micelles: A Study of "Polymerization" Kinetics.

PubMed

Yang, Chaoying; Ma, Xiaodong; Lin, Jiaping; Wang, Liquan; Lu, Yingqing; Zhang, Liangshun; Cai, Chunhua; Gao, Liang

2018-03-01

In nature, sophisticated functional materials are created through hierarchical self-assembly of nanoscale motifs, which has inspired the fabrication of man-made materials with complex architectures for a variety of applications. Herein, a kinetic study on the self-assembly of spindle-like micelles preassembled from polypeptide graft copolymers is reported. The addition of dimethylformamide and, subsequently, a selective solvent (water) can generate a "reactive point" at both ends of the spindles as a result of the existence of structural defects, which induces the "polymerization" of the spindles into nanowires. Experimental results combined with dissipative particle dynamics simulations show that the polymerization of the micellar subunits follows a step-growth polymerization mechanism with a second-order reaction characteristic. The assembly rate of the micelles is dependent on the subunit concentration and on the activity of the reactive points. The present work reveals a law governing the self-assembly kinetics of micelles with structural defects and opens the door for the construction of hierarchical structures with a controllable size through supramolecular step polymerization. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

New generation of electrochemical immunoassay based on polymeric nanoparticles for early detection of breast cancer

PubMed Central

Mouffouk, Fouzi; Aouabdi, Sihem; Al-Hetlani, Entesar; Serrai, Hacene; Alrefae, Tareq; Leo Chen, Liaohai

2017-01-01

Screening and early diagnosis are the key factors for the reduction of mortality rate and treatment cost of cancer. Therefore, sensitive and selective methods that can reveal the low abundance of cancer biomarkers in a biological sample are always desired. Here, we report the development of a novel electrochemical biosensor for early detection of breast cancer by using bioconjugated self-assembled pH-responsive polymeric micelles. The micelles were loaded with ferrocene molecules as “tracers” to specifically target cell surface-associated epithelial mucin (MUC1), a biomarker for breast and other solid carcinoma. The synthesis of target-specific, ferrocene-loaded polymeric micelles was confirmed, and the resulting sensor was capable of detecting the presence of MUC1 in a sample containing about 10 cells/mL. Such a high sensitivity was achieved by maximizing the loading capacity of ferrocene inside the polymeric micelles. Every single event of binding between the antibody and antigen was represented by the signal of hundreds of thousands of ferrocene molecules that were released from the polymeric micelles. This resulted in a significant increase in the intensity of the ferrocene signal detected by cyclic voltammetry. PMID:28450780

Control of in vivo disposition and immunogenicity of polymeric micelles by adjusting poly(sarcosine) chain lengths on surface

NASA Astrophysics Data System (ADS)

Kurihara, Kensuke; Ueda, Motoki; Hara, Isao; Ozeki, Eiichi; Togashi, Kaori; Kimura, Shunsaku

2017-07-01

Four kinds of A3B-type amphiphilic polydepsipeptides, (poly(sarcosine))3- b-poly( l-lactic acid) (the degree of polymerization of poly(sarcosine) are 10, 33, 55, and 85; S10 3 , S33 3 , S55 3 , and S85 3 ) were synthesized to prepare core-shell type polymeric micelles. Their in vivo dispositions and stimulations to trigger immune system to produce IgM upon multiple administrations to mice were examined. With increasing poly(sarcosine) chain lengths, the hydrophilic shell became thicker and the surface density at the most outer surface decreased on the basis of dynamic and static light scattering measurements. These two physical elements of polymeric micelles elicited opposite effects on the immune response in light of the chain length therefore to show an optimized poly(sarcosine) chain length existing between 33mer and 55mer to suppress the accelerated blood clearance phenomenon associated with polymeric micelles.

Neutral Polymeric Micelles for RNA Delivery

PubMed Central

Lundy, Brittany B.; Convertine, Anthony; Miteva, Martina; Stayton, Patrick S.

2013-01-01

RNA interference (RNAi) drugs have significant therapeutic potential but delivery systems with appropriate efficacy and toxicity profiles are still needed. Here, we describe a neutral, ampholytic polymeric delivery system based on conjugatable diblock polymer micelles. The diblock copolymer contains a hydrophilic poly[N-(2-hydroxypropyl) methacrylamide-co-N-(2-(pyridin-2- yldisulfanyl)ethyl)methacrylamide) (poly[HPMA-co-PDSMA]) segment to promote aqueous stability and facilitate thiol-disulfide exchange reactions, and a second ampholytic block composed of propyl acrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The poly[(HPMA-co-PDSMA)-b-(PAA-co-DMAEMA-co-BMA)] was synthesized using Reversible Addition-Fragmentation chain Transfer (RAFT) polymerization with an overall molecular weight of 22,000 g/mol and a PDI of 1.88. Dynamic light scattering and fluorescence measurements indicated that the diblock copolymers self-assemble under aqueous conditions to form polymeric micelles with a hydrodynamic radius and critical micelle concentration of 25 nm and 25 μg/mL respectively. Red blood cell hemolysis experiments show that the neutral hydrophilic micelles have potent membrane destabilizing activity at endosomal pH values. Thiolated siRNA targeting glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was directly conjugated to the polymeric micelles via thiol exchange reactions with the pyridal disulfide groups present in the micelle corona. Maximum silencing activity in HeLa cells was observed at a 1:10 molar ratio of siRNA to polymer following a 48 h incubation period. Under these conditions 90 % mRNA knockdown and 65 % and protein knockdown of at 48 h was achieved with negligible toxicity. In contrast the polymeric micelles lacking a pH-responsive endosomalytic segment demonstrated negligible mRNA and protein knockdown under these conditions. The potent mRNA knockdown and excellent biocompatibility of the neutral siRNA conjugates demonstrate the potential utility if this carrier design for delivering therapeutic siRNA drugs. PMID:23360541

Stimuli-sensitive polymeric micelles as anticancer drug carriers.

PubMed

Na, Kun; Sethuraman, Vijay T; Bae, You Han

2006-11-01

Amphiphilic block copolymers often form core-shell type micelles by self-organization of the blocks in an aqueous medium or under specific experimental conditions. Polymeric micelles constructed from these polymers that contain a segment whose physical or chemical properties respond to small changes in environmental conditions are collectively called 'stimuli-sensitive' micelles. This class of nano-scaled constructs has been investigated as a promising anti-cancer drug carrier because the micelles are able to utilize small environmental changes and modify drug release kinetics, biodistribution and the interactions with tissues and cells. This review summarizes the recent progress in stimuli-sensitive micelles for tumor chemotherapy, particularly for those responding to hyperthermic conditions, tumor pH and endosomal/lysosomal pH.

Quantitative structure-property relationship (QSPR) modeling of drug-loaded polymeric micelles via genetic function approximation.

PubMed

Wu, Wensheng; Zhang, Canyang; Lin, Wenjing; Chen, Quan; Guo, Xindong; Qian, Yu; Zhang, Lijuan

2015-01-01

Self-assembled nano-micelles of amphiphilic polymers represent a novel anticancer drug delivery system. However, their full clinical utilization remains challenging because the quantitative structure-property relationship (QSPR) between the polymer structure and the efficacy of micelles as a drug carrier is poorly understood. Here, we developed a series of QSPR models to account for the drug loading capacity of polymeric micelles using the genetic function approximation (GFA) algorithm. These models were further evaluated by internal and external validation and a Y-randomization test in terms of stability and generalization, yielding an optimization model that is applicable to an expanded materials regime. As confirmed by experimental data, the relationship between microstructure and drug loading capacity can be well-simulated, suggesting that our models are readily applicable to the quantitative evaluation of the drug-loading capacity of polymeric micelles. Our work may offer a pathway to the design of formulation experiments.

Quantitative Structure-Property Relationship (QSPR) Modeling of Drug-Loaded Polymeric Micelles via Genetic Function Approximation

PubMed Central

Lin, Wenjing; Chen, Quan; Guo, Xindong; Qian, Yu; Zhang, Lijuan

2015-01-01

Self-assembled nano-micelles of amphiphilic polymers represent a novel anticancer drug delivery system. However, their full clinical utilization remains challenging because the quantitative structure-property relationship (QSPR) between the polymer structure and the efficacy of micelles as a drug carrier is poorly understood. Here, we developed a series of QSPR models to account for the drug loading capacity of polymeric micelles using the genetic function approximation (GFA) algorithm. These models were further evaluated by internal and external validation and a Y-randomization test in terms of stability and generalization, yielding an optimization model that is applicable to an expanded materials regime. As confirmed by experimental data, the relationship between microstructure and drug loading capacity can be well-simulated, suggesting that our models are readily applicable to the quantitative evaluation of the drug-loading capacity of polymeric micelles. Our work may offer a pathway to the design of formulation experiments. PMID:25780923

Tumor environment changed by combretastatin derivative (Cderiv) pretreatment that leads to effective tumor targeting, MRI studies, and antitumor activity of polymeric micelle carrier systems.

PubMed

Shiraishi, Kouichi; Harada, Yoshiko; Kawano, Kumi; Maitani, Yoshie; Hori, Katsuyoshi; Yanagihara, Kazuyoshi; Takigahira, Misato; Yokoyama, Masayuki

2012-01-01

To evaluate effect of a vascular disrupting agent, a combretastatin derivative (Cderiv), on tumor targeting for polymeric micelle carrier systems, containing either a diagnostic MRI contrast agent or a therapeutic anticancer drug. Cderiv was pre-administered 72 h before polymeric micelle MRI contrast agent injection. Accumulation of the MRI contrast agent in colon 26 murine tumor was evaluated with or without pretreatment of Cderiv by ICP and MRI. Significantly higher accumulation of the MRI contrast agent was found in tumor tissues when Cderiv was administered at 72 h before MRI contrast agent injection. T(1)-weighted images of the tumor exhibited substantial signal enhancement in tumor area at 24 h after the contrast agent injection. In T(1)-weighted images, remarkable T(1)-signal enhancements were observed in part of tumor, not in whole tumor. These results indicate that Cderiv pretreatment considerably enhanced the permeability of the tumor blood vessels. Antitumor activity of adriamycin encapsulated polymeric micelles with the Cderiv pretreatment suppressed tumor growth in 44As3 human gastric scirrhous carcinoma-bearing nude mice. Pretreatment of Cderiv enhanced tumor permeability, resulting in higher accumulation of polymeric micelle carrier systems in solid tumors.

Rapid analysis of water- and fat-soluble vitamins by electrokinetic chromatography with polymeric micelle as pseudostationary phase.

PubMed

Ni, Xinjiong; Xing, Xiaoping; Cao, Yuhua; Cao, Guangqun

2014-11-28

A novel polymeric micelle, formed by random copolymer poly (stearyl methacrylate-co-methacrylic acid) (P(SMA-co-MAA)) has been used as pseudostationary phase (PSP) in electrokinetic chromatography (EKC) for simultaneous and rapid determination of 11 kinds of water- and fat-soluble vitamins in this work. The running buffer consisting of 1% (w/v) P(SMA-co-MAA), 10% (v/v) 1-butanol, 20% (v/v) acetonitrile, and 30 mM Palitzsch buffer solution (pH 9.2) was applied to improve the selectivity and efficiency, as well as to shorten analysis time. 1-Butanol and acetonitrile as the organic solvent modifiers played the most important roles for rapid separation of these vitamins. The effects of organic solvents on microstructure of the polymeric micelle were investigated. The organic solvents swell the polymeric micelle by three folds, lower down the surface charge density and enhance the microenviromental polarity of the polymeric micelle. The 11 kinds of water- and fat-soluble vitamins could be baseline separated within 13 min. The method was applied to determine water- and fat-soluble vitamins in commercial vitamin sample; the recoveries were between 93% and 111% with the relative standard derivations (RSDs) less than 5%. The determination results matched the label claim. Copyright © 2014 Elsevier B.V. All rights reserved.

Solubilization of poorly soluble photosensitizer hypericin by polymeric micelles and polyethylene glycol.

PubMed

Búzová, Diana; Kasák, Peter; Miškovský, Pavol; Jancura, Daniel

2013-06-01

Hypericin (Hyp) is a promising photosensitizer for photodiagnostic and photodynamic therapy of cancer. However, Hyp has a large conjugated system and in aqueous solutions forms insoluble aggregates which do not possess biological activity. This makes intravenous injection of Hyp problematic and restricts its medical applications. To overcome this problem, Hyp is incorporated into drug delivery systems which can increase its solubility and bioavailability. One of the possibilities is utilization of polymeric micelles. The most used hydrophilic block for preparation of polymeric micelles is polyethylen glycol (PEG). PEG is a polymer which for its lack of immunogenicity, antigenicity and toxicity obtained approval for use in human medicine. In this work we have studied the solubilization of Hyp aggregates in the presence of PEG-PE and PEG-cholesterol micelles. The concentration of polymeric micelles which allows total monomerization of Hyp corresponds to the critical micellar concentration of these micelles (~10(-6) M). We have also investigated the effect of the molecular weight and concentration of PEG on the transition of aggregated Hyp to its monomeric form. PEGs with low molecular weight (< 1000 g/mol) do not significantly contribute to the solubilization of Hyp. However, PEGs with molecular weight > 2000 g/mol efficiently transform Hyp aggregates to the monomeric state of this photosensitizer.

Selective in vitro anticancer effect of superparamagnetic iron oxide nanoparticles loaded in hyaluronan polymeric micelles.

PubMed

Smejkalová, Daniela; Nešporová, Kristina; Huerta-Angeles, Gloria; Syrovátka, Jakub; Jirák, Daniel; Gálisová, Andrea; Velebný, Vladimír

2014-11-10

Due to its native origin, excellent biocompatibility and biodegradability, hyaluronan (HA) represents an attractive polymer for superparamagnetic iron oxide nanoparticles (SPION) coating. Herein, we report HA polymeric micelles encapsulating oleic acid coated SPIONs, having a hydrodynamic size of about 100 nm and SPION loading capacity of 1-2 wt %. The HA-SPION polymeric micelles were found to be selectively cytotoxic toward a number of human cancer cell lines, mainly those of colon adenocarcinoma (HT-29). The selective inhibition of cell growth was even observed when the SPION loaded HA polymeric micelles were incubated with a mixture of control and cancer cells. The selective in vitro inhibition could not be connected with an enhanced CD44 uptake or radical oxygen species formation and was rather connected with a different way of SPION intracellular release. While aggregated iron particles were visualized in control cells, nonaggregated solubilized iron oxide particles were detected in cancer cells. In vivo SPION accumulation in intramuscular tumor following an intravenous micelle administration was confirmed by magnetic resonance (MR) imaging and histological analysis. Having a suitable hydrodynamic size, high magnetic relaxivity, and being cancer specific and able to accumulate in vivo in tumors, SPION-loaded HA micelles represent a promising platform for theranostic applications.

Ionically fixed polymeric nanoparticles as a novel drug carrier.

PubMed

Lee, Sa-Won; Chang, Dong-Hoon; Shim, Myung-Seop; Kim, Bong-Oh; Kim, Sun-Ok; Seo, Min-Hyo

2007-08-01

In this study, we have prepared a novel polymeric drug delivery system comprised of ionically fixed polymeric nanoparticles (IFPN) and investigated their potential as a drug carrier for the passive targeting of water-insoluble anticancer drugs. For this purpose, the physicochemical characteristics of the IFPN were investigated by comparing them with conventional polymeric micelles. IFPN containing paclitaxel were prepared and evaluated for in vitro stability and in vivo pharmacokinetics. The IFPN were successfully fabricated using a monomethoxypolyethylene glycol-polylactide (mPEG-PLA) diblock copolymer and a sodium salt of D,L-poly(lactic acid) (D,L-PLACOONa) upon the addition of CaCl2. The transmittance of the IFPN solution was much lower than that of a polymeric micelle solution at the same polymer concentration implicating an increase in the number of appreciable particles. The particle size of the IFPN was approximately 20 approximately 30 nm which is in the range of particle sizes that facilitate sterile filtration using a membrane filter. The IFPN also have a regular spherical shape with a narrow size distribution. The zeta potential of the IFPN was almost neutral, similar to that of the polymeric micelles. In contrast, mixed micelles with a combination of mPEG-PLA and D,L-PLACOONa prior to the addition of Ca2+ showed a negative charge (-17 mV), possibly due to the carboxyl anion of polylactic acid exposed on the surface of the micelles. The IFPN formulation was highly kinetically stable in aqueous medium compared to the polymeric micelle formulation. The molecular weight of D,L-PLACOONa in the IFPN and the mPEG-PLA/D,L-PLACOONa molar ratio had a great influence upon the kinetic stability of the IFPN. Pharmacokinetic studies showed that the area under the concentration vs time curve (AUC) of IFPN in blood was statistically higher (about two times) when compared with that of Cremophor EL-based formulation (Taxol equivalent) or polymeric micelle formulation. The results suggests that the IFPN were retained in the circulation long enough to play a significant role as a drug carrier in the bloodstream, possibly resulting in improved therapeutic efficiency. Therefore, the IFPN are expected to be a promising novel polymeric nanoparticulate system for passive tumor targeting of water-insoluble anticancer drugs including paclitaxel.

Synthesis and in vitro evaluation of a pH-sensitive PLA-PEG-folate based polymeric micelle for controlled delivery of docetaxel.

PubMed

Hami, Zahra; Amini, Mohsen; Ghazi-Khansari, Mahmoud; Rezayat, Seyed Mehdi; Gilani, Kambiz

2014-04-01

pH-responsive docetaxel-conjugated poly (lactic acid) (PLA)-polyethyleneglycol (PEG) micellar formulation was synthesized via acid labile hydrazone linkage. Levulinic acid (LEV) was used as a linker between docetaxel (DTX) and hydrazine. Targeted delivery of DTX was achieved by conjugation of folate to PEG segment. The DTX conjugated polymeric micelles were about 181 nm in diameter and their critical micelle concentration was 5.18 μg/ml. DTX was released from micelles in a pH-dependent manner. The results showed a significant difference in DTX release from polymeric micelles at pH 5.0 and pH 7.4. Cytotoxicity assays using methyl tetrazolium (MTT), neutral red (NR) and lactate dehydrogenase (LDH) demonstrated a decreased cytotoxic activity of the drug containing nanoconjugate compared with free DTX that appears to be contributed to the sustained release of drug from micelles. Based on these results, it is expected that this pH-responsive nanoconjugate is promising as a useful carrier for targeted delivery of anticancer agents. Copyright © 2014 Elsevier B.V. All rights reserved.

Responsive polymer-based colloids for drug delivery and bioconversion

NASA Astrophysics Data System (ADS)

Kudina, Olena

Responsive polymer-based colloids (RPBC) are the colloidal structures containing responsive polymeric component which is able to adapt its physico-chemical properties to the environment by undergoing chemical and/or conformational changes. The goal of the dissertation is to develop and characterize several groups of RPBC with different morphological complexity and explore their potential in drug delivery and bioconversion. The role of RPBC morphology for these specific applications is discussed in details. Three groups of RPBC were fabricated: i. polymeric micelles; ii. mixed polymeric micelles; iii. hybrid polymer-inorganic particles. All fabricated RPBCs contain polymeric component in their structure. The dissertation investigates how the changes of the responsive polymeric component properties are reflected in morphologies of RPBC. The first group of RPBC, polymeric micelles, was formed by the self-assembly of amphiphilic invertible polymers (AIPs) synthesized in our group. AIPs self-assemble into invertible micellar assemblies (IMAs) in solvents of different polarity. In this work, IMAs ability to invert the structure as a response to the change in solvent polarity was demonstrated using 1H NMR spectroscopy and SANS. It was shown that the IMAs incorporate hydrophobic cargo either in the core or in the shell, depending on the chemical structure of cargo molecules. Following in vitro study demonstrates that loaded with drug (curcumin) IMAs are cytotoxic to osteosarcoma cells. Mixed polymeric micelles represent another, more complex, RPBC morphologies studied in the dissertation. Mixed micelles were fabricated from AIPs and amphiphilic oligomers synthesized from pyromellitic dianhydride, polyethylene glycol methyl ethers, and alkanols/cholesterol. The combination of selected AIP and oligomers based on cholesterol results in mixed micelles with an increased drug-loading capacity (from 10% w/w loaded curcumin in single component IMAs to 26%w/w in mixed micelles). Even more complex colloids are hybrid polymer-inorganic particles, the third RPBC group studied in dissertation. Material was designed as core--shell particles with superparamagnetic core engulfed by grafted polymer brushes. These particles were loaded with enzymes (cellulases), thus, are turned into enzymogels for cellulose bioconversion. The study demonstrates that such RPBCs can be used multiple times during hydrolysis and provide an about four-fold increase in glucose production in comparison to free enzymes.

Cell membrane-inspired polymeric micelles as carriers for drug delivery.

PubMed

Liu, Gongyan; Luo, Quanqing; Gao, Haiqi; Chen, Yuan; Wei, Xing; Dai, Hong; Zhang, Zongcai; Ji, Jian

2015-03-01

In cancer therapy, surface engineering of drug delivery systems plays an essential role in their colloidal stability, biocompatibility and prolonged blood circulation. Inspired by the cell membrane consisting of phospholipids and glycolipids, a zwitterionic phosphorylcholine functionalized chitosan oligosaccharide (PC-CSO) was first synthesized to mimic the hydrophilic head groups of those amphipathic lipids. Then hydrophobic stearic acid (SA) similar to lipid fatty acids was grafted onto PC-CSO to form amphiphilic PC-CSO-SA copolymers. Cell membrane-mimetic micelles with a zwitterionic surface and a hydrophobic SA core were prepared by the self-assembly of PC-CSO-SA copolymers, showing excellent stability under extreme conditions including protein containing media, high salt content or a wide pH range. Doxorubicin (DOX) was successfully entrapped into polymeric micelles through the hydrophobic interaction between DOX and SA segments. After fast internalization by cancer cells, sustained drug release from micelles to the cytoplasm and nucleus was achieved. This result suggests that these biomimetic polymeric micelles may be promising drug delivery systems in cancer therapy.

Multifunctional polymeric micelles loaded with doxorubicin and poly(dithienyl-diketopyrrolopyrrole) for near-infrared light-controlled chemo-phototherapy of cancer cells.

PubMed

Liu, Hui; Wang, Kai; Yang, Cangjie; Huang, Shuo; Wang, Mingfeng

2017-09-01

Polymeric micelles loaded with multiple therapeutic modalities are important to overcome challenges such as drug resistance and improve the therapeutic efficacy. Here we report a new polymer micellar drug carrier that integrates chemotherapy and photothermal therapy in a single platform. Specifically, a narrow bandgap poly(dithienyl-diketopyrrolopyrrole) (PDPP) polymer was encapsulated together with a model anticancer drug doxorubicin (DOX) in the hydrophobic cores of polymeric micelles formed by Pluronic F127, an amphiphilic poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymer. The PDPP polymer served as an organic photothermal agent that absorbs near-infrared light (700-1000nm) and transforms into heat efficiently. The dual functional micelles co-loaded with PDPP and DOX in the hydrophobic compartment showed good colloidal stability after being stored at 4°C at least over two months, and remained visibly stable after 808-nm laser irradiation. The loaded DOX had negligible effect on the size and photothermal property of the micelles. The release of DOX from the micelles could be enhanced by the "breathing" effect of shrinking/swelling of the micelles induced by the temperature change, owing to the thermosensitive nature of the F127 polymers. Importantly, the ternary F127/PDPP/DOX micelles under 808-nm laser irradiation showed enhanced cytotoxicity against cancer cells such as HeLa cells, compared to F127 micelles containing single modality of either PDPP or DOX only. Copyright © 2017 Elsevier B.V. All rights reserved.

Folate-bovine serum albumin functionalized polymeric micelles loaded with superparamagnetic iron oxide nanoparticles for tumor targeting and magnetic resonance imaging.

PubMed

Li, Huan; Yan, Kai; Shang, Yalei; Shrestha, Lochan; Liao, Rufang; Liu, Fang; Li, Penghui; Xu, Haibo; Xu, Zushun; Chu, Paul K

2015-03-01

Polymeric micelles functionalized with folate conjugated bovine serum albumin (FA-BSA) and loaded with superparamagnetic iron oxide nanoparticles (SPIONs) are investigated as a specific contrast agent for tumor targeting and magnetic resonance imaging (MRI) in vitro and in vivo. The SPIONs-loaded polymeric micelles are produced by self-assembly of amphiphilic poly(HFMA-co-MOTAC)-g-PEGMA copolymers and oleic acid modified Fe3O4 nanoparticles and functionalized with FA-BSA by electrostatic interaction. The FA-BSA modified magnetic micelles have a hydrodynamic diameter of 196.1 nm, saturation magnetization of 5.5 emu/g, and transverse relaxivity of 167.0 mM(-1) S(-1). In vitro MR imaging, Prussian blue staining, and intracellular iron determination studies demonstrate that the folate-functionalized magnetic micelles have larger cellular uptake against the folate-receptor positive hepatoma cells Bel-7402 than the unmodified magnetic micelles. In vivo MR imaging conducted on nude mice bearing the Bel-7402 xenografts after bolus intravenous administration reveals excellent tumor targeting and MR imaging capabilities, especially at 24h post-injection. These findings suggest the potential of FA-BSA modified magnetic micelles as targeting MRI probe in tumor detection. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Polymeric micelles with stimuli-triggering systems for advanced cancer drug targeting.

PubMed

Nakayama, Masamichi; Akimoto, Jun; Okano, Teruo

2014-08-01

Since the 1990s, nanoscale drug carriers have played a pivotal role in cancer chemotherapy, acting through passive drug delivery mechanisms and subsequent pharmaceutical action at tumor tissues with reduction of adverse effects. Polymeric micelles, as supramolecular assemblies of amphiphilic polymers, have been considerably developed as promising drug carrier candidates, and a number of clinical studies of anticancer drug-loaded polymeric micelle carriers for cancer chemotherapy applications are now in progress. However, these systems still face several issues; at present, the simultaneous control of target-selective delivery and release of incorporated drugs remains difficult. To resolve these points, the introduction of stimuli-responsive mechanisms to drug carrier systems is believed to be a promising approach to provide better solutions for future tumor drug targeting strategies. As possible trigger signals, biological acidic pH, light, heating/cooling and ultrasound actively play significant roles in signal-triggering drug release and carrier interaction with target cells. This review article summarizes several molecular designs for stimuli-responsive polymeric micelles in response to variation of pH, light and temperature and discusses their potentials as next-generation tumor drug targeting systems.

Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles

NASA Astrophysics Data System (ADS)

Dian, Linghui; Yu, Enjiang; Chen, Xiaona; Wen, Xinguo; Zhang, Zhengzan; Qin, Lingzhen; Wang, Qingqing; Li, Ge; Wu, Chuanbin

2014-12-01

To improve its poor aqueous solubility and stability, the potential chemotherapeutic drug quercetin was encapsulated in soluplus polymeric micelles by a modified film dispersion method. With the encapsulation efficiency over 90%, the quercetin-loaded polymeric micelles (Qu-PMs) with drug loading of 6.7% had a narrow size distribution around mean size of 79.00 ± 2.24 nm, suggesting the complete dispersibility of quercetin in water. X-ray diffraction (XRD) patterns illustrated that quercetin was in amorphous or molecular form within PMs. Fourier transform infrared spectroscopy (FTIR) indicated that quercetin formed intermolecular hydrogen bonding with carriers. An in vitro dialysis test showed the Qu-PMs possessed significant sustained-release property, and the formulation was stable for at least 6 months under accelerated conditions. The pharmacokinetic study in beagle dogs showed that absorption of quercetin after oral administration of Qu-PMs was improved significantly, with a half-life 2.19-fold longer and a relative oral bioavailability of 286% as compared to free quercetin. Therefore, these novel soluplus polymeric micelles can be applied to encapsulate various poorly water-soluble drugs towards a development of more applicable therapeutic formulations.

[Utilization of polymeric micelle magnetic resonance imaging (MRI) contrast agent for theranostic system].

PubMed

Shiraishi, Kouichi

2013-01-01

We applied a polymeric micelle carrier system for the targeting of a magnetic resonance imaging (MRI) contrast agent. Prepared polymeric micelle MRI contrast agent exhibited a long circulation characteristic in blood, and considerable amount of the contrast agent was found to accumulate in colon 26 solid tumor by the EPR effect. The signal intensities of tumor area showed 2-folds increase in T1-weighted images at 24 h after i.v. injection. To observe enhancement of the EPR effect by Cderiv pretreatment on tumor targeting, we used the contrast agent for the evaluation by means of MRI. Cderiv pretreatment significantly enhanced tumor accumulation of the contrast agent. Interestingly, very high signal intensity in tumor region was found at 24 h after the contrast agent injection in Cderiv pretreated mice. The contrast agent visualized a microenvironmental change in tumor. These results indicate that the contrast agent exhibits potential use for tumor diagnostic agent. To combine with a polymeric micelle carrier system for therapeutic agent, the usage of the combination makes a new concept of "theranostic" for a better cancer treatment.

Polyphosphoester-Camptothecin Prodrug with Reduction-Response Prepared via Michael Addition Polymerization and Click Reaction.

PubMed

Du, Xueqiong; Sun, Yue; Zhang, Mingzu; He, Jinlin; Ni, Peihong

2017-04-26

Polyphosphoesters (PPEs), as potential candidates for biocompatible and biodegradable polymers, play an important role in material science. Various synthetic methods have been employed in the preparation of PPEs such as polycondensation, polyaddition, ring-opening polymerization, and olefin metathesis polymerization. In this study, a series of linear PPEs has been prepared via one-step Michael addition polymerization. Subsequently, camptothecin (CPT) derivatives containing disulfide bonds and azido groups were linked onto the side chain of the PPE through Cu(I)-catalyzed azidealkyne cyclo-addition "click" chemistry to yield a reduction-responsive polymeric prodrug P(EAEP-PPA)-g-ss-CPT. The chemical structures were characterized by nuclear magnetic resonance spectroscopy, gel permeation chromatography, Fourier transform infrared, ultraviolet-visible spectrophotometer, and high performance liquid chromatograph analyses, respectively. The amphiphilic prodrug could self-assemble into micelles in aqueous solution. The average particle size and morphology of the prodrug micelles were measured by dynamic light scattering and transmission electron microscopy, respectively. The results of size change under different conditions indicate that the micelles possess a favorable stability in physiological conditions and can be degraded in reductive medium. Moreover, the studies of in vitro drug release behavior confirm the reduction-responsive degradation of the prodrug micelles. A methyl thiazolyl tetrazolium assay verifies the good biocompatibility of P(EAEP-PPA) not only for normal cells, but also for tumor cells. The results of cytotoxicity and the intracellular uptake about prodrug micelles further demonstrate that the prodrug micelles can efficiently release CPT into 4T1 or HepG2 cells to inhibit the cell proliferation. All these results show that the polyphosphoester-based prodrug can be used for triggered drug delivery system in cancer treatment.

Factors affecting the stability of drug-loaded polymeric micelles and strategies for improvement

NASA Astrophysics Data System (ADS)

Zhou, Weisai; Li, Caibin; Wang, Zhiyu; Zhang, Wenli; Liu, Jianping

2016-09-01

Polymeric micelles (PMs) self-assembled by amphiphilic block copolymers have been used as promising nanocarriers for tumor-targeted delivery due to their favorable properties, such as excellent biocompatibility, prolonged circulation time, favorable particle sizes (10-100 nm) to utilize enhanced permeability and retention effect and the possibility for functionalization. However, PMs can be easily destroyed due to dilution of body fluid and the absorption of proteins in system circulation, which may induce drug leakage from these micelles before reaching the target sites and compromise the therapeutic effect. This paper reviewed the factors that influence stability of micelles in terms of thermodynamics and kinetics consist of the critical micelle concentration of block copolymers, glass transition temperature of hydrophobic segments and polymer-polymer and polymer-cargo interaction. In addition, some effective strategies to improve the stability of micelles were also summarized.

Vital microscopic analysis of polymeric micelle extravasation from tumor vessels: macromolecular delivery according to tumor vascular growth stage.

PubMed

Hori, Katsuyoshi; Nishihara, Masamichi; Yokoyama, Masayuki

2010-01-01

Particles larger than a specific size have been thought to extravasate from tumor vessels but not from normal vessels. Therefore, various nanoparticles incorporating anticancer drugs have been developed to realize selective drug delivery to solid tumors. However, it is not yet clear whether nanoparticles extravasate readily from all tumor vessels including vessels of microtumors. To answer this question, we synthesized new polymeric micelles labeled with fluorescein isothiocyanate (FITC) and injected them into the tail vein of rats with implanted skinfold transparent chambers. We also analyzed, by means of time-lapse vital microscopy with image analysis, extravasation of FITC micelles from tumor vessels at different stages of growth of Yoshida ascites sarcoma LY80. Polymeric micelles readily leaked from vessels at the interface between normal and tumor tissues and those at the interface between tumor tissues and necrotic areas. The micelles showed negligible extravasation, however, from the vascular network of microtumors less than 1 mm in diameter and did not accumulate in the microtumor. Our results suggest that we must develop a novel therapeutic strategy that can deliver sufficient nanomedicine to microtumors.

Targeted polymeric micelles for delivery of poorly soluble drugs.

PubMed

Torchilin, V P

2004-10-01

Polymeric micelles (micelles formed by amphiphilic block copolymers) demonstrate a series of attractive properties as drug carriers, such as high stability both in vitro and in vivo and good biocompatibility, and can be successfully used for the solubilization of various poorly soluble pharmaceuticals. These micelles can also be used as targeted drug delivery systems. The targeting can be achieved via the enhanced permeability and retention effect (into the areas with the compromised vasculature), by making micelles of stimuli-responsive amphiphilic block copolymers, or by attaching specific targeting ligand molecules to the micelle surface. Immunomicelles prepared by coupling monoclonal antibody molecules to p-nitrophenylcarbonyl groups on the water-exposed termini of the micelle corona-forming blocks demonstrate high binding specificity and targetability. Immunomicelles prepared with cancer-specific monoclonal antibody 2C5 specifically bind to different cancer cells in vitro and demonstrate increased therapeutic activity in vivo. This new family of pharmaceutical carriers can be used for the solubilization and targeted delivery of poorly soluble drugs to various pathological sites in the body.

Reduction-Degradable Polymeric Micelles Decorated with PArg for Improving Anticancer Drug Delivery Efficacy.

PubMed

Cui, Yani; Sui, Junhui; He, Mengmeng; Xu, Zhiyi; Sun, Yong; Liang, Jie; Fan, Yujiang; Zhang, Xingdong

2016-01-27

In this study, five kinds of reduction-degradable polyamide amine-g-polyethylene glycol/polyarginine (PAA-g-PEG/PArg) micelles with different proportions of hydrophilic and hydrophobic segments were synthesized as novel drug delivery vehicles. Polyarginine not only acted as a hydrophilic segment but also possessed a cell-penetrating function to carry out a rapid transduction into target cells. Polyamide amine-g-polyethylene glycol (PAA-g-PEG) was prepared for comparison. The characterization and antitumor effect of the DOX-incorporated PAA-g-PEG/PArg cationic polymeric micelles were investigated in vitro and in vivo. The cytotoxicity experiments demonstrated that the PAA-g-PEG/PArg micelles have good biocompatibility. Compared with DOX-incorporated PAA-g-PEG micelles, the DOX-incorporated PAA-g-PEG/PArg micelles were more efficiently internalized into human hepatocellular carcinoma (HepG2) cells and more rapidly released DOX into the cytoplasm to inhibit cell proliferation. In the 4T1-bearing nude mouse tumor models, the DOX-incorporated PAA-g-PEG/PArg micelles could efficiently accumulate in the tumor site and had a longer accumulation time and more significant aggregation concentration than those of PAA-g-PEG micelles. Meanwhile, it excellently inhibited the solid tumor growth and extended the survival period of the tumor-bearing Balb/c mice. These results could be attributed to their appropriate nanosize and the cell-penetrating peculiarity of polyarginine as a surface layer. The PAA-g-PEG/PArg polymeric micelles as a safe and high efficiency drug delivery system were expected to be a promising delivery carrier that targeted hydrophobic chemotherapy drugs to tumors and significantly enhanced antitumor effects.

Polymeric micelle for tumor pH and folate-mediated targeting.

PubMed

Lee, Eun Seong; Na, Kun; Bae, You Han

2003-08-28

Novel pH-sensitive polymeric mixed micelles composed of poly(L-histidine) (polyHis; M(w) 5000)/PEG (M(n) 2000) and poly(L-lactic acid) (PLLA) (M(n) 3000)/PEG (M(n) 2000) block copolymers with or without folate conjugation were prepared by diafiltration. The micelles were investigated for pH-dependent drug release, folate receptor-mediated internalization and cytotoxicity using MCF-7 cells in vitro. The polyHis/PEG micelles showed accelerated adriamycin release as the pH decreased from 8.0. When the cumulative release for 24 h was plotted as a function of pH, the gradual transition in release rate appeared in a pH range from 8.0 to 6.8. In order to tailor the triggering pH of the polymeric micelles to the more acidic extracellular pH of tumors, while improving the micelle stability at pH 7.4, the PLLA/PEG block copolymer was blended with polyHis/PEG to form mixed micelles. Blending shifted the triggering pH to a lower value. Depending on the amount of PLLA/PEG, the mixed micelles were destabilized in the pH range of 7.2-6.6 (triggering pH for adriamycin release). When the mixed micelles were conjugated with folic acid, the in vitro results demonstrated that the micelles were more effective in tumor cell kill due to accelerated drug release and folate receptor-mediated tumor uptake. In addition, after internalization polyHis was found to be effective for cytosolic ADR delivery by virtue of fusogenic activity. This approach is expected to be useful for treatment of solid tumors in vivo.

Glycyrrhetinic Acid-Mediated Polymeric Drug Delivery Targeting the Acidic Microenvironment of Hepatocellular Carcinoma.

PubMed

Zhang, Jinming; Zhang, Min; Ji, Juan; Fang, Xiefan; Pan, Xin; Wang, Yitao; Wu, Chuanbin; Chen, Meiwan

2015-10-01

The major hurdle of current drug carrier against hepatocellular carcinoma (HCC) is the lack of specific and selective drug delivery to HCC. In this study, a novel glycyrrhetinic acid (GA) and poly(L-Histidine) (PHIS) mediated polymeric drug delivery system was developed to target HCC that have GA binding receptors and release its encapsulated anticancer drug in the acidic microenvironment of HCC. Firstly, GA and PHIS were conjugated to form poly (ethylene glycol)-poly(lactic-co-glycolic acid) (GA-PEG-PHIS-PLGA, GA-PPP) micelles by grafting reaction between active terminal groups. Secondly, andrographolide (AGP) was encapsulated to GA-PPP to make AGP/GA-PPP using the solvent evaporation method. The pH-responsive property of AGP/GA-PPP micelles was validated by monitoring its stability and drug release behavior in different pH conditions. Furthermore, selective hepatocellular uptake of GA-PPP micelles in vitro, liver specific drug accumulation in vivo, as well as the enhanced antitumor effects of AGP/GA-PPP micelles confirmed the HCC targeting property of our novel drug delivery system. Average size of AGP/GA-PPP micelles increased significantly and the encapsulated AGP released faster in vitro at pH 5.0, while micelles keeping stable in pH 7.4. AGP/GA-PPP micelles were uptaken more efficiently by human Hep3B liver cells than that by human MDA-MB-231 breast cancer cells. GA-PPP micelles accumulated specifically in the liver and possessed long retention time in vivo. AGP/GA-PPP micelles significantly inhibited tumor growth and provided better therapeutic outcomes compared to free AGP and AGP/PEG-PLGA(AGP/PP) micelles without GA and PHIS decoration. This novel GA-PPP polymeric carrier is promising for targeted treatment of HCC.

Design, synthesis and evaluation of biotin decorated inulin-based polymeric micelles as long-circulating nanocarriers for targeted drug delivery.

PubMed

Mandracchia, Delia; Rosato, Antonio; Trapani, Adriana; Chlapanidas, Theodora; Montagner, Isabella Monia; Perteghella, Sara; Di Franco, Cinzia; Torre, Maria Luisa; Trapani, Giuseppe; Tripodo, Giuseppe

2017-04-01

Here, long-circulating behaviors of Inulin-based nanomicelles are demonstrated for the first time in vivo. We show the synthesis and evaluation of biotin (BIO)-decorated polymeric INVITE micelles constituted of substances of natural origin, Inulin (INU) and Vitamin E (VITE), as long-circulating carriers for receptor-mediated targeted drug delivery. The resulting INVITE or INVITE-BIO micelles, nanometrically sized, did not reveal any cytotoxicity after 24h of incubation with Caco-2 cells. Moreover, in vitro studies on Caco-2 cells monolayers indicated that the transport of INVITE-BIO micelles was faster than surface unmodified INVITE micelles. In vivo optical imaging studies evidenced that, upon intravenous administration, INVITE-BIO micelles were quantitatively present in the body up to 48h. Instead, after oral administration, the micelles were not found in the systemic circulation but eliminated with the normal intestinal content. In conclusion, INVITE-BIO micelles may enhance drug accumulation in tumor-cells over-expressing the receptor for biotin through receptor mediated endocytosis. Copyright © 2017 Elsevier Inc. All rights reserved.

Controlled Fab installation onto polymeric micelle nanoparticles for tuned bioactivity

NASA Astrophysics Data System (ADS)

Chen, Shaoyi; Florinas, Stelios; Teitgen, Abigail; Xu, Ze-Qi; Gao, Changshou; Wu, Herren; Kataoka, Kazunori; Cabral, Horacio; Christie, R. James

2017-12-01

Antibodies and antigen-binding fragments (Fabs) can be used to modify the surface of nanoparticles for enhanced target binding. In our previous work, site-specific conjugation of Fabs to polymeric micelles using conventional methods was limited to approximately 30% efficiency, possibly due to steric hindrance related to macromolecular reactants. Here, we report a new method that enables conjugation of Fabs onto a micelle surface in a controlled manner with up to quantitative conversion of nanoparticle reactive groups. Variation of (i) PEG spacer length in a heterofunctionalized cross-linker and (ii) Fab/polymer feed ratios resulted in production of nanoparticles with a range of Fab densities on the surface up to the theoretical maximum value. The biological impact of variable Fab density was evaluated in vitro with respect to cell uptake and cytotoxicity of a drug-loaded (SN38) targeted polymeric micelle bearing anti-EphA2 Fabs. Fab conjugation increased cell uptake and potency compared with non-targeted micelles, although a Fab density of 60% resulted in decreased uptake and potency of the targeted micelles. Altogether, our findings demonstrate that conjugation strategies can be optimized to allow control of Fab density on the surface of nanoparticles and also that Fab density may need to be optimized for a given cell-surface target to achieve the highest bioactivity.

Core-crosslinked polymeric micelles with controlled release of covalently entrapped doxorubicin.

PubMed

Talelli, Marina; Iman, Maryam; Varkouhi, Amir K; Rijcken, Cristianne J F; Schiffelers, Raymond M; Etrych, Tomas; Ulbrich, Karel; van Nostrum, Cornelus F; Lammers, Twan; Storm, Gert; Hennink, Wim E

2010-10-01

Doxorubicin (DOX) is clinically applied in cancer therapy, but its use is associated with dose limiting severe side effects. Core-crosslinked biodegradable polymeric micelles composed of poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) diblock copolymers have shown prolonged circulation in the blood stream upon intravenous administration and enhanced tumor accumulation through the enhanced permeation and retention (EPR) effect. However a (physically) entrapped anticancer drug (paclitaxel) was previously shown to be rapidly eliminated from the circulation, likely because the drug was insufficiently retained in the micelles. To fully exploit the EPR effect for drug targeting, a DOX methacrylamide derivative (DOX-MA) was covalently incorporated into the micellar core by free radical polymerization. The structure of the doxorubicin derivative is susceptible to pH-sensitive hydrolysis, enabling controlled release of the drug in acidic conditions (in either the intratumoral environment and/or the endosomal vesicles). 30-40% w/w of the added drug was covalently entrapped, and the micelles with covalently entrapped DOX had an average diameter of 80 nm. The entire drug payload was released within 24 h incubation at pH 5 and 37 degrees C, whereas only around 5% release was observed at pH 7.4. DOX micelles showed higher cytotoxicity in B16F10 and OVCAR-3 cells compared to DOX-MA, likely due to cellular uptake of the micelles via endocytosis and intracellular drug release in the acidic organelles. The micelles showed better anti-tumor activity than free DOX in mice bearing B16F10 melanoma carcinoma. The results presented in this paper show that mPEG-b-p(HPMAm-Lac(n)) polymeric micelles with covalently entrapped doxorubicin is a system highly promising for the targeted delivery of cytostatic agents. Copyright 2010 Elsevier Ltd. All rights reserved.

Facile Synthesis of Worm-like Micelles by Visible Light Mediated Dispersion Polymerization Using Photoredox Catalyst

PubMed Central

Yeow, Jonathan; Xu, Jiangtao; Boyer, Cyrille

2016-01-01

Presented herein is a protocol for the facile synthesis of worm-like micelles by visible light mediated dispersion polymerization. This approach begins with the synthesis of a hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) homopolymer using reversible addition-fragmentation chain-transfer (RAFT) polymerization. Under mild visible light irradiation (λ = 460 nm, 0.7 mW/cm2), this macro-chain transfer agent (macro-CTA) in the presence of a ruthenium based photoredox catalyst, Ru(bpy)3Cl2 can be chain extended with a second monomer to form a well-defined block copolymer in a process known as Photoinduced Electron Transfer RAFT (PET-RAFT). When PET-RAFT is used to chain extend POEGMA with benzyl methacrylate (BzMA) in ethanol (EtOH), polymeric nanoparticles with different morphologies are formed in situ according to a polymerization-induced self-assembly (PISA) mechanism. Self-assembly into nanoparticles presenting POEGMA chains at the corona and poly(benzyl methacrylate) (PBzMA) chains in the core occurs in situ due to the growing insolubility of the PBzMA block in ethanol. Interestingly, the formation of highly pure worm-like micelles can be readily monitored by observing the onset of a highly viscous gel in situ due to nanoparticle entanglements occurring during the polymerization. This process thereby allows for a more reproducible synthesis of worm-like micelles simply by monitoring the solution viscosity during the course of the polymerization. In addition, the light stimulus can be intermittently applied in an ON/OFF manner demonstrating temporal control over the nanoparticle morphology. PMID:27340940

Facile Synthesis of Worm-like Micelles by Visible Light Mediated Dispersion Polymerization Using Photoredox Catalyst.

PubMed

Yeow, Jonathan; Xu, Jiangtao; Boyer, Cyrille

2016-06-08

Presented herein is a protocol for the facile synthesis of worm-like micelles by visible light mediated dispersion polymerization. This approach begins with the synthesis of a hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) homopolymer using reversible addition-fragmentation chain-transfer (RAFT) polymerization. Under mild visible light irradiation (λ = 460 nm, 0.7 mW/cm(2)), this macro-chain transfer agent (macro-CTA) in the presence of a ruthenium based photoredox catalyst, Ru(bpy)3Cl2 can be chain extended with a second monomer to form a well-defined block copolymer in a process known as Photoinduced Electron Transfer RAFT (PET-RAFT). When PET-RAFT is used to chain extend POEGMA with benzyl methacrylate (BzMA) in ethanol (EtOH), polymeric nanoparticles with different morphologies are formed in situ according to a polymerization-induced self-assembly (PISA) mechanism. Self-assembly into nanoparticles presenting POEGMA chains at the corona and poly(benzyl methacrylate) (PBzMA) chains in the core occurs in situ due to the growing insolubility of the PBzMA block in ethanol. Interestingly, the formation of highly pure worm-like micelles can be readily monitored by observing the onset of a highly viscous gel in situ due to nanoparticle entanglements occurring during the polymerization. This process thereby allows for a more reproducible synthesis of worm-like micelles simply by monitoring the solution viscosity during the course of the polymerization. In addition, the light stimulus can be intermittently applied in an ON/OFF manner demonstrating temporal control over the nanoparticle morphology.

Theranostic reduction-sensitive gemcitabine prodrug micelles for near-infrared imaging and pancreatic cancer therapy

NASA Astrophysics Data System (ADS)

Han, Haijie; Wang, Haibo; Chen, Yangjun; Li, Zuhong; Wang, Yin; Jin, Qiao; Ji, Jian

2015-12-01

A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy.A biodegradable and reduction-cleavable gemcitabine (GEM) polymeric prodrug with in vivo near-infrared (NIR) imaging ability was reported. This theranostic GEM prodrug PEG-b-[PLA-co-PMAC-graft-(IR820-co-GEM)] was synthesized by ring-opening polymerization and ``click'' reaction. The as-prepared reduction-sensitive prodrug could self-assemble into prodrug micelles in aqueous solution confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). In vitro drug release studies showed that these prodrug micelles were able to release GEM in an intracellular-mimicking reductive environment. These prodrug micelles could be effectively internalized by BxPC-3 pancreatic cancer cells, which were observed by confocal laser scanning microscopy (CLSM). Meanwhile, a methyl thiazolyl tetrazolium (MTT) assay demonstrated that this prodrug exhibited high cytotoxicity against BxPC-3 cells. The in vivo whole-animal near-infrared (NIR) imaging results showed that these prodrug micelles could be effectively accumulated in tumor tissue and had a longer blood circulation time than IR820-COOH. The endogenous reduction-sensitive gemcitabine prodrug micelles with the in vivo NIR imaging ability might have great potential in image-guided pancreatic cancer therapy. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06734k

Complete Regression of Xenograft Tumors upon Targeted Delivery of Paclitaxel via Π-Π Stacking Stabilized Polymeric Micelles

PubMed Central

Shi, Yang; van der Meel, Roy; Theek, Benjamin; Blenke, Erik Oude; Pieters, Ebel H.E.; Fens, Marcel H.A.M.; Ehling, Josef; Schiffelers, Raymond M.; Storm, Gert; van Nostrum, Cornelus F.; Lammers, Twan; Hennink, Wim E.

2015-01-01

Treatment of cancer patients with taxane-based chemotherapeutics, such as paclitaxel (PTX), is complicated by their narrow therapeutic index. Polymeric micelles are attractive nanocarriers for tumor-targeted delivery of PTX, as they can be tailored to encapsulate large amounts of hydrophobic drugs and achieve prolonged circulation kinetics. As a result, PTX deposition in tumors is increased while drug exposure to healthy tissues is reduced. However, many PTX-loaded micelle formulations suffer from low stability and fast drug release in the circulation, limiting their suitability for systemic drug targeting. To overcome these limitations, we have developed paclitaxel (PTX)-loaded micelles which are stable without chemical crosslinking and covalent drug attachment. These micelles are characterized by excellent loading capacity and strong drug retention, attributed to π-π stacking interaction between PTX and the aromatic groups of the polymer chains in the micellar core. The micelles are based on methoxy poly(ethylene glycol)-b-(N-(2-benzoyloxypropyl) methacrylamide) (mPEG-b-p(HPMAm-Bz)) block copolymers, which improved the pharmacokinetics and the biodistribution of PTX, and substantially increased PTX tumor accumulation (by more than 2000%; as compared to Taxol® or control micellar formulations). Improved biodistribution and tumor accumulation were confirmed by hybrid μCT-FMT imaging using near-infrared labeled micelles and payload. The PTX-loaded micelles were well tolerated at different doses while they induced complete tumor regression in two different xenograft models (i.e. A431 and MDA-MB-468). Our findings consequently indicate that π-π stacking-stabilized polymeric micelles are promising carriers to improve the delivery of highly hydrophobic drugs to tumors and to increase their therapeutic index. PMID:25831471

Physico-chemical strategies to enhance stability and drug retention of polymeric micelles for tumor-targeted drug delivery

PubMed Central

Shi, Yang; Lammers, Twan; Storm, Gert; Hennink, Wim E.

2017-01-01

Polymeric micelles (PM) have been extensively used for tumor-targeted delivery of hydrophobic anti-cancer drugs. The lipophilic core of PM is naturally suitable for loading hydrophobic drugs and the hydrophilic shell endows them with colloidal stability and stealth properties. Decades of research on PM have resulted in tremendous numbers of PM-forming amphiphilic polymers, and approximately a dozen micellar nanomedicines have entered the clinic. The first generation of PM can be considered solubilizers of hydrophobic drugs, with short circulation times resulting from poor micelle stability and unstable drug entrapment. To more optimally exploit the potential of PM for targeted drug delivery, several physical (e.g. π-π stacking, stereocomplexation, hydrogen bonding, host-guest complexation and coordination interaction) and chemical (e.g. free radical polymerization, click chemistry, disulfide and hydrazone bonding) strategies have been developed to improve micelle stability and drug retention. In this review, we describe the most promising physico-chemical approaches to enhance micelle stability and drug retention, and we summarize how these strategies have resulted in systems with promising therapeutic efficacy in animal models, paving the way for clinical translation. PMID:27413999

Folate-conjugated pH-responsive nanocarrier designed for active tumor targeting and controlled release of doxorubicin

NASA Astrophysics Data System (ADS)

Wei, Lulu; Lu, Beibei; Cui, Lin; Peng, Xueying; Wu, Jianning; Li, Deqiang; Liu, Zhiyong; Guo, Xuhong

2017-12-01

A novel type of amphiphilic pH-responsive folate-poly(ɛ-caprolactone)- block-poly(2-hydroxyethylmethacrylate)- co-poly(2-(dimethylamino)-ethylmethacrylate) (FA-PCL- b-P(HEMA- co-DMAEMA)) (MFP) block copolymers were designed and synthesized via atom transfer radical polymerization (ATRP) and ring opening polymerization (ROP) techniques. The molecular structures of the copolymers were confirmed with 1H NMR, FTIR and GPC measurements. The critical micelle concentration (CMC) of MFP in aqueous solution was extremely low (about 6.54 mg/L). The in vitro release behavior of DOX-loaded micelles was significantly accelerated when the pH value of solution decreased from 7.4 to 5.0. In vitro antitumor efficiency was evaluated by incubating DOX-loaded micelles with Hela cells. The results demonstrated that this copolymer possessed excellent biocompatibility, and FA-decorated micelles MFP showed higher cellular uptake than those micelles without the FA moiety, indicating their unique targetability. These folate-conjugated biodegradable micelles are highly promising for targeted cancer chemothe-rapy.

Targeting NF-kB signaling with polymeric hybrid micelles that co-deliver siRNA and dexamethasone for arthritis therapy.

PubMed

Wang, Qin; Jiang, Hao; Li, Yan; Chen, Wenfei; Li, Hanmei; Peng, Ke; Zhang, Zhirong; Sun, Xun

2017-04-01

The transcription factor NF-kB plays a pivotal role in the pathogenesis of rheumatoid arthritis. Here we attempt to slow arthritis progression by co-delivering the glucocorticoid dexamethasone (Dex) and small-interfering RNA targeting NF-kB p65 using our previously developed polymeric hybrid micelle system. These micelles contain two similar amphiphilic copolymers: polycaprolactone-polyethylenimine (PCL-PEI) and polycaprolactone-polyethyleneglycol (PCL-PEG). The hybrid micelles loaded with Dex and siRNA effectively inhibited NF-kB signaling in murine macrophages more efficiently than micelles containing either Dex or siRNA on their own. In addition, the co-delivery system was able to switch macrophages from the M1 to M2 state. Injecting hybrid micelles containing Dex and siRNA into mice with collagen-induced arthritis led the therapeutic agents to accumulate in inflamed joints and reduce inflammation, without damaging renal or liver function. Thus, blocking NF-kB activation in inflammatory tissue using micelle-based co-delivery may provide a new approach for treating inflammatory disease. Copyright © 2017 Elsevier Ltd. All rights reserved.

Light-responsive micelles of spiropyran initiated hyperbranched polyglycerol for smart drug delivery.

PubMed

Son, Suhyun; Shin, Eeseul; Kim, Byeong-Su

2014-02-10

Light-responsive polymeric micelles have emerged as site-specific and time-controlled systems for advanced drug delivery. Spiropyran (SP), a well-known photochromic molecule, was used to initiate the ring-opening multibranching polymerization of glycidol to afford a series of hyperbranched polyglycerols (SP-hb-PG). The micelle assembly and disassembly were induced by an external light source owing to the reversible photoisomerization of hydrophobic SP to hydrophilic merocyanine (MC). Transmission electron microscopy, atomic force microscopy, UV/vis spectroscopy, and dynamic light scattering demonstrated the successful assembly and disassembly of SP-hb-PG micelles. In addition, the critical micelle concentration (CMC) was determined through the fluorescence analysis of pyrene to confirm the amphiphilicity of respective SP-hb-PGn (n = 15, 29, and 36) micelles, with CMC values ranging from 13 to 20 mg/L, which is correlated to the length of the polar polyglycerol backbone. Moreover, the superior biocompatibility of the prepared SP-hb-PG was evaluated using WI-38 cells and HeLa cells, suggesting the prospective applicability of the micelles in smart drug delivery systems.

Drug Combination Synergy in Worm-like Polymeric Micelles Improves Treatment Outcome for Small Cell and Non-Small Cell Lung Cancer.

PubMed

Wan, Xiaomeng; Min, Yuanzeng; Bludau, Herdis; Keith, Andrew; Sheiko, Sergei S; Jordan, Rainer; Wang, Andrew Z; Sokolsky-Papkov, Marina; Kabanov, Alexander V

2018-03-27

Nanoparticle-based systems for concurrent delivery of multiple drugs can improve outcomes of cancer treatments, but face challenges because of differential solubility and fairly low threshold for incorporation of many drugs. Here we demonstrate that this approach can be used to greatly improve the treatment outcomes of etoposide (ETO) and platinum drug combination ("EP/PE") therapy that is the backbone for treatment of prevalent and deadly small cell lung cancer (SCLC). A polymeric micelle system based on amphiphilic block copolymer poly(2-oxazoline)s (POx) poly(2-methyl-2-oxazoline- block-2-butyl-2-oxazoline- block-2-methyl-2-oxazoline) (P(MeOx- b-BuOx- b-MeOx) is used along with an alkylated cisplatin prodrug to enable co-formulation of EP/PE in a single high-capacity vehicle. A broad range of drug mixing ratios and exceptionally high two-drug loading of over 50% wt. drug in dispersed phase is demonstrated. The highly loaded POx micelles have worm-like morphology, unprecedented for drug loaded polymeric micelles reported so far, which usually form spheres upon drug loading. The drugs co-loading in the micelles result in a slowed-down release, improved pharmacokinetics, and increased tumor distribution of both drugs. A superior antitumor activity of co-loaded EP/PE drug micelles compared to single drug micelles or their combination as well as free drug combination was demonstrated using several animal models of SCLC and non-small cell lung cancer.

Polymeric micelles with ionic cores containing biodegradable cross-links for delivery of chemotherapeutic agents.

PubMed

Kim, Jong Oh; Sahay, Gaurav; Kabanov, Alexander V; Bronich, Tatiana K

2010-04-12

Novel functional polymeric nanocarriers with ionic cores containing biodegradable cross-links were developed for delivery of chemotherapeutic agents. Block ionomer complexes (BIC) of poly(ethylene oxide)-b-poly(methacylic acid) (PEO-b-PMA) and divalent metal cations (Ca(2+)) were utilized as templates. Disulfide bonds were introduced into the ionic cores by using cystamine as a biodegradable cross-linker. The resulting cross-linked micelles with disulfide bonds represented soft, hydrogel-like nanospheres and demonstrated a time-dependent degradation in the conditions mimicking the intracellular reducing environment. The ionic character of the cores allowed to achieve a very high level of doxorubicin (DOX) loading (50% w/w) into the cross-linked micelles. DOX-loaded degradable cross-linked micelles exhibited more potent cytotoxicity against human A2780 ovarian carcinoma cells as compared to micellar formulations without disulfide linkages. These novel biodegradable cross-linked micelles are expected to be attractive candidates for delivery of anticancer drugs.

Synthesis and Self-Assembly of Block Copolymers Containing Temperature Sensitive and Degradable Chain Segments.

PubMed

Gong, Hong-Liang; Lei, Lei; Shi, Shu-Xian; Xia, Yu-Zheng; Chen, Xiao-Nong

2018-05-01

In this work, polylactide-b-poly(N-isopropylacrylamide) were synthesized by the combination of controlled ring-opening polymerization and reversible addition fragmentation chain transfer polymerization. These block copolymers with molecular weight range from 7,900 to 12,000 g/mol and narrow polydispersity (≤1.19) can self-assemble into micelles (polylactide core, poly(N-isopropylacrylamide) shell) in water at certain temperature range, which have been evidenced by laser particle size analyzer proton nuclear magnetic resonance and transmission electron microscopy. Such micelles exhibit obvious thermo-responsive properties: (1) Poly(N-isopropylacrylamide) blocks collapse on the polylactide core as system temperature increase, leading to reduce of micelle size. (2) Micelles with short poly(N-isopropylacrylamide) blocks tend to aggregate together when temperature increased, which is resulted from the reduction of the system hydrophilicity and the decreased repulsive force between micelles.

Design and Synthesis of Self-Assembled Polymeric Nanoparticles for Cancer Drug Delivery

NASA Astrophysics Data System (ADS)

Logie, Jennifer

Current chemotherapeutics are plagued by poor solubility and selectivity, requiring toxic excipients in formulations and causing a number of dose limiting side effects. Nanoparticle delivery has emerged as a strategy to more effectively deliver chemotherapeutics to the tumour site. Specifically, polymeric micelles enable the solubilization of hydrophobic small molecule drugs within the core and mitigate the necessity of excipients. Notwithstanding the significant progress made in polymeric micelle delivery, translation is limited by poor stability and low drug loading. In this work, a rational design approach is used to chemically modify poly(D,L-lactide-co-2-methyl-2-carboxytrimethylene carbonate)-graft-poly(ethylene glycol) (P(LA-co-TMCC)-g-PEG) in order to overcome these limitations and effectively deliver drug to tumours. The PEG density of the polymer system was optimized to enhance the stability of our polymeric micelles. Higher PEG densities permitted the lyophilization of micelles and enhanced the serum stability of the system. To increase the drug loading of our system, we facilitated specific intermolecular interactions within the micelle core. For drugs that form colloidal aggregates, such as pentyl-PABC doxazolidine, polymers were used to stabilize the colloidal core against aggregation and protein adsorption. For more challenging molecules, where self-assembly cannot be controlled, such as docetaxel, we modified the polymeric backbone with a peptide from the binding site of the drug to achieve loadings five times higher than those achieved in conventional micelle systems. This novel docetaxel nanoparticle was assessed in vivo in an orthotopic mouse model of breast cancer, where it showed a wider therapeutic index than the conventional ethanolic polysorbate 80 formulation. The improved tolerability of this formulation enabled higher dosing regimens and led to heightened efficacy and survival in this mouse model. Combined, these studies validated P(LA-co-TMCC)-g-PEG nanoparticles as an effective delivery vehicle for two chemotherapeutics, and presents approaches amenable to the delivery of many other clinically relevant hydrophobic drugs or drug combinations.

Photocytotoxicity of mTHPC (Temoporfin) Loaded Polymeric Micelles Mediated by Lipase Catalyzed Degradation

PubMed Central

Hofman, Jan-Willem; Carstens, Myrra G.; van Zeeland, Femke; Helwig, Conny; Flesch, Frits M.; Hennink, Wim E.

2008-01-01

Purpose To study the in vitro photocytotoxicity and cellular uptake of biodegradable polymeric micelles loaded with the photosensitizer mTHPC, including the effect of lipase-catalyzed micelle degradation. Methods Micelles of mPEG750-b-oligo(ɛ-caprolactone)5 (mPEG750-b-OCL5) with a hydroxyl (OH), benzoyl (Bz) or naphthoyl (Np) end group were formed and loaded with mTHPC by the film hydration method. The cellular uptake of the loaded micelles, and their photocytotoxicity on human neck squamous carcinoma cells in the absence and presence of lipase were compared with free and liposomal mTHPC (Fospeg®). Results Micelles composed of mPEG750-b-OCL5 with benzoyl and naphtoyl end groups had the highest loading capacity up to 30% (w/w), likely due to π–π interactions between the aromatic end group and the photosensitizer. MTHPC-loaded benzoylated micelles (0.5 mg/mL polymer) did not display photocytotoxicity or any mTHPC-uptake by the cells, in contrast to free and liposomal mTHPC. After dilution of the micelles below the critical aggregation concentration (CAC), or after micelle degradation by lipase, photocytotoxicity and cellular uptake of mTHPC were restored. Conclusion The high loading capacity of the micelles, the high stability of mTHPC-loaded micelles above the CAC, and the lipase-induced release of the photosensitizer makes these micelles very promising carriers for photodynamic therapy in vivo. PMID:18597164

PEG-b-PCL polymeric nano-micelle inhibits vascular angiogenesis by activating p53-dependent apoptosis in zebrafish

PubMed Central

Zhou, Tian; Dong, Qinglei; Shen, Yang; Wu, Wei; Wu, Haide; Luo, Xianglin; Liao, Xiaoling; Wang, Guixue

2016-01-01

Micro/nanoparticles could cause adverse effects on cardiovascular system and increase the risk for cardiovascular disease-related events. Nanoparticles prepared from poly(ethylene glycol) (PEG)-b-poly(ε-caprolactone) (PCL), namely PEG-b-PCL, a widely studied biodegradable copolymer, are promising carriers for the drug delivery systems. However, it is unknown whether polymeric PEG-b-PCL nano-micelles give rise to potential complications of the cardiovascular system. Zebrafish were used as an in vivo model to evaluate the effects of PEG-b-PCL nano-micelle on cardiovascular development. The results showed that PEG-b-PCL nano-micelle caused embryo mortality as well as embryonic and larval malformations in a dose-dependent manner. To determine PEG-b-PCL nano-micelle effects on embryonic angiogenesis, a critical process in zebrafish cardiovascular development, growth of intersegmental vessels (ISVs) and caudal vessels (CVs) in flk1-GFP transgenic zebrafish embryos using fluorescent stereomicroscopy were examined. The expression of fetal liver kinase 1 (flk1), an angiogenic factor, by real-time quantitative polymerase chain reaction (qPCR) and in situ whole-mount hybridization were also analyzed. PEG-b-PCL nano-micelle decreased growth of ISVs and CVs, as well as reduced flk1 expression in a concentration-dependent manner. Parallel to the inhibitory effects on angiogenesis, PEG-b-PCL nano-micelle exposure upregulated p53 pro-apoptotic pathway and induced cellular apoptosis in angiogenic regions by qPCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay. This study further showed that inhibiting p53 activity, either by pharmacological inhibitor or RNA interference, could abrogate the apoptosis and angiogenic defects caused by PEG-b-PCL nano-micelles, indicating that PEG-b-PCL nano-micelle inhibits angiogenesis by activating p53-mediated apoptosis. This study indicates that polymeric PEG-b-PCL nano-micelle could pose potential hazards to cardiovascular development. PMID:27980407

PEG-b-PCL polymeric nano-micelle inhibits vascular angiogenesis by activating p53-dependent apoptosis in zebrafish.

PubMed

Zhou, Tian; Dong, Qinglei; Shen, Yang; Wu, Wei; Wu, Haide; Luo, Xianglin; Liao, Xiaoling; Wang, Guixue

Micro/nanoparticles could cause adverse effects on cardiovascular system and increase the risk for cardiovascular disease-related events. Nanoparticles prepared from poly(ethylene glycol) (PEG)- b -poly( ε -caprolactone) (PCL), namely PEG- b -PCL, a widely studied biodegradable copolymer, are promising carriers for the drug delivery systems. However, it is unknown whether polymeric PEG- b -PCL nano-micelles give rise to potential complications of the cardiovascular system. Zebrafish were used as an in vivo model to evaluate the effects of PEG- b -PCL nano-micelle on cardiovascular development. The results showed that PEG- b -PCL nano-micelle caused embryo mortality as well as embryonic and larval malformations in a dose-dependent manner. To determine PEG- b -PCL nano-micelle effects on embryonic angiogenesis, a critical process in zebrafish cardiovascular development, growth of intersegmental vessels (ISVs) and caudal vessels (CVs) in flk1-GFP transgenic zebrafish embryos using fluorescent stereomicroscopy were examined. The expression of fetal liver kinase 1 (flk1), an angiogenic factor, by real-time quantitative polymerase chain reaction (qPCR) and in situ whole-mount hybridization were also analyzed. PEG- b -PCL nano-micelle decreased growth of ISVs and CVs, as well as reduced flk1 expression in a concentration-dependent manner. Parallel to the inhibitory effects on angiogenesis, PEG- b -PCL nano-micelle exposure upregulated p53 pro-apoptotic pathway and induced cellular apoptosis in angiogenic regions by qPCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay. This study further showed that inhibiting p53 activity, either by pharmacological inhibitor or RNA interference, could abrogate the apoptosis and angiogenic defects caused by PEG- b -PCL nano-micelles, indicating that PEG- b -PCL nano-micelle inhibits angiogenesis by activating p53-mediated apoptosis. This study indicates that polymeric PEG- b -PCL nano-micelle could pose potential hazards to cardiovascular development.

Polymeric micelles from poly(ethylene glycol)–poly(amino acid) block copolymer for drug and gene delivery

PubMed Central

Osada, Kensuke; Christie, R. James; Kataoka, Kazunori

2009-01-01

Dramatic advances in biological research have revealed the mechanisms underlying many diseases at the molecular level. However, conventional techniques may be inadequate for direct application of this new knowledge to medical treatments. Nanobiotechnology, which integrates biology with the rapidly growing field of nanotechnology, has great potential to overcome many technical problems and lead to the development of effective therapies. The use of nanobiotechnology in drug delivery systems (DDS) is attractive for advanced treatment of conditions such as cancer and genetic diseases. In this review paper for a special issue on biomaterial research in Japan, we discuss the development of DDS based on polymeric micelles mainly in our group for anti-cancer drug and gene delivery, and also address our challenges associated with developing polymeric micelles as super-functionalized nanodevices with intelligent performance. PMID:19364722

Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles

NASA Astrophysics Data System (ADS)

Sawant, Rishikesh M.; Sawant, Rupa R.; Gultepe, Evin; Nagesha, Dattatri; Papahadjopoulos-Sternberg, Brigitte; Sridhar, Srinivas; Torchilin, Vladimir P.

2009-10-01

Stable 30-50 nm polymeric polyethylene glycol-phosphatidylethanolamine (PEG-PE)-based micelles entrapping superparamagnetic iron oxide nanoparticles (SPION) have been prepared. At similar concentrations of SPION, the SPION-micelles had significantly better magnetic resonance imaging (MRI) T2 relaxation signal compared to `plain' SPION. Freeze-fracture electron microscopy confirmed SPION entrapment in the lipid core of the PEG-PE micelles. To enhance the targeting capability of these micelles, their surface was modified with the cancer cell-specific anti-nucleosome monoclonal antibody 2C5 (mAb 2C5). Such mAb 2C5-SPION immunomicelles demonstrated specific binding with cancer cells in vitro and were able to bring more SPION to the cancer cells thus demonstrating the potential to be used as targeted MRI contrast agents for tumor imaging.

Novel Redox-Responsive Amphiphilic Copolymer Micelles for Drug Delivery: Synthesis and Characterization.

PubMed

Bae, Jungeun; Maurya, Abhijeet; Shariat-Madar, Zia; Murthy, S Narasimha; Jo, Seongbong

2015-11-01

A novel redox-responsive amphiphilic polymer was synthesized with bioreductive trimethyl-locked quinone propionic acid for a potential triggered drug delivery application. The aim of this study was to synthesize and characterize the redox-responsive amphiphilic block copolymer micelles containing pendant bioreductive quinone propionic acid (QPA) switches. The redox-responsive hydrophobic block (polyQPA), synthesized from QPA-serinol and adipoyl chloride, was end-capped with methoxy poly(ethylene glycol) of molecular weight 750 (mPEG750) to achieve a redox-responsive amphiphilic block copolymer, polyQPA-mPEG750. PolyQPA-mPEG750 was able to self-assemble as micelles to show a critical micelle concentration (CMC) of 0.039% w/v (0.39 mg/ml, 0.107 mM) determined by a dye solubilization method using 1,6-diphenyl-1,3,5-hexatriene (DPH) in phosphate-buffered saline (PBS). The mean diameter of polymeric micelles was found to be 27.50 nm (PI = 0.064) by dynamic light scattering. Furthermore, redox-triggered destabilization of the polymeric micelles was confirmed by (1)H-NMR spectroscopy and particle size measurements in a simulated redox state. PolyQPA-mPEG750 underwent triggered reduction to shed pendant redox-responsive QPA groups and its polymeric micelles were swollen to be dissembled in the presence of a reducing agent, thereby enabling the release of loaded model drug, paclitaxel. The redox-responsive polyQPA-mPEG750 polymer micelles would be useful as a drug delivery system allowing triggered drug release in an altered redox state such as tumor microenvironments with an altered redox potential and/or redox enzyme upregulation.

Premature drug release of polymeric micelles and its effects on tumor targeting.

PubMed

Miller, Tobias; Breyer, Sandra; van Colen, Gwenaelle; Mier, Walter; Haberkorn, Uwe; Geissler, Simon; Voss, Senta; Weigandt, Markus; Goepferich, Achim

2013-03-10

Based on the enhanced permeability and retention (EPR) effect, nanoparticles are believed to accumulate in tumors. In this conjunction, the stability of drug encapsulation is assumed to be sufficient. For clarification purposes, PEGylated poly-(D,L-lactic acid) (PEG-PDLLA) micelles which incorporated the hydrophobic model drug dechloro-4-iodo-fenofibrate (IFF) were investigated. H2N-PEG-PDLLA was synthesized, coupled to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with 111-indium. From this polymeric species, mixed micelles with H3CO-PEG-PDLLA were prepared which encapsulated the 125-iodine or 131-iodine labeled drug IFF. Bioimaging and biodistribution experiments in healthy and AR42J-tumor bearing mice were carried out to quantify the uptake of the drug and its carrier in single organs. As a result, upon injection of this system, a rapid dissociation of the polymeric carrier and the incorporated drug (<10 min post inj.) was revealed. Regardless of the premature release, the drug showed an enhanced tumor accumulation compared to the polymeric carrier. In conclusion, the self-assembling system allowed for successful solubilization of the hydrophobic drug by physical incorporation into micelles whereas the tumor targeting properties of the drug delivery system could not be sufficiently shown. Copyright © 2013 Elsevier B.V. All rights reserved.

Core-Crosslinked Polymeric Micelles: Principles, Preparation, Biomedical Applications and Clinical Translation

PubMed Central

Rijcken, Cristianne J.; Kiessling, Fabian; Hennink, Wim E.; Lammers, Twan

2015-01-01

Polymeric micelles (PM) are extensively used to improve the delivery of hydrophobic drugs. Many different PM have been designed and evaluated over the years, and some of them have steadily progressed through clinical trials. Increasing evidence suggests, however, that for prolonged circulation times and for efficient EPR-mediated drug targeting to tumors and to sites of inflammation, PM need to be stabilized, to prevent premature disintegration. Core-crosslinking is among the most popular methods to improve the in vivo stability of PM, and a number of core-crosslinked polymeric micelles (CCPM) have demonstrated promising efficacy in animal models. The latter is particularly true for CCPM in which (pro−) drugs are covalently entrapped. This ensures proper drug retention in the micelles during systemic circulation, efficient drug delivery to pathological sites via EPR, and tailorable drug release kinetics at the target site. We here summarize recent advances in the CCPM field, addressing the chemistry involved in preparing them, their in vitro and in vivo performance, potential biomedical applications, and guidelines for efficient clinical translation. PMID:25893004

Self-assembly of block copolymer micelles: synthesis via reversible addition-fragmentation chain transfer polymerization and aqueous solution properties.

PubMed

Mya, Khine Y; Lin, Esther M J; Gudipati, Chakravarthy S; Gose, Halima B A S; He, Chaobin

2010-07-22

Poly(hexafluorobutyl methacrylate) (PHFBMA) homopolymer was synthesized by reversible addition-fragmentation chain transfer (RAFT)-mediated living radical polymerization in the presence of cyano-2-propyl dithiobenzoate (CPDB) RAFT agent. A block copolymer of PHFBMA-poly(propylene glycol acrylate) (PHFBMA-b-PPGA) with dangling poly(propylene glycol) (PPG) side chains was then synthesized by using CPDB-terminated PHFBMA as a macro-RAFT agent. The amphiphilic properties and self-assembly of PHFBMA-b-PPGA block copolymer in aqueous solution were investigated by dynamic and static light scattering (DLS and SLS) studies, in combination with fluorescence spectroscopy and transmission electron microscopy (TEM). Although PPG shows moderately hydrophilic character, the formation of nanosize polymeric micelles was confirmed by fluorescence and TEM studies. The low value of the critical aggregation concentration exhibited that the tendency for the formation of copolymer aggregates in aqueous solution was very high due to the strong hydrophobicity of the PHFBMA(145)-b-PPGA(33) block copolymer. The combination of DLS and SLS measurements revealed the existence of micellar aggregates in aqueous solution with an association number of approximately 40 +/- 7 for block copolymer micelles. It was also found in TEM observation that there are 40-50 micelles accumulated into one aggregate and these micelles are loosely packed inside the aggregate.

Fabrication of Polymeric Micelles with Aggregation-Induced Emission and Forster Resonance Energy Transfer for Anticancer Drug Delivery.

PubMed

Hao, Na; Sun, Changzhen; Wu, Zhengfei; Xu, Long; Gao, Wenxia; Cao, Jun; Li, Li; He, Bin

2017-07-19

With the aim of obtaining effective cancer therapy with simultaneous cellular imaging, dynamic drug-release monitoring, and chemotherapeutic treatment, a polymeric micelle with aggregation-induced emission (AIE) imaging and a Forster resonance energy transfer (FRET) effect was fabricated as the drug carrier. An amphiphilic conjugate of 1H-pyrrole-1-propanoicacid (MAL)-poly(ethylene glycol) (PEG)-Tripp-bearing AIE molecules were synthesized and self-assembled into micelles to load the anticancer drug doxorubicin (DOX). Spherical DOX-loaded micelles with the mean size of 106 nm were obtained with good physiological stability (CMC, 12.5 μg/mL), high drug-loading capacity (10.4%), and encapsulation efficiency (86%). The cellular uptake behavior of DOX-loaded MAL-PEG-Tripp micelles was visible for high-quality intracellular imaging due to the AIE property. The delivery of DOX from the drug-loaded micelles was dynamic monitored by the FRET effect between the DOX and MAL-PEG-Tripp. Both in vitro (IC50, 2.36 μg/mL) and in vivo anticancer activity tests revealed that the DOX-loaded MAL-PEG-Tripp micelles exhibited promising therapeutic efficacy to cancer with low systematic toxicity. In summary, this micelle provided an effective way to fabricate novel nanoplatform for intracellular imaging, drug-delivery tracing, and chemotherapy.

Enhanced blood-brain barrier transport of vinpocetine by oral delivery of mixed micelles in combination with a message guider.

PubMed

Ding, Jiaojiao; Sun, Yujiao; Li, Jinfeng; Wang, Huimin; Mao, Shirui

2017-07-01

The blood-brain barrier represents an insurmountable obstacle for the therapy of central nervous system related diseases. Polymeric micelles have many desirable properties for brain targeting by oral delivery, but the stability and targeting efficiency needs to be improved. In this study, it was demonstrated that binary micelle system can compensate the drawbacks of mono system by preparing mixed micelles in combination with PEG-based copolymers. Here, we explored a brain targeting drug delivery system via facile approaches using P123 based mixed micelles in combination with a message guider from traditional Chinese medicine, borneol, for oral delivery. With higher drug-loading, improved stability, prolonged in vitro release profile, increased bioavailability and enhanced brain targeting effect was achieved after peroral delivery of the mixed micelles. More importantly, without extra structure modification for active targeting, it was demonstrated for the first time that oral delivery of vinpocetine loaded mixed micelles together with borneol is an effective way to increase drug concentration in the brain and the targeting efficiency is borneol dose dependent. Such a "simple but effective" modality may shed light on the potential use of polymeric micelles in combination with a message drug to achieve drug brain targeting or other targeting sites via oral delivery.

Fluorophore-labeling of core-crosslinked polymeric micelles for multimodal in vivo and ex vivo optical imaging

PubMed Central

Shi, Yang; Kunjachan, Sijumon; Wu, Zhuojun; Gremse, Felix; Moeckel, Diana; van Zandvoort, Marc; Kiessling, Fabian; Storm, Gert; van Nostrum, Cornelus F.; Hennink, Wim E.; Lammers, Twan

2015-01-01

Aim To enable multimodal in vivo and ex vivo optical imaging of the biodistribution and tumor accumulation of core-crosslinked polymeric micelles (CCPM). Materials & Methods mPEG-b-p(HPMAm-Lac)-based polymeric micelles, core-crosslinked via cystamine and covalently labeled with two fluorophores (Dy-676/488) were synthesized. The CCPM were intravenously injected in CT26 tumor-bearing mice. Results Upon intravenous injection, the CCPM accumulated in CT26 tumors reasonably efficiently, with values reaching ~4 %ID at 24 hours. Ex vivo TPLSM confirmed efficient extravasation of the iCCPM out of tumor blood vessels and deep penetration into the tumor interstitium. Conclusions CCPM were labeled with multiple fluorophores, and they exemplify that combining different in vivo and ex vivo optical imaging techniques is highly useful for analyzing the biodistribution and tumor accumulation of nanomedicines. PMID:25929568

Self-assembled polymeric nanocarriers for the targeted delivery of retinoic acid to the hair follicle

NASA Astrophysics Data System (ADS)

Lapteva, Maria; Möller, Michael; Gurny, Robert; Kalia, Yogeshvar N.

2015-11-01

Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A® Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 +/- 1.1% vs. 0.4 +/- 0.1% and 7.5 +/- 0.8% vs. 0.8 +/- 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm® (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A® Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A® Micro in terms of delivery efficiency to PSU presenting human skin (10.4 +/- 3.2% vs. 0.6 +/- 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient clinical management of acne.Acne vulgaris is a highly prevalent dermatological disease of the pilosebaceous unit (PSU). An inability to target drug delivery to the PSU results in poor treatment efficacy and the incidence of local side-effects. Cutaneous application of nanoparticulate systems is reported to induce preferential accumulation in appendageal structures. The aim of this work was to prepare stable polymeric micelles containing retinoic acid (RA) using a biodegradable and biocompatible diblock methoxy-poly(ethylene glycol)-poly(hexylsubstituted lactic acid) copolymer (MPEG-dihexPLA) and to evaluate their ability to deliver RA to skin. An innovative punch biopsy sample preparation method was developed to selectively quantify follicular delivery; the amounts of RA present were compared to those in bulk skin, (i.e. without PSU), which served as the control. RA was successfully incorporated into micelle nanocarriers and protected from photoisomerization by inclusion of Quinoline Yellow. Incorporation into the spherical, homogeneous and nanometer-scale micelles (dn < 20 nm) increased the aqueous solubility of RA by >400-fold. Drug delivery experiments in vitro showed that micelles were able to deliver RA to porcine and human skins more efficiently than Retin-A® Micro (0.04%), a marketed gel containing RA loaded microspheres, (7.1 +/- 1.1% vs. 0.4 +/- 0.1% and 7.5 +/- 0.8% vs. 0.8 +/- 0.1% of the applied dose, respectively). In contrast to a non-colloidal RA solution, Effederm® (0.05%), both the RA loaded MPEG-dihexPLA polymeric micelles (0.005%) and Retin-A® Micro (0.04%) displayed selectivity for delivery to the PSU with 2-fold higher delivery to PSU containing samples than to control samples. Moreover, the micelle formulation outperformed Retin-A® Micro in terms of delivery efficiency to PSU presenting human skin (10.4 +/- 3.2% vs. 0.6 +/- 0.2%, respectively). The results indicate that the polymeric micelle formulation enabled an increased and targeted delivery of RA to the PSU, potentially translating to a safer and more efficient clinical management of acne. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr04770f

Nanotransforming Assemblies

NASA Astrophysics Data System (ADS)

Discher, Dennis

2005-03-01

Degradable polymeric materials with hydrolysable backbones have attracted much attention because they break down to non-toxic metabolites. They are the key solutions to many environmental problems, and are particularly useful for various biomedical applications. Much work has been focused on degradable polymers and their co-polymers as bulk, or films and monolayers.^2 Only limited work has explored the degradable amphiphilic copolymer self-assemblies (spherical micelles, worm micelles and vesicles) in solutions, which are quite important for soft-material engineering. Mostly spherical micelles, and in rare cases, vesicles, have been reported made from copolymers with degradable polyester, typically polylactide or polycaprolactone, as the hydrophobic block, connected to biocompatible, stealthy poly (ethylene oxide) as hydrophilic block. Morphological change of such spherical micelles induced by degradation is subtle, and the degradation kinetics and mechanism in assemblies, which can be quite different from that in bulk or film, are not well understood. Here we will describe the phase transformations of worm micelles and vesicles as they degrade and also highlight how these polymeric self-assemblies interact with lipid membranes.

A ROS-responsive polymeric micelle with a π-conjugated thioketal moiety for enhanced drug loading and efficient drug delivery.

PubMed

Sun, Changzhen; Liang, Yan; Hao, Na; Xu, Long; Cheng, Furong; Su, Ting; Cao, Jun; Gao, Wenxia; Pu, Yuji; He, Bin

2017-11-07

As the implications of reactive oxygen species (ROS) are elucidated in many diseases, ROS-responsive nanoparticles are attracting great interest from researchers. In this work, a ROS sensitive thioketal (TK) moiety with a π-conjugated structure was introduced into biodegradable methoxy poly(ethylene glycol)-thioketal-poly(ε-caprolactone)mPEG-TK-PCL micelles as a linker, which was designed to speed up the drug release and thus enhance the therapeutic efficacy. The micelle showed a high drug loading content of 12.8% and excellent stability under physiological conditions because of the evocation of π-π stacking and hydrophobic interactions with the anticancer drug doxorubicin (DOX). The polymeric micelle presented a better drug carrier capacity and higher in vitro anticancer efficacy towards cancer cells. The in vivo study showed that DOX-loaded mPEG-TK-PCL micelles displayed lower toxicity towards normal cells and remarkably enhanced antitumor efficacy. This research provides a way to design potential drug carriers for efficient cancer chemotherapy.

Micelles based on methoxy poly(ethylene glycol)-cholesterol conjugate for controlled and targeted drug delivery of a poorly water soluble drug.

PubMed

Li, Junming; He, Zhiyao; Yu, Shui; Li, Shuangzhi; Ma, Qing; Yu, Yiyi; Zhang, Jialin; Li, Rui; Zheng, Yu; He, Gu; Song, Xiangrong

2012-10-01

In this study, quercetin (QC) with cancer chemoprevention effect and anticancer potential was loaded into polymeric micelles of methoxy poly(ethylene glycol)-cholesterol conjugate (mPEG-Chol) in order to increase its water solubility. MPEG-Chol with lower critical micelle concentration (CMC) value (4.0 x 10(-7) M - 13 x 10(-7) M) was firstly synthesized involving two steps of chemical modification on cholesterol by esterification, and then QC was incorporated into mPEG-Chol micelles by self-assembly method. After the process parameters were optimized, QC-loaded micelles had higher drug loading (3.66%) and entrapment efficiency (93.51%) and nano-sized diameter (116 nm). DSC analysis demonstrated that QC had been incorporated non-covalently into the micelles and existed as an amorphous state or a solid solution in the polymeric matrix. The freeze-dried formulation with addition of 1% (w/v) mannitol as cryoprotectant was successfully developed for the long-term storage of QC-loaded micelles. Compared to free QC, QC-loaded micelles could release QC more slowly. Moreover, the release of QC from micelles was slightly faster in PBS at pH 5 than that in PBS at pH 7.4, which implied that QC-loaded micelles might be pH-sensitive and thereby selectively deliver QC to tumor tissue with unwanted side effects. Therefore, mPEG-Chol was a promising micellar vector for the controlled and targeted drug delivery of QC to tumor and QC-loaded micelles were also worth being further investigated as a potential formulation for cancer chemoprevention and treatment.

Polymeric micelles and nanoemulsions as tumor-targeted drug carriers: Insight through intravital imaging.

PubMed

Rapoport, Natalya; Gupta, Roohi; Kim, Yoo-Shin; O'Neill, Brian E

2015-05-28

Intravital imaging of nanoparticle extravasation and tumor accumulation has revealed, for the first time, detailed features of carrier and drug behavior in circulation and tissue that suggest new directions for optimization of drug nanocarriers. Using intravital fluorescent microscopy, the extent of the extravasation, diffusion in the tissue, internalization by tissue cells, and uptake by the RES system were studied for polymeric micelles, nanoemulsions, and nanoemulsion-encapsulated drug. Discrimination of vascular and tissue compartments in the processes of micelle and nanodroplet extravasation and tissue accumulation was possible. A simple 1-D continuum model was suggested that allowed discriminating between various kinetic regimes of nanocarrier (or released drug) internalization in tumors of various sizes and cell density. The extravasation and tumor cell internalization occurred much faster for polymeric micelles than for nanoemulsion droplets. Fast micelle internalization resulted in the formation of a perivascular fluorescent coating around blood vessels. A new mechanism of micelle extravasation and internalization was suggested, based on the fast extravasation and internalization rates of copolymer unimers while maintaining micelle/unimer equilibrium in the circulation. The data suggested that to be therapeutically effective, nanoparticles with high internalization rate should manifest fast diffusion in the tumor tissue in order to avoid generation of concentration gradients that induce drug resistance. However an extra-fast diffusion should be avoided as it may result in the flow of extravasated nanoparticles from the tumor to normal organs, which would compromise targeting efficiency. The extravasation kinetics were different for nanodroplets and nanodroplet-encapsulated drug F-PTX suggesting a premature release of some fraction of the drug from the carrier. In conclusion, the development of an "ideal" drug carrier should involve the optimization of both drug retention and carrier diffusion parameters. Copyright © 2015 Elsevier B.V. All rights reserved.

Polymeric micelles for parenteral delivery of sagopilone: physicochemical characterization, novel formulation approaches and their toxicity assessment in vitro as well as in vivo.

PubMed

Richter, Annett; Olbrich, Carsten; Krause, Michael; Hoffmann, Jens; Kissel, Thomas

2010-06-01

The block copolymers PEG(2000)-b-PLA(2200), PEG(2000)-b-PCL(2600) and PEG(5000)-b-PCL(5000) have been currently identified as optimal solubilizing agents for Sagopilone, a poorly water-soluble anticancer drug. In the present study, the stability, formulation feasibility and in vitro as well as in vivo toxicity were evaluated. Dispersion media, storage conditions, and dilutions were varied for stability assessment. The critical micelle concentration (CMC) was determined using a fluorescent probe technique. Lyophilizates and polymeric films were investigated as formulation options. Furthermore, the toxicity was studied in vitro and in vivo using HeLa/MaTu cells and a nude mouse model, respectively. A drug-polymer ratio as low as 1:20 (w/w) was sufficient to solubilize Sagopilone effectively and to obtain stable dispersions (24h: drug content >or= 95%). Although the micelles exhibited a similar thermodynamic stability (CMC: 10(-7)-10(-6)M), PEG-b-PCL micelles were kinetically more stable than PEG(2000)-b-PLA(2200) (24h at 37 degrees C: drug content >or= 90% compared to 30%, respectively). Lyophilization of PEG-b-PCL micelles and storage stability of solid drug-loaded PEG(2000)-b-PLA(2200) films (3m, 6 degrees C: drug content of (95.6+/-1.4)%) were demonstrated for the first time. The high antiproliferative activity has been maintained in vitro (IC(50)<1 nM). Carrier-associated side effects have not been observed in vivo and the maximum tolerated dose of micellar Sagopilone was determined to be 6 mg/kg. The results of this study indicate that polymeric micelles, especially PEG-b-PCL micelles, offer excellent potential for further preclinical and clinical cancer studies using Sagopilone. Copyright 2010 Elsevier B.V. All rights reserved.

Cylindrical micelles of a POSS amphiphilic dendrimer as nano-reactors for polymerization.

PubMed

Weng, Jing-Ting; Yeh, Tso-Fan; Samuel, Ashok Zachariah; Huang, Yi-Fan; Sie, Jyun-Hao; Wu, Kuan-Yi; Peng, Chi-How; Hamaguchi, Hiro-O; Wang, Chien-Lung

2018-02-15

A low generation amphiphilic dendrimer, POSS-AD, which has a POSS core and eight amphiphilic arms, was synthesized and used as a nano-reactor to produce well-defined polymer nano-cylinders. Confirmed by small-angle X-ray scattering (SAXS), Raman and NMR spectrometry, monodispersed cylindrical micelles that contain a hydrophilic cavity with a diameter of 2.09 nm and a length of 4.26 nm were produced via co-assembling POSS-AD with hydrophilic liquids, such as H 2 O and HEMA in hydrophobic solvents. Taking the HEMA/POSS-AD cylindrical micelles as nano-reactors, polymerization of HEMA within the micelles results in polymer nano-cylinders (POSS-ADNPs) with a diameter of 2.24 nm and a length of 5.02 nm. The study confirmed that despite the inability to maintain specific shape in solution, low generation dendrimers form well-defined nano-containers or nano-reactors, which relies on co-assembling with hydrophilic guest molecules. These nano-reactors are robust enough to maintain their shape during the polymerization of the guest molecules. Polymer nano-cylinders with dimensions less than 10 nm can thus be produced from the HEMA/POSS-AD micelles. Since the chemical structure of low-generation dendrimers and the contents of the co-assembled nano-reactors can be easily adjusted, the concept holds the potential for the further developments of low-generation amphiphilic dendrimers.

Multimodality CT/SPECT Evaluation of Micelle Drug Carriers for Treatment of Breast Tumors

DTIC Science & Technology

2008-07-01

Sherry, D.A. Boothman, J. Gao, Multifunctional polymeric micelles as cancer -targeted, MRI-ultrasensitive drug delivery systems , Nano Lett. 6 (11) (2006...1–4) (1999) 3–27. [40] D. Sutton, N. Nasongkla, E. Blanco, J. Gao, Functionalized micellar systems for cancer targeted drug delivery . Pharm. Res. (in...Polymer micelles are nanoscale drug delivery systems that have the potential to improve breast tumor treatment. Micelles can increase the half-life

pH-Dependent, Thermosensitive Polymeric Nanocarriers for Drug Delivery to Solid Tumors

PubMed Central

Chen, Ching-Yi; Kim, Tae Hee; Wu, Wen-Chung; Huang, Chi-Ming; Wei, Hua; Mount, Christopher W.; Tian, Yanqing; Jang, Sei-Hum; Pun, Suzie H.; Jen, Alex K-Y

2013-01-01

Polymeric micelles are promising carriers for anticancer agents due to their small size, ease of assembly, and versatility for functionalization. A current challenge in the use of polymeric micelles is the sensitive balance that must be achieved between stability during prolonged blood circulation and release of active drug at the tumor site. Stimuli-responsive materials provide a mechanism for triggered drug release in the acidic tumor and intracellular microenvironments. In this work, we synthesized a series of dual pH- and temperature-responsive block copolymers containing a poly(ε-caprolactone) (PCL) hydrophobic block with a poly(triethylene glycol) block that were copolymerized with an amino acid-functionalized monomer. The block copolymers formed micellar structures in aqueous solutions. An optimized polymer that was functionalized with 6-aminocaproic acid (ACA) possessed pH-sensitive phase transitions at mildly acidic pH and body temperature. Doxorubicin-loaded micelles formed from these polymers were stable at blood pH (~7.4) and showed increased drug release at acidic pH. In addition, these micelles displayed more potent anti-cancer activity than free doxorubicin when tested in a tumor xenograft model in mice. PMID:23498892

Conjugated and Entrapped HPMA-PLA Nano-Polymeric Micelles Based Dual Delivery of First Line Anti TB Drugs: Improved and Safe Drug Delivery against Sensitive and Resistant Mycobacterium Tuberculosis.

PubMed

Upadhyay, Seema; Khan, Iliyas; Gothwal, Avinash; Pachouri, Praveen K; Bhaskar, N; Gupta, Umesh D; Chauhan, Devendra S; Gupta, Umesh

2017-09-01

First line antiTB drugs have several physical and toxic manifestations which limit their applications. RIF is a hydrophobic drug and has low water solubility and INH is hepatotoxic. The main objective of the study was to synthesize, characterize HPMA-PLA co-polymeric micelles for the effective dual delivery of INH and RIF. HPMA-PLA co-polymer and HPMA-PLA-INH (HPI) conjugates were synthesized and characterized by FT-IR and 1 H-NMR spectroscopy. Later on RIF loaded HPMA-PLA-INH co-polymeric micelles (PMRI) were formulated and characterized for size, zeta potential and surface morphology (SEM, TEM) as well as critical micellar concentration. The safety was assessed through RBC's interaction study. The prepared PMRI were evaluated through MABA assay against sensitive and resistant strains of M. Tuberculosis. Size, zeta and entrapment efficiency for RIF loaded HPMA-PLA-INH polymeric micelles (PMRI) was 87.64 ± 1.98 nm, -19 ± 1.93 mV and 97.2 ± 1.56%, respectively. In vitro release followed controlled and sustained delivery pattern. Sustained release was also supported by release kinetics. Haemolytic toxicity of HPI and PMRI was 8.57 and 7.05% (p < 0.01, INH Vs PMRI; p < 0.0001, RIF Vs PMRI), respectively. MABA assay (cytotoxicity) based MIC values of PMRI formulation was observed as ≥0.0625 and ≥0.50 μg/mL (for sensitive and resistant strain). The microscopic analysis further confirmed that the delivery approach was effective than pure drugs. RIF loaded and INH conjugated HPMA-PLA polymeric micelles (PMRI) were more effective against sensitive and resistant M tuberculosis. The developed approach can lead to improved patient compliance and reduced dosing in future, offering improved treatment of tuberculosis.

Self-Assembled pH-Responsive Polymeric Micelles for Highly Efficient, Noncytotoxic Delivery of Doxorubicin Chemotherapy To Inhibit Macrophage Activation: In Vitro Investigation.

PubMed

Liao, Zhi-Sheng; Huang, Shan-You; Huang, Jyun-Jie; Chen, Jem-Kun; Lee, Ai-Wei; Lai, Juin-Yih; Lee, Duu-Jong; Cheng, Chih-Chia

2018-04-26

Self-assembled pH-responsive polymeric micelles, a combination of hydrophilic poly(ethylene glycol) segments and hydrogen bonding interactions within a biocompatible polyurethane substrate, can spontaneously self-assemble into highly controlled, nanosized micelles in aqueous solution. These newly developed micelles exhibit excellent pH-responsive behavior and biocompatibility, highly controlled drug (doxorubicin; DOX) release behavior, and high drug encapsulation stability in different aqueous environments, making the micelles highly attractive potential candidates for safer, more effective drug delivery in applications such as cancer chemotherapy. In addition, in vitro cell studies revealed the drug-loaded micelles possessed excellent drug entrapment stability and low cytotoxicity toward macrophages under normal physiological conditions (pH 7.4, 37 °C). When the pH of the culture media was reduced to 6.0 to mimic the acidic tumor microenvironment, the drug-loaded micelles triggered rapid release of DOX within the cells, which induced potent antiproliferative and cytotoxic effects in vitro. Importantly, fluorescent imaging and flow cytometric analyses confirmed the DOX-loaded micelles were efficiently delivered into the cytoplasm of the cells via endocytosis and then subsequently gradually translocated into the nucleus. Therefore, these multifunctional micelles could serve as delivery vehicles for precise, effective, controlled drug release to prevent accumulation and activation of tumor-promoting tumor-associated macrophages in cancer tissues. Thus, this unique system may offer a potential route toward the practical realization of next-generation pH-responsive therapeutic delivery systems.

Surface sulfonamide modification of poly(N-isopropylacrylamide)-based block copolymer micelles to alter pH and temperature responsive properties for controlled intracellular uptake.

PubMed

Cyphert, Erika L; von Recum, Horst A; Yamato, Masayuki; Nakayama, Masamichi

2018-06-01

Two different surface sulfonamide-functionalized poly(N-isopropylacrylamide)-based polymeric micelles were designed as pH-/temperature-responsive vehicles. Both sulfadimethoxine- and sulfamethazine-surface functionalized micelles were characterized to determine physicochemical properties, hydrodynamic diameters, zeta potentials, temperature-dependent size changes, and lower critical solution temperatures (LCST) in both pH 7.4 and 6.8 solutions (simulating both physiological and mild low pH conditions), and tested in the incorporation of a proof-of-concept hydrophobic antiproliferative drug, paclitaxel. Cellular uptake studies were conducted using bovine carotid endothelial cells and fluorescently labeled micelles to evaluate if there was enhanced cellular uptake of the micelles in a low pH environment. Both variations of micelles showed enhanced intracellular uptake under mildly acidic (pH 6.8) conditions at temperatures slightly above their LCST and minimal uptake at physiological (pH 7.4) conditions. Due to the less negative zeta potential of the sulfamethazine-surface micelles compared to sulfadimethoxine-surface micelles, and the proximity of their LCST to physiological temperature (37°C), the sulfamethazine variation was deemed more amenable for clinically relevant temperature and pH-stimulated applications. Nevertheless, we believe both polymeric micelle variations have the capacity to be implemented as an intracellular drug or gene delivery system in response to mildly acidic conditions. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1552-1560, 2018. © 2018 Wiley Periodicals, Inc.

High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging

PubMed Central

Xiao, Yunbin; Lin, Zuan Tao; Chen, Yanmei; Wang, He; Deng, Ya Li; Le, D Elizabeth; Bin, Jianguo; Li, Meiyu; Liao, Yulin; Liu, Yili; Jiang, Gangbiao; Bin, Jianping

2015-01-01

Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors. PMID:25709439

High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging.

PubMed

Xiao, Yunbin; Lin, Zuan Tao; Chen, Yanmei; Wang, He; Deng, Ya Li; Le, D Elizabeth; Bin, Jianguo; Li, Meiyu; Liao, Yulin; Liu, Yili; Jiang, Gangbiao; Bin, Jianping

2015-01-01

Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors.

Tumor-targeting peptide conjugated pH-responsive micelles as a potential drug carrier for cancer therapy.

PubMed

Wu, Xiang Lan; Kim, Jong Ho; Koo, Heebeom; Bae, Sang Mun; Shin, Hyeri; Kim, Min Sang; Lee, Byung-Heon; Park, Rang-Woon; Kim, In-San; Choi, Kuiwon; Kwon, Ick Chan; Kim, Kwangmeyung; Lee, Doo Sung

2010-02-17

Herein, we prepared tumor-targeting peptide (AP peptide; CRKRLDRN) conjugated pH-responsive polymeric micelles (pH-PMs) in cancer therapy by active and pH-responsive tumor targeting delivery systems, simultaneously. The active tumor targeting and tumoral pH-responsive polymeric micelles were prepared by mixing AP peptide conjugated PEG-poly(d,l-lactic acid) block copolymer (AP-PEG-PLA) into the pH-responsive micelles of methyl ether poly(ethylene glycol) (MPEG)-poly(beta-amino ester) (PAE) block copolymer (MPEG-PAE). These mixed amphiphilic block copolymers were self-assembled to form stable AP peptide-conjugated and pH-responsive AP-PEG-PLA/MPEG-PAE micelles (AP-pH-PMs) with an average size of 150 nm. The AP-pH-PMs containing 10 wt % of AP-PEG-PLA showed a sharp pH-dependent micellization/demicellization transition at the tumoral acid pH. Also, they presented the pH-dependent drug release profile at the acidic pH of 6.4. The fluorescence dye, TRITC, encapsulated AP-pH-PMs (TRITC-AP-pH-PMs) presented the higher tumor-specific targeting ability in vitro cancer cell culture system and in vivo tumor-bearing mice, compared to control pH-responsive micelles of MPEG-PAE. For the cancer therapy, the anticancer drug, doxorubicin (DOX), was efficiently encapsulated into the AP-pH-PMs (DOX-AP-pH-PMs) with a higher loading efficiency. DOX-AP-pH-PMs efficiently deliver anticancer drugs in MDA-MB231 human breast tumor-bearing mice, resulted in excellent anticancer therapeutic efficacy, compared to free DOX and DOX encapsulated MEG-PAE micelles, indicating the excellent tumor targeting ability of AP-pH-PMs. Therefore, these tumor-targeting peptide-conjugated and pH-responsive polymeric micelles have great potential application in cancer therapy.

Biodegradable polymeric micelles encapsulated JK184 suppress tumor growth through inhibiting Hedgehog signaling pathway

NASA Astrophysics Data System (ADS)

Zhang, Nannan; Liu, Shichang; Wang, Ning; Deng, Senyi; Song, Linjiang; Wu, Qinjie; Liu, Lei; Su, Weijun; Wei, Yuquan; Xie, Yongmei; Gong, Changyang

2015-01-01

JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in vitro release behavior and had a stronger inhibitory effect on proliferation, migration and invasion of HUVECs than free JK184. Furthermore, JK184 micelles had stronger tumor growth inhibiting effects in subcutaneous Panc-1 and BxPC-3 tumor models. Histological analysis showed that JK184 micelles improved anti-tumor activity by inducing more apoptosis, decreasing microvessel density and reducing expression of CD31, Ki67, and VEGF in tumor tissues. JK184 micelles showed a stronger inhibition of Gli expression in Hh signaling, which played an important role in pancreatic carcinoma. Furthermore, circulation time of JK184 in blood was prolonged after entrapment in polymeric micelles. Our results suggested that JK184 micelles are a promising drug candidate for treating pancreatic tumors with a highly inhibitory effect on Hh activity.JK184 can specially inhibit Gli in the Hedgehog (Hh) pathway, which showed great promise for cancer therapeutics. For developing aqueous formulation and improving anti-tumor activity of JK184, we prepared JK184 encapsulated MPEG-PCL micelles by the solid dispersion method without using surfactants or toxic organic solvents. The cytotoxicity and cellular uptake of JK184 micelles were both increased compared with the free drug. JK184 micelles induced more apoptosis and blocked proliferation of Panc-1 and BxPC-3 tumor cells. In addition, JK184 micelles exerted a sustained in vitro release behavior and had a stronger inhibitory effect on proliferation, migration and invasion of HUVECs than free JK184. Furthermore, JK184 micelles had stronger tumor growth inhibiting effects in subcutaneous Panc-1 and BxPC-3 tumor models. Histological analysis showed that JK184 micelles improved anti-tumor activity by inducing more apoptosis, decreasing microvessel density and reducing expression of CD31, Ki67, and VEGF in tumor tissues. JK184 micelles showed a stronger inhibition of Gli expression in Hh signaling, which played an important role in pancreatic carcinoma. Furthermore, circulation time of JK184 in blood was prolonged after entrapment in polymeric micelles. Our results suggested that JK184 micelles are a promising drug candidate for treating pancreatic tumors with a highly inhibitory effect on Hh activity. Electronic supplementary information (ESI) available. See DOI: 10.1039/c4nr06300g

Self-assembled polymeric nanoparticles as new, smart contrast agents for cancer early detection using magnetic resonance imaging.

PubMed

Mouffouk, Fouzi; Simão, Teresa; Dornelles, Daniel F; Lopes, André D; Sau, Pablo; Martins, Jorge; Abu-Salah, Khalid M; Alrokayan, Salman A; Rosa da Costa, Ana M; dos Santos, Nuno R

2015-01-01

Early cancer detection is a major factor in the reduction of mortality and cancer management cost. Here we developed a smart and targeted micelle-based contrast agent for magnetic resonance imaging (MRI), able to turn on its imaging capability in the presence of acidic cancer tissues. This smart contrast agent consists of pH-sensitive polymeric micelles formed by self-assembly of a diblock copolymer (poly(ethyleneglycol-b-trimethylsilyl methacrylate)), loaded with a gadolinium hydrophobic complex ((t)BuBipyGd) and exploits the acidic pH in cancer tissues. In vitro MRI experiments showed that (t)BuBipyGd-loaded micelles were pH-sensitive, as they turned on their imaging capability only in an acidic microenvironment. The micelle-targeting ability toward cancer cells was enhanced by conjugation with an antibody against the MUC1 protein. The ability of our antibody-decorated micelles to be switched on in acidic microenvironments and to target cancer cells expressing specific antigens, together with its high Gd(III) content and its small size (35-40 nm) reveals their potential use for early cancer detection by MRI.

New thiol-responsive mono-cleavable block copolymer micelles labeled with single disulfides.

PubMed

Sourkohi, Behnoush Khorsand; Schmidt, Rolf; Oh, Jung Kwon

2011-10-18

Thiol-responsive symmetric triblock copolymers having single disulfide linkages in the middle blocks (called mono-cleavable block copolymers, ss-ABP(2)) were synthesized by atom transfer radical polymerization in the presence of a disulfide-labeled difunctional Br-initiator. These brush-like triblock copolymers consist of a hydrophobic polyacrylate block having pendent oligo(propylene oxide) and a hydrophilic polymethacrylate block having pendent oligo(ethylene oxide). Gel permeation chromatography and (1)H NMR results confirmed the synthesis of well-defined mono-cleavable block copolymers and revealed that polymerizations were well controlled. Because of amphiphilic nature, these copolymers self-assembled to form colloidally stable micelles above critical micellar concentration of 0.032 mg · mL(-1). In response to reductive reactions, disulfides in thiol-responsive micelles were cleaved. Atomic force microscopy and dynamic light scattering analysis suggested that the cleavage of disulfides caused dissociation of micelles to smaller-sized assembled structures in water. Moreover, in a biomedical perspective, the mono-cleavable block copolymer micelles are not cytotoxic and thus biocompatible. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Coordinated pH/redox dual-sensitive and hepatoma-targeted multifunctional polymeric micelle system for stimuli-triggered doxorubicin release: Synthesis, characterization and in vitro evaluation.

PubMed

Wang, Lele; Tian, Baocheng; Zhang, Jing; Li, Keke; Liang, Yan; Sun, Yujie; Ding, Yuanyuan; Han, Jingtian

2016-03-30

Multifunctional polymeric micelles self-assembled from a DOX-conjugated methoxypolyethylene glycols-b-poly (6-O-methacryloyl-D-galactopyranose)-disulfide bond-DOX (mPEG-b-PMAGP-SS-DOX) copolymer were prepared as an antitumor carrier for doxorubicin delivery, of which the chemical modification with disulfide bonds and hydrazone bonds allowed micelles to release doxorubicin (DOX) selectively at acidic pH and high redox conditions. The resulting micelles exhibited coordinated pH/redox dual-sensitive and hepatoma-targeted multifunction with sustaining stability in aqueous media. The multifunctional micelles showed spherical shapes with a mean diameter of 93 ± 2.08 nm, a low polydispersity index (PDI) of 0.21, a low CMC value of 0.095 mg/mL, a high drug grafting degree of 56.9% and a drug content of 39.0%. Remarkably, in vitro drug release studies clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release treated with pH 5.0 and 10mM GSH (88.4% in 72 h) without drug burst release. The tumor proliferation assays indicated that DOX-grafted micelles, along with low cytotoxicity and well biocompatibility to normal cells up to a concentration of 10 μg/mL, inhibited the proliferation of HepG2 cells in a formulation-, time- and concentration-dependent manner in comparison with MCF-7 cells which was similar to free DOX. Anticancer activity releaved that the disulfide-modified micelles possessed much higher anti-hepatoma activity with a low IC50 value of 1.1 μg/mL following a 72 h incubation. Furthermore, the intracellular uptake tested by CLSM and FCM demonstrated that multifunctional polymeric micelles could be more efficiently taken up by HepG2 cells compared with MCF-7 cells, agreed well with MTT assays, suggesting these well-defined micelles provide a potential drug delivery system for dual-responsive controlled drug release and enhanced anti-hepatoma therapy. Copyright © 2016 Elsevier B.V. All rights reserved.

PSMA-mediated endosome escape-accelerating polymeric micelles for targeted therapy of prostate cancer and the real time tracing of their intracellular trafficking

NASA Astrophysics Data System (ADS)

Gao, Yajie; Li, Yanfang; Li, Yushu; Yuan, Lan; Zhou, Yanxia; Li, Jinwen; Zhao, Lei; Zhang, Chao; Li, Xinru; Liu, Yan

2014-12-01

The cytotoxicity of chemotherapeutic agents to healthy organs and drug resistance of tumor cells are believed to be the main obstacles to the successful cancer chemotherapy in the clinic. To ensure that anticancer drugs could be delivered to the tumor region, are quickly released from carriers in tumor cells and rapidly escape from endo/lysosomes, YPSMA-1-modified pH-sensitive polymeric micelles, which would be advantageous in recognizing the prostate specific membrane antigen (PSMA), were designed and fabricated for targeted delivery of paclitaxel to tumors based on the pH-sensitive diblock copolymer poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) (PEOz-PLA) and YPSMA-1-PEOz-PLA for treating prostate cancer. HOOC-PEOz-PLA with a critical micelle concentration of 5.0 mg L-1 was synthesized and characterized by 1H NMR and gel permeation chromatography. The prepared YPSMA-1-modified micelles, about 30 nm in diameter, exhibited a rapid release behavior at endo/lysosome pH and a favorable ability of fast endo/lysosome escape as observed by confocal microscopy. More importantly, we evidenced for the first time that both endosome and lysosome escape existed for pH-sensitive micelles via real time tracing using confocal microscopy, and the real time endo/lysosome escape process was also presented. The YPSMA-1-modified micelles were very effective in enhancing the cytotoxicity of paclitaxel by increasing the cellular uptake in PSMA-positive 22Rv1 cells, which was verified the correlation with PSMA expression in tumor cells by flow cytometric analysis and confocal microscopy. Moreover, the active targeting and pH-sensitivity endowed YPSMA-1-modified micelles with a higher antitumor efficacy and negligible systemic toxicity in 22Rv1 xenograft-bearing nude mice compared with unmodified micelles and Taxol®. These results suggested that the application of combining YPSMA-1 modification with pH-sensitivity to polymeric micelles may be one approach in the efficient delivery of anticancer drugs for treating PSMA-positive prostate cancers.

Positron emission tomography based analysis of long-circulating cross-linked triblock polymeric micelles in a U87MG mouse xenograft model and comparison of DOTA and CB-TE2A as chelators of copper-64.

PubMed

Jensen, Andreas I; Binderup, Tina; Kumar EK, Pramod; Kjær, Andreas; Rasmussen, Palle H; Andresen, Thomas L

2014-05-12

Copolymers of ABC-type (PEG-PHEMA-PCMA) architecture were prepared by atom transfer radical polymerization and formulated as micelles with functionalizable primary alcohols in the shell-region (PHEMA-block) to which the metal-ion chelators DOTA or CB-TE2A were conjugated. Using this micelle system we compared the in vivo stabilities of DOTA and CB-TE2A as chelators of (64)Cu in micelle nanoparticles. The coumarin polymer (PCMA-block) micelle core was cross-linked by UV irradiation at 2 W/cm(2) for 30 min. The cross-linked micelles were labeled with (64)Cu at room temperature for 2 h (DOTA) or 80 °C for 3 h (CB-TE2A), giving labeling efficiencies of 60-76% (DOTA) and 40-47% (CB-TE2A). (64)Cu-micelles were injected into tumor-bearing mice (8 mg/kg) and PET/CT scans were carried out at 1, 22, and 46 h postinjection. The micelles showed good blood stability (T1/2: 20-26 h) and tumor uptake that was comparable with other nanoparticle systems. The DOTA micelles showed a biodistribution similar to the CB-TE2A micelles and the tumor uptake was comparable for both micelle types at 1 h (1.9% ID/g) and 22 h (3.9% ID/g) but diverged at 46 h with 3.6% ID/g (DOTA) and 4.9% ID/g (CB-TE2A). On the basis of our data, we conclude that cross-linked PEG-PHEMA-PCMA micelles have long circulating properties resulting in tumor accumulation and that DOTA and CB-TE2A (64)Cu-chelates show similar in vivo stability for the studied micelle system.

Dissipative particle dynamics simulation on the self-assembly and disassembly of pH-sensitive polymeric micelle with coating repair agent

NASA Astrophysics Data System (ADS)

Wang, Xiumin; Gao, Jianbang; Wang, Zhikun; Xu, Jianchang; Li, Chunling; Sun, Shuangqing; Hu, Songqing

2017-10-01

Dissipative particle dynamics (DPD) simulations were applied to investigate the coating repair agent dicyclopentadience (DCPD) in pH-sensitive micelles. The results show micelles self-assembled from triblock copolymers with strong hydrophobic interaction are not conducive to loading DCPD, and only micelles with weak interaction parameter can encapsulate DCPD well. After protonation, the structure of micelle was disassembled and DCPD beads have a stronger ability to shrink polymer chains and exposed to water. This work provides mesoscopic insight into self-assembly and disassembly of desired agent-loaded micelle, and might be useful for the design of new materials for agent delivery.

Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery

PubMed Central

Qiu, Liang; Hong, Chun-Yan; Pan, Cai-Yuan

2015-01-01

Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAIGP)ns, have been successively prepared by two steps of reversible addition–fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p-(methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2′-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)ns (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system. PMID:26056444

Curcumin-Loading-Dependent Stability of PEGMEMA-Based Micelles Affects Endocytosis and Exocytosis in Colon Carcinoma Cells.

PubMed

Chang, Teddy; Trench, David; Putnam, Joshua; Stenzel, Martina H; Lord, Megan S

2016-03-07

Polymeric micelles were formed from poly(poly(ethylene glycol) methyl ether methacrylate)-block-poly(styrene) (P(PEGMEMA)-b-PS) block copolymer of two different chain lengths. The micelles formed were approximately 16 and 46 nm in diameter and used to encapsulate curcumin. Upon loading of the curcumin into the micelles, their size increased to approximately 34 and 80 nm in diameter, respectively, with a loading efficiency of 58%. The unloaded micelles were not cytotoxic to human colon carcinoma cells, whereas only the smaller loaded micelles were cytotoxic after 72 h of exposure. The micelles were rapidly internalized by the cells within minutes of exposure, with the loaded micelles internalized to a greater extent owing to their enhanced stability compared to that of the unloaded micelles. The larger micelles were more rapidly internalized and exocytosed than the smaller micelles, demonstrating the effect of micelle size and drug loading on drug delivery and cytotoxicity.

pH-responsive micelles based on (PCL)2(PDEA-b-PPEGMA)2 miktoarm polymer: controlled synthesis, characterization, and application as anticancer drug carrier.

PubMed

Lin, Wenjing; Nie, Shuyu; Xiong, Di; Guo, Xindong; Wang, Jufang; Zhang, Lijuan

2014-01-01

Amphiphilic A2(BC)2 miktoarm star polymers [poly(ϵ-caprolactone)]2-[poly(2-(diethylamino)ethyl methacrylate)-b- poly(poly(ethylene glycol) methyl ether methacrylate)]2 [(PCL)2(PDEA-b-PPEGMA)2] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC50 of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)2(PDEA-b-PPEGMA)2 micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.

Off-resonance saturation magnetic resonance imaging of superparamagnetic polymeric micelles.

PubMed

Khemtong, Chalermchai; Kessinger, Chase W; Togao, Osamu; Ren, Jimin; Takahashi, Masaya; Sherry, A Dean; Gao, Jinming

2009-01-01

An off-resonance saturation (ORS) method was used for magnetic resonance imaging of superparamagnetic polymeric micelles (SPPM). SPPM was produced by encapsulating a cluster of magnetite nanoparticles (9.9+/-0.4 nm in diameter) in poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PLA) copolymer micelles (micelle diameter: 60+/-9 nm). In ORS MRI, a selective radiofrequency (RF) pulse was applied at an off-resonance position (0-50 ppm) from the bulk water signal, and the SPPM particles were visualized by the contrast on a division image constructed from two images acquired with and without pre-saturation. Here, the effects of saturation offset frequencies, saturation durations, and RF powers on ORS contrasts were investigated as these parameters are critical for optimization of ORS MRI for in vivo imaging applications. The ability to turn "ON" and "OFF" ORS contrast of SPPM solutions permits for an accurate image subtraction and a contrast enhancement to visualize SPPM probes for in vivo imaging of cancer.

A fluorescent molecular sensor for pH windows in traditional and polymeric biocompatible micelles: comicellization of anionic species to shift and reshape the ON window.

PubMed

Cavallaro, Gennara; Giammona, Gaetano; Pasotti, Luca; Pallavicini, Piersandro

2011-09-12

A new approach is presented to obtain fluorescent sensors for pH windows that work in water and under biomimetic conditions. A single molecule that features all-covalently linked components is used, thus making it capable of working as a fluorescent sensor with an OFF/ON/OFF response to pH value. The components are a tertiary amine, a pyridine, and a fluorophore (pyrene). The forms with both protonated bases or both neutral bases quench the pyrene fluorescence, whereas the form with the neutral pyridine and protonated amine groups is fluorescent. The molecular sensor is also equipped with a long alkyl chain to make it highly hydrophobic in all its protonated and unprotonated forms, that is, either when neutral or charged. Accordingly, it can be confined at any pH value either in traditional (i.e., low-molecular-weight) nonionic surfactant micelles or inside polymeric, biocompatible micellar containers. Relevant for future applications in vivo, thanks to its strong hydrophobicity, no leakage of the molecular sensor is observed from the polymeric biocompatible micelles. Due to the proximity of the pyridine and amine functions in the molecular structure and the poor hydration inside the micelles, the observed pK(a) values are low so that the ON window is positioned at very low pH values. However, the window can be shifted to biologically relevant values by comicellization of anionic species. In particular, in the micelles of the nonionic surfactant TritonX-100, a shift of the ON window to pH 4-6 is obtained by addition of the anionic sodium dodecyl sulphate surfactant, whose negative charge promotes the stability of the protonated forms of the pyridine and amine fragments. In the case of the polymeric micelles, we introduce the use of the amphiphilic polystyrene sulfonate anionic polyelectrolyte, the comicellization of which induces a shift and sharpening of the ON window that is centered at pH 4. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Highly Viscoelastic Reverse Wormlike Micellar Systems from a Mixture of Lecithin, Polyglycerol Fatty Acid Monoesters, and an Oil.

PubMed

Hashizaki, Kaname; Imai, Miko; Yako, Shuhei; Tsusaka, Hitomi; Sakanishi, Yuichi; Saito, Yoshihiro; Fujii, Makiko

2017-09-01

We report new lecithin reverse wormlike micelles with high viscoelasticity formed using lecithin/polyglycerol fatty acid monoester (PGLFA)/oil systems. In this study, the influence of the amphiphilicity (i.e., hydrophile-lipophile balance, HLB) of PGLFA on the phase behavior and rheological properties of reverse wormlike micelles was investigated in detail. PGLFAs with degrees of polymerization of polyglycerol varying between 6-40 and constituent fatty acids with chains between 6-18 carbon atoms long were used. Partial phase diagrams of the lecithin/PGLFA/n-decane systems indicated that the appropriate PGLFA could change the lecithin/oil solution into a highly viscoelastic solution comprising reverse wormlike micelles. Rheological measurements showed that all systems that formed reverse wormlike micelles exhibited an unusual phenomenon called "shear-thickening". Furthermore, reverse wormlike micelles grew as the PGLFA concentration increased and the zero-shear viscosity (η 0 ) of the solution rapidly increased. Our results indicate that the magnitude of the maximum η 0 depends on the degree of polymerization of the constituent polyglycerol in the PGLFA, while the size of the reverse micellar region and the highly viscous region in the phase diagram depends on the HLB value of the PGLFA.

miktoarm polymer: controlled synthesis, characterization, and application as anticancer drug carrier

NASA Astrophysics Data System (ADS)

Lin, Wenjing; Nie, Shuyu; Xiong, Di; Guo, Xindong; Wang, Jufang; Zhang, Lijuan

2014-05-01

Amphiphilic A2(BC)2 miktoarm star polymers [poly(ɛ-caprolactone)]2-[poly(2-(diethylamino)ethyl methacrylate)- b- poly(poly(ethylene glycol) methyl ether methacrylate)]2 [(PCL)2(PDEA- b-PPEGMA)2] were developed by a combination of ring opening polymerization (ROP) and continuous activators regenerated by electron transfer atom transfer radical polymerization (ARGET ATRP). The critical micelle concentration (CMC) values were extremely low (0.0024 to 0.0043 mg/mL), depending on the architecture of the polymers. The self-assembled empty and doxorubicin (DOX)-loaded micelles were spherical in morphologies, and the average sizes were about 63 and 110 nm. The release of DOX at pH 5.0 was much faster than that at pH 6.5 and pH 7.4. Moreover, DOX-loaded micelles could effectively inhibit the growth of cancer cells HepG2 with IC50 of 2.0 μg/mL. Intracellular uptake demonstrated that DOX was delivered into the cells effectively after the cells were incubated with DOX-loaded micelles. Therefore, the pH-sensitive (PCL)2(PDEA- b-PPEGMA)2 micelles could be a prospective candidate as anticancer drug carrier for hydrophobic drugs with sustained release behavior.

Measuring the Acoustic Release of a Chemotherapeutic Agent from Folate-Targeted Polymeric Micelles.

PubMed

Abusara, Ayah; Abdel-Hafez, Mamoun; Husseini, Ghaleb

2018-08-01

In this paper, we compare the use of Bayesian filters for the estimation of release and re-encapsulation rates of a chemotherapeutic agent (namely Doxorubicin) from nanocarriers in an acoustically activated drug release system. The study is implemented using an advanced kinetic model that takes into account cavitation events causing the antineoplastic agent's release from polymeric micelles upon exposure to ultrasound. This model is an improvement over the previous representations of acoustic release that used simple zero-, first- and second-order release and re-encapsulation kinetics to study acoustically triggered drug release from polymeric micelles. The new model incorporates drug release and micellar reassembly events caused by cavitation allowing for the controlled release of chemotherapeutics specially and temporally. Different Bayesian estimators are tested for this purpose including Kalman filters (KF), Extended Kalman filters (EKF), Particle filters (PF), and multi-model KF and EKF. Simulated and experimental results are used to verify the performance of the above-mentioned estimators. The proposed methods demonstrate the utility and high-accuracy of using estimation methods in modeling this drug delivery technique. The results show that, in both cases (linear and non-linear dynamics), the modeling errors are expensive but can be minimized using a multi-model approach. In addition, particle filters are more flexible filters that perform reasonably well compared to the other two filters. The study improved the accuracy of the kinetic models used to capture acoustically activated drug release from polymeric micelles, which may in turn help in designing hardware and software capable of precisely controlling the delivered amount of chemotherapeutics to cancerous tissue.

Polymeric micelles for potentiated antiulcer and anticancer activities of naringin

PubMed Central

Mohamed, Elham Abdelmonem; Abu Hashim, Irhan Ibrahim; Yusif, Rehab Mohammad; Shaaban, Ahmed Abdel Aziz; El-Sheakh, Ahmed Ramadan; Hamed, Mohammed Fawzy; Badria, Farid Abd Elreheem

2018-01-01

Naringin is one of the most interesting phytopharmaceuticals that has been widely investigated for various biological actions. Yet, its low water solubility, limited permeability, and suboptimal bioavailability limited its use. Therefore, in this study, polymeric micelles of naringin based on pluronic F68 (PF68) were developed, fully characterized, and optimized. The optimized formula was investigated regarding in vitro release, storage stability, and in vitro cytotoxicity vs different cell lines. Also, cytoprotection against ethanol-induced ulcer in rats and antitumor activity against Ehrlich ascites carcinoma in mice were investigated. Nanoscopic and nearly spherical 1:50 micelles with the mean diameter of 74.80±6.56 nm and narrow size distribution were obtained. These micelles showed the highest entrapment efficiency (EE%; 96.14±2.29). The micelles exhibited prolonged release up to 48 vs 10 h for free naringin. The stability of micelles was confirmed by insignificant changes in drug entrapment, particle size, and retention (%) (91.99±3.24). At lower dose than free naringin, effective cytoprotection of 1:50 micelles against ethanol-induced ulcer in rat model has been indicated by significant reduction in mucosal damage, gastric level of malondialdehyde, gastric expression of tumor necrosis factor-alpha, caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, and interleukin-6 with the elevation of gastric reduced glutathione and superoxide dismutase when compared with the positive control group. As well, these micelles provoked pronounced antitumor activity assessed by potentiated in vitro cytotoxicity particularly against colorectal carcinoma cells and tumor growth inhibition when compared with free naringin. In conclusion, 1:50 naringin–PF68 micelles can be represented as a potential stable nanodrug delivery system with prolonged release and enhanced antiulcer as well as antitumor activities. PMID:29497294

Polymeric micelles for potentiated antiulcer and anticancer activities of naringin.

PubMed

Mohamed, Elham Abdelmonem; Abu Hashim, Irhan Ibrahim; Yusif, Rehab Mohammad; Shaaban, Ahmed Abdel Aziz; El-Sheakh, Ahmed Ramadan; Hamed, Mohammed Fawzy; Badria, Farid Abd Elreheem

2018-01-01

Naringin is one of the most interesting phytopharmaceuticals that has been widely investigated for various biological actions. Yet, its low water solubility, limited permeability, and suboptimal bioavailability limited its use. Therefore, in this study, polymeric micelles of naringin based on pluronic F68 (PF68) were developed, fully characterized, and optimized. The optimized formula was investigated regarding in vitro release, storage stability, and in vitro cytotoxicity vs different cell lines. Also, cytoprotection against ethanol-induced ulcer in rats and antitumor activity against Ehrlich ascites carcinoma in mice were investigated. Nanoscopic and nearly spherical 1:50 micelles with the mean diameter of 74.80±6.56 nm and narrow size distribution were obtained. These micelles showed the highest entrapment efficiency (EE%; 96.14±2.29). The micelles exhibited prolonged release up to 48 vs 10 h for free naringin. The stability of micelles was confirmed by insignificant changes in drug entrapment, particle size, and retention (%) (91.99±3.24). At lower dose than free naringin, effective cytoprotection of 1:50 micelles against ethanol-induced ulcer in rat model has been indicated by significant reduction in mucosal damage, gastric level of malondialdehyde, gastric expression of tumor necrosis factor-alpha, caspase-3, nuclear factor kappa-light-chain-enhancer of activated B cells, and interleukin-6 with the elevation of gastric reduced glutathione and superoxide dismutase when compared with the positive control group. As well, these micelles provoked pronounced antitumor activity assessed by potentiated in vitro cytotoxicity particularly against colorectal carcinoma cells and tumor growth inhibition when compared with free naringin. In conclusion, 1:50 naringin-PF68 micelles can be represented as a potential stable nanodrug delivery system with prolonged release and enhanced antiulcer as well as antitumor activities.

Current trends in the use of vitamin E-based micellar nanocarriers for anticancer drug delivery.

PubMed

Muddineti, Omkara Swami; Ghosh, Balaram; Biswas, Swati

2017-06-01

Owing to the complexity of cancer pathogenesis, conventional chemotherapy can be an inadequate method of killing cancer cells effectively. Nanoparticle-based drug delivery systems have been widely exploited pre-clinically in recent years. Areas covered: Incorporation of vitamin-E in nanocarriers have the advantage of (1) improving the hydrophobicity of the drug delivery system, thereby improving the solubility of the loaded poorly soluble anticancer drugs, (2) enhancing the biocompatibility of the polymeric drug carriers, and (3) improving the anticancer potential of the chemotherapeutic agents by reversing the cellular drug resistance via simultaneous administration. In addition to being a powerful antioxidant, vitamin E demonstrated its anticancer potential by inducing apoptosis in various cancer cell lines. Various vitamin E analogs have proven their ability to cause marked inhibition of drug efflux transporters. Expert opinion: The review discusses the potential of incorporating vitamin E in the polymeric micelles which are designed to carry poorly water-soluble anticancer drugs. Current applications of various vitamin E-based polymeric micelles with emphasis on the use of α-tocopherol, D-α-tocopheryl succinate (α-TOS) and its conjugates such as D-α-tocopheryl polyethylene glycol-succinate (TPGS) in micellar system is delineated. Advantages of utilizing polymeric micelles for drug delivery and the challenges to treat cancer, including multiple drug resistance have been discussed.

Preparation of multilocation reduction-sensitive core crosslinked folate-PEG-coated micelles for rapid release of doxorubicin and tariquidar to overcome drug resistance

NASA Astrophysics Data System (ADS)

Yi, Xiaoqing; Zhao, Dan; Zhang, Quan; Xu, Jiaqi; Yuan, Gongdao; Zhuo, Renxi; Li, Feng

2017-02-01

Herein, we prepared folate-targeting core crosslinked polymeric micelles (CCL/FA) containing multiple disulfide bonds located at the interface and core of the micelles to co-deliver doxorubicin (DOX) and the P-glycoprotein (P-gp) inhibitor tariquidar (TQR) for reversing drug resistance. The stability and redox-responsive behavior of the CCL/FA micelles was evaluated through the changes in morphology, molecular weight and hydrodynamic size. On the one hand, the micelles possessed good stability, which led to the suppression of drug release from the CCL micelles in the physiological environment. On the other hand, under reductive conditions, the CCL micelles collapsed rapidly and accelerated drug release markedly. In vitro cytotoxicity measurements, combined with confocal laser scanning microscopy (CLSM) and flow cytometry, confirmed that the dual-drug-loaded micelles exhibited obviously higher cytotoxicity to MCF-7/ADR-resistant cells than free DOX · HCl, single-drug loaded CCL micelles and nontargeted CCL micelles. The results imply that co-delivering DOX and TQR by CCL/FA micelles may be a promising way of overcoming multidrug resistance in tumor treatments.

Scalable and uniform 1D nanoparticles by synchronous polymerization, crystallization and self-assembly

NASA Astrophysics Data System (ADS)

Boott, Charlotte E.; Gwyther, Jessica; Harniman, Robert L.; Hayward, Dominic W.; Manners, Ian

2017-08-01

The preparation of well-defined nanoparticles based on soft matter, using solution-processing techniques on a commercially viable scale, is a major challenge of widespread importance. Self-assembly of block copolymers in solvents that selectively solvate one of the segments provides a promising route to core-corona nanoparticles (micelles) with a wide range of potential uses. Nevertheless, significant limitations to this approach also exist. For example, the solution processing of block copolymers generally follows a separate synthesis step and is normally performed at high dilution. Moreover, non-spherical micelles—which are promising for many applications—are generally difficult to access, samples are polydisperse and precise dimensional control is not possible. Here we demonstrate the formation of platelet and cylindrical micelles at concentrations up to 25% solids via a one-pot approach—starting from monomers—that combines polymerization-induced and crystallization-driven self-assembly. We also show that performing the procedure in the presence of small seed micelles allows the scalable formation of low dispersity samples of cylindrical micelles of controlled length up to three micrometres.

Amphiphilic polymeric micelles originating from 1,4-β-D-glucan-g-polyphenylene oxide as the carriers for delivery of docetaxel and the corresponding release behaviors.

PubMed

Yang, Fang; Xiao, Dan; Han, Huaxin; Chen, Yuhuan; Li, Gang

2018-07-15

A novel amphiphilic polymeric drug carrier was synthesized through grafting polymerization of water-soluble 1,4-β-D-glucan from cotton cellulose tailored and polypropylene oxide (PPO), and then use thereof to synthesize graft copolymer 1,4-β-D-glucan-PPO-docetaxel (DTX). The products were characterized by FTIR, 1 H NMR, and 13 C NMR. The physicochemical characteristics of 1,4-β-D-glucan-PPO and 1,4-β-D-glucan-PPO-DTX such as molecular weight distribution (MWD), micro-morphology, size, critical micelle concentration (CMC), aggregation number of micelle (N), in vitro stability and drug pharmacokinetic study in vivo were investigated. The results reveal that the degree of polymerization (DP) of the water-soluble 1,4-β-D-glucan from cotton cellulose tailored is equal to 7; the 1,4-β-D-glucan-PPO surfactant possesses good surface activity while the adduct number of propylene oxide reaches appropriately to 20; the DTX is completely dispersed in water medium with 1,4-β-D-glucan-PPO-DTX micelle and the drug conjugated percent is up to 40.3%; In vitro study confirms that 1,4-β-D-glucan-PPO-DTX has the capacity for sustained drug release; In plasma, 1,4-β-D-glucan-PPO-DTX exhibits a significantly enhanced C max , AUC (0-t) and T 1/2 compared with DTX. These results demonstrate that 1,4-β-D-glucan-PPO has the potential to be used as a novel biocompatible biomaterial for drug delivery. Copyright © 2018 Elsevier B.V. All rights reserved.

Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery.

PubMed

Zhang, Can Yang; Xiong, Di; Sun, Yao; Zhao, Bin; Lin, Wen Jing; Zhang, Li Juan

2014-01-01

A novel amphiphilic triblock pH-sensitive poly(β-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation-deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy.

Self-assembled micelles based on pH-sensitive PAE-g-MPEG-cholesterol block copolymer for anticancer drug delivery

PubMed Central

Zhang, Can Yang; Xiong, Di; Sun, Yao; Zhao, Bin; Lin, Wen Jing; Zhang, Li Juan

2014-01-01

A novel amphiphilic triblock pH-sensitive poly(β-amino ester)-g-poly(ethylene glycol) methyl ether-cholesterol (PAE-g-MPEG-Chol) was designed and synthesized via the Michael-type step polymerization and esterification condensation method. The synthesized copolymer was determined with proton nuclear magnetic resonance and gel permeation chromatography. The grafting percentages of MPEG and cholesterol were determined as 10.93% and 62.02%, calculated from the area of the characteristic peaks, respectively. The amphiphilic copolymer was confirmed to self-assemble into core/shell micelles in aqueous solution at low concentrations. The critical micelle concentrations were 6.92 and 15.14 mg/L at pH of 7.4 and 6.0, respectively, obviously influenced by the changes of pH values. The solubility of pH-responsive PAE segment could be transformed depending on the different values of pH because of protonation–deprotonation of the amino groups, resulting in pH sensitivity of the copolymer. The average particle size of micelles increased from 125 nm to 165 nm with the pH decreasing, and the zeta potential was also significantly changed. Doxorubicin (DOX) was entrapped into the polymeric micelles with a high drug loading level. The in vitro DOX release from the micelles was distinctly enhanced with the pH decreasing from 7.4 to 6.0. Toxicity testing proved that the DOX-loaded micelles exhibited high cytotoxicity in HepG2 cells, whereas the copolymer showed low toxicity. The results demonstrated how pH-sensitive PAE-g-MPEG-Chol micelles were proved to be a potential vector in hydrophobic drug delivery for tumor therapy. PMID:25364250

Effect of Dendritic Polymer Architecture on Biological Behaviors of Self-Assembled Nanocarriers

NASA Astrophysics Data System (ADS)

Hsu, Hao-Jui

Polymeric self-assembled nanocarriers represent one of the most versatile platforms for drug delivery. Through tailoring the physiochemical properties of amphiphilic block copolymers, self-assembled nanocarriers with great thermodynamic stability and desired biological properties could be achieved. The PEGylated dendron-based copolymers (PDCs) are one of the novel amphiphilic copolymers that have attracted a great deal of scientific interest due to their unique dendritic structure and properties. While the dendritic polymer architecture of PDC has been shown to enhance the thermodynamic stability of the self-assembling PDCs, dendron micelles, the effect of this polymer architecture on the biological properties of dendron micelles has not yet been studied. Therefore, this dissertation research is focused on understanding the role of dendritic polymer structure on moderating the biological properties of various self-assembled nanocarriers. To systematically investigate this, three studies have been designed and performed. First, we studied whether the dendritic structure of PDC allows dendron micelles to behave non-specific cellular interactions in a similar way that dendrimers would do. Second, cell-specific interactions of dendron micelles mediated by conjugated ligands were investigated. Third, we investigated the influence of dendritic PEG outer shell on micelle-serum protein interactions and its subsequent implication. Our results revealed that both non-specific and specific cellular interactions of dendron micelles were controllable through modulation of the PEG corona length. While the non-specific charge-dependent cellular interactions of dendron micelles were tunable through controlling the length of PEG corona, the use of long PEG tether was found to enhance the ligand-mediated cellular interactions of dendron micelles. With the ligand tethers, a 27-fold enhancement in ligand-mediated cellular interactions can be achieved, compared to non-targeted dendron micelles. Furthermore, we demonstrate that the dense PEG outer shell introduced by its dendritic structure reduced non-specific micelle-serum protein interactions and suppressed the subsequent micelle disintegration or premature drug release, which was not the case for linear block copolymer (LBC)-based micelles. Molecular dynamic (MD) simulation results also supported that dendron micelles exhibited a weaker interaction with serum albumin compared to LBC-based micelles. In the presence of serum proteins, the half-life of dendron micelles was 2-fold longer than that of LBC-based micelles, which could be attributed to their low serum protein interactions. In conclusion, our results provide fundamental understanding on the role of PEG corona and the effect of polymeric architecture on biological properties of polymer micelles, all indicating that dendron micelles have great potential as a novel drug delivery platform.

Polymeric Micelles in Anticancer Therapy: Targeting, Imaging and Triggered Release

PubMed Central

Bult, Wouter; Bos, Mariska; Storm, Gert; Nijsen, J. Frank W.; Hennink, Wim E.

2010-01-01

ABSTRACT Micelles are colloidal particles with a size around 5–100 nm which are currently under investigation as carriers for hydrophobic drugs in anticancer therapy. Currently, five micellar formulations for anticancer therapy are under clinical evaluation, of which Genexol-PM has been FDA approved for use in patients with breast cancer. Micelle-based drug delivery, however, can be improved in different ways. Targeting ligands can be attached to the micelles which specifically recognize and bind to receptors overexpressed in tumor cells, and chelation or incorporation of imaging moieties enables tracking micelles in vivo for biodistribution studies. Moreover, pH-, thermo-, ultrasound-, or light-sensitive block copolymers allow for controlled micelle dissociation and triggered drug release. The combination of these approaches will further improve specificity and efficacy of micelle-based drug delivery and brings the development of a ‘magic bullet’ a major step forward. PMID:20725771

Engineering single-polymer micelle shape using nonuniform spontaneous surface curvature

NASA Astrophysics Data System (ADS)

Moths, Brian; Witten, T. A.

2018-03-01

Conventional micelles, composed of simple amphiphiles, exhibit only a few standard morphologies, each characterized by its mean surface curvature set by the amphiphiles. Here we demonstrate a rational design scheme to construct micelles of more general shape from polymeric amphiphiles. We replace the many amphiphiles of a conventional micelle by a single flexible, linear, block copolymer chain containing two incompatible species arranged in multiple alternating segments. With suitable segment lengths, the chain exhibits a condensed spherical configuration in solution, similar to conventional micelles. Our design scheme posits that further shapes are attained by altering the segment lengths. As a first study of the power of this scheme, we demonstrate the capacity to produce long-lived micelles of horseshoe form using conventional bead-spring simulations in two dimensions. Modest changes in the segment lengths produce smooth changes in the micelle's shape and stability.

Pharmacological and toxicological assessment of innovative self-assembled polymeric micelles as powders for insulin pulmonary delivery.

PubMed

Andrade, Fernanda; Fonte, Pedro; Costa, Ana; Reis, Cassilda Cunha; Nunes, Rute; Almeida, Andreia; Ferreira, Domingos; Oliva, Mireia; Sarmento, Bruno

2016-09-01

Explore the use of polymeric micelles in the development of powders intended for pulmonary delivery of biopharmaceuticals, using insulin as a model protein. Formulations were assessed in vitro for aerosolization properties and in vivo for efficacy and safety using a streptozotocin-induced diabetic rat model. Powders presented good aerosolization properties like fine particle fraction superior to 40% and a mass median aerodynamic diameter inferior of 6 μm. Endotracheally instilled powders have shown a faster onset of action than subcutaneous administration of insulin at a dose of 10 IU/kg, with pharmacological availabilities up to 32.5% of those achieved by subcutaneous route. Additionally, micelles improved the hypoglycemic effect of insulin. Bronchoalveolar lavage screening for toxicity markers (e.g., lactate dehydrogenase, cytokines) revealed no signs of lung inflammation and cytotoxicity 14 days postadministration. Developed powders showed promising safety and efficacy characteristics for the systemic delivery of insulin by pulmonary administration.

RGD peptide-mediated chitosan-based polymeric micelles targeting delivery for integrin-overexpressing tumor cells.

PubMed

Cai, Li-Li; Liu, Ping; Li, Xi; Huang, Xuan; Ye, Yi-Qing; Chen, Feng-Ying; Yuan, Hong; Hu, Fu-Qiang; Du, Yong-Zhong

2011-01-01

Solid tumors need new blood vessels to feed and nourish them as well as to allow tumor cells to escape into the circulation and lodge in other organs, which is termed "angiogenesis." Some tumor cells within solid tumors can overexpress integrins α(v)β(3) and α(v)β(5), which can specifically recognize the peptide motif Arg-Gly-Asp (RGD). Thus, the targeting of RGD-modified micelles to tumor vasculature is a promising strategy for tumor-targeting treatment. RGD peptide (GSSSGRGDSPA) was coupled to poly(ethylene glycol)-modified stearic acid-grafted chitosan (PEG-CS-SA) micelles via chemical reaction in the presence of N,N'-Disuccinimidyl carbonate. The critical micelle concentration of the polymeric micelles was determined by measuring the fluorescence intensity of pyrene as a fluorescent probe. The micelle size, size distribution, and zeta potential were measured by light scattering and electrophoretic mobility. Doxorubicin (DOX) was chosen as a model anticancer drug to investigate the drug entrapment efficiency, in vitro drug-release profile, and in vitro antitumor activities of drug-loaded RGD-PEG-CS-SA micelles in cells that overexpress integrins (α(ν)β(3) and α(ν)β(5)) and integrin-deficient cells. Using DOX as a model drug, the drug encapsulation efficiency could reach 90%, and the in vitro drug-release profiles suggested that the micelles could be used as a controlled-release carrier for the hydrophobic drug. Qualitative and quantitative analysis of cellular uptake indicated that RGD-modified micelles could significantly increase the DOX concentration in integrin-overexpressing human hepatocellular carcinoma cell line (BEL-7402), but not in human epithelial carcinoma cell line (Hela). The competitive cellular-uptake test showed that the cellular uptake of RGD-modified micelles in BEL-7402 cells was significantly inhibited in the presence of excess free RGD peptides. In vitro cytotoxicity tests demonstrated DOX-loaded RGD-modified micelles could specifically enhance the cytotoxicity against BEL-7402 compared with DOX-loaded PEG-CS-SA and doxorubicin hydrochlorate. This study suggests that RGD-modified PEG-CS-SA micelles are promising drug carriers for integrin-overexpressing tumor active targeting therapy.

Facile fabrication of redox-responsive thiol-containing drug delivery system via RAFT polymerization.

PubMed

Zhuang, Yuanyuan; Su, Yue; Peng, Yu; Wang, Dali; Deng, Hongping; Xi, Xiaodong; Zhu, Xinyuan; Lu, Yunfeng

2014-04-14

A novel kind of redox-responsive polymeric drug delivery system has been designed and prepared successfully through the coupling of the multithiol branched polymers and thiol-containing drugs. The branched poly((S-(4-vinyl) benzyl S'-propyltrithiocarbonate)-co-(poly(ethylene glycol) methacrylate)) (poly(VBPT-co-PEGMA)) was synthesized by one-pot reaction via reversible addition-fragmentation chain transfer (RAFT) copolymerization. Subsequently, the hydrophobic thiol-containing anticancer drug 6-mercaptopurine (MP) was conjugated to poly(VBPT-co-PEGMA) by thiol-disulfide exchange reaction, resulting in the formation of poly(VBPT-co-PEGMA)-S-S-MP conjugate. Due to its amphiphilicity, poly(VBPT-co-PEGMA)-S-S-MP conjugate self-assembled into amphiphilic micelles in aqueous solution. Under a reductive environment, the disassembly of polymeric micelles resulted in the MP release. Flow cytometry and confocal laser scanning microscopy (CLSM) measurements demonstrated that the poly(VBPT-co-PEGMA)-S-S-MP micelles could be taken up by Raji cells (a Burkitt lymphoma cell line). The viability of the Raji cells incubated with the glutathione (GSH) mediated poly(VBPT-co-PEGMA)-S-S-MP micelles was investigated by Cell Counting Kit-8 (CCK-8) assay. The experimental results showed that the viability of the glutathione monoester (GSH-OEt) pretreated cells was lower than that without pretreatment, while the viability of the buthionine sulfoximine (BSO) pretreated cells was higher than that without pretreatment. The poly(VBPT-co-PEGMA)-S-S-MP micelles could induce the apoptosis of Raji cells, and the apoptosis behavior was dose-dependent. This redox-responsive polymer-drug conjugate provides a promising platform for the delivery of thiol-containing biological molecules.

Toxicity evaluation of methoxy poly(ethylene oxide)-block-poly(ε-caprolactone) polymeric micelles following multiple oral and intraperitoneal administration to rats.

PubMed

Binkhathlan, Ziyad; Qamar, Wajhul; Ali, Raisuddin; Kfoury, Hala; Alghonaim, Mohammed

2017-09-01

Methoxy poly(ethylene oxide)- block -poly(ɛ-caprolactone) (PEO- b -PCL) copolymers are amphiphilic and biodegradable copolymers designed to deliver a variety of drugs and diagnostic agents. The aim of this study was to synthesize PEO- b -PCL block copolymers and assess the toxic effects of drug-free PEO- b -PCL micelles after multiple-dose administrations via oral or intraperitoneal (ip) administration in rats. Assembly of block copolymers was achieved by co-solvent evaporation method. To investigate the toxicity profile of PEO- b -PCL micelles, sixty animals were divided into two major groups: The first group received PEO- b -PCL micelles (100 mg/kg) by oral gavage daily for seven days, while the other group received the same dose of micelles by ip injections daily for seven days. Twenty-four hours following the last dose, half of the animals from each group were sacrificed and blood and organs (lung, liver, kidneys, heart and spleen) were collected. Remaining animals were observed for further 14 days and was sacrificed at the end of the third week, and blood and organs were collected. None of the polymeric micelles administered caused any significant effects on relative organ weight, animal body weight, leucocytes count, % lymphocytes, liver and kidney toxicity markers and organs histology. Although the dose of copolymers used in this study is much higher than those used for drug delivery, it did not cause any significant toxic effects in rats. Histological examination of all the organs confirmed the nontoxic nature of the micelles.

pH-sensitive micelles self-assembled from polymer brush (PAE-g-cholesterol)-b-PEG-b-(PAE-g-cholesterol) for anticancer drug delivery and controlled release

PubMed Central

Huang, Xiangxuan; Liao, Wenbo; Zhang, Gang; Kang, Shimin; Zhang, Can Yang

2017-01-01

A novel amphiphilic pH-sensitive triblock polymer brush (poly(β-amino esters)-g-cholesterol)-b-poly(ethylene glycol)-b-(poly(β-amino esters)-g-cholesterol) ((PAE-g-Chol)-b-PEG-b-(PAE-g-Chol)) was designed and synthesized successfully through a three-step reaction, and their self-assembled polymeric micelles were used as hydrophobic anticancer drug delivery carriers to realize effectively controlled release. The critical micelle concentrations were 6.8 μg/mL, 12.6 μg/mL, 17.4 μg/mL, and 26.6 μg/mL at pH values of 7.4, 6.5, 6.0, and 5.0, respectively. The trend of critical micelle concentrations indicated that the polymer had high stability that could prolong the circulation time in the body. The hydrodynamic diameter and zeta potential of the polymeric micelles were influenced significantly by the pH values. As pH decreased from 7.4 to 5.0, the particle size and zeta potential increased from 205.4 nm to 285.7 nm and from +12.7 mV to +47.0 mV, respectively. The pKb of the polymer was confirmed to be approximately 6.5 by the acid–base titration method. The results showed that the polymer had sharp pH-sensitivity because of the protonation of the amino groups, resulting in transformation of the PAE segment from hydrophobic to hydrophilic. Doxorubicin-loaded polymeric micelles were prepared with a high loading content (20%) and entrapment efficiency (60%) using the dialysis method. The in vitro results demonstrated that drug release rate and cumulative release were obviously dependent on pH values. Furthermore, the drug release mechanism was also controlled by the pH values. The polymer had barely any cytotoxicity, whereas the doxorubicin-loaded system showed high toxicity for HepG2 cells as free drugs. All the results proved that the pH-sensitive triblock polymer brush and its self-assembled micelle might be a potential delivery carrier for anticancer drugs with sustained release. PMID:28356738

pH-sensitive micelles self-assembled from polymer brush (PAE-g-cholesterol)-b-PEG-b-(PAE-g-cholesterol) for anticancer drug delivery and controlled release.

PubMed

Huang, Xiangxuan; Liao, Wenbo; Zhang, Gang; Kang, Shimin; Zhang, Can Yang

2017-01-01

A novel amphiphilic pH-sensitive triblock polymer brush (poly(β-amino esters)- g -cholesterol)- b -poly(ethylene glycol)- b -(poly(β-amino esters)- g -cholesterol) ((PAE- g -Chol)- b -PEG- b -(PAE- g -Chol)) was designed and synthesized successfully through a three-step reaction, and their self-assembled polymeric micelles were used as hydrophobic anticancer drug delivery carriers to realize effectively controlled release. The critical micelle concentrations were 6.8 μg/mL, 12.6 μg/mL, 17.4 μg/mL, and 26.6 μg/mL at pH values of 7.4, 6.5, 6.0, and 5.0, respectively. The trend of critical micelle concentrations indicated that the polymer had high stability that could prolong the circulation time in the body. The hydrodynamic diameter and zeta potential of the polymeric micelles were influenced significantly by the pH values. As pH decreased from 7.4 to 5.0, the particle size and zeta potential increased from 205.4 nm to 285.7 nm and from +12.7 mV to +47.0 mV, respectively. The p K b of the polymer was confirmed to be approximately 6.5 by the acid-base titration method. The results showed that the polymer had sharp pH-sensitivity because of the protonation of the amino groups, resulting in transformation of the PAE segment from hydrophobic to hydrophilic. Doxorubicin-loaded polymeric micelles were prepared with a high loading content (20%) and entrapment efficiency (60%) using the dialysis method. The in vitro results demonstrated that drug release rate and cumulative release were obviously dependent on pH values. Furthermore, the drug release mechanism was also controlled by the pH values. The polymer had barely any cytotoxicity, whereas the doxorubicin-loaded system showed high toxicity for HepG2 cells as free drugs. All the results proved that the pH-sensitive triblock polymer brush and its self-assembled micelle might be a potential delivery carrier for anticancer drugs with sustained release.

Fabrication of supramolecular star-shaped amphiphilic copolymers for ROS-triggered drug release.

PubMed

Zuo, Cai; Peng, Jinlei; Cong, Yong; Dai, Xianyin; Zhang, Xiaolong; Zhao, Sijie; Zhang, Xianshuo; Ma, Liwei; Wang, Baoyan; Wei, Hua

2018-03-15

Star-shaped copolymers with branched structures can form unimolecular micelles with better stability than the micelles self-assembled from conventional linear copolymers. However, the synthesis of star-shaped copolymers with precisely controlled degree of branching (DB) suffers from complicated sequential polymerizations and multi-step purification procedures, as well as repeated optimizations of polymer compositions. The use of a supramolecular host-guest pair as the block junction would significantly simplify the preparation. Moreover, the star-shaped copolymer-based unimolecular micelle provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy if the association/dissociation of the supramolecular host-guest joint can be triggered by the biologically relevant stimuli. For this purpose, in this study, a panel of supramolecular star-shaped amphiphilic block copolymers with 9, 12, and 18 arms were designed and fabricated by host-guest complexations between the ring-opening polymerization (ROP)-synthesized star-shaped poly(ε-caprolactone) (PCL) with 3, 4, and 6 arms end-capped with ferrocene (Fc) (PCL-Fc) and the atom transfer radical polymerization (ATRP)-produced 3-arm poly(oligo ethylene glycol) methacrylates (POEGMA) with different degrees of polymerization (DPs) of 24, 30, 47 initiated by β-cyclodextrin (β-CD) (3Br-β-CD-POEGMA). The effect of DB and polymer composition on the self-assembled properties of the five star-shaped copolymers was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence spectrometery. Interestingly, the micelles self-assembled from 12-arm star-shaped copolymers exhibited greater stability than the 9- and 18-arm formulations. The potential of the resulting supramolecular star-shaped amphiphilic copolymers as drug carriers was evaluated by an in vitro drug release study, which confirmed the ROS-triggered accelerated drug release from the doxorubicin (DOX)-loaded supramolecular star-shaped micelles due to the oxidation-induced dissociation of β-CD/Fc pair and the consequent loss of the colloidal stability of the star-shaped micelles. Studies of the delivery efficacy by an in vitro cytotoxicity study further indicated that higher DBs and longer hydrophilic arm compromised the therapeutic efficacy of the DOX-loaded supramolecular star-shaped micelles, resulting in significantly reduced cytotoxicity, as measured by increased IC 50 value. Overall, our results revealed that the screening of hydrophilic block by DB and MW for an optimized star-shaped copolymer should balance the stability versus therapeutic efficacy tradeoff for a comprehensive consideration. Therefore, the 12-arm star-shaped copolymer with POEGMA 30 is the best formulation tested. Copyright © 2017 Elsevier Inc. All rights reserved.

Filamentous, mixed micelles of triblock copolymers enhance tumor localization of indocyanine green in a murine xenograft model

PubMed Central

Kim, Tae Hee; Mount, Christopher W; Dulken, Benjamin W; Ramos, Jenelyn; Fu, Caroline J; Khant, Htet A; Chiu, Wah; Gombotz, Wayne R; Pun, Suzie H

2012-01-01

Polymeric micelles formed by the self-assembly of amphiphilic block copolymers can be used to encapsulate hydrophobic drugs for tumor-delivery applications. Filamentous carriers with high aspect ratios offer potential advantages over spherical carriers, including prolonged circulation times. In this work, mixed micelles comprised of poly (ethylene oxide)-poly-[(R)-3-hydroxybutyrate]-poly (ethylene oxide) (PEO-PHB-PEO) and Pluronic F-127 (PF-127) were used to encapsulate a near-infrared fluorophore. The micelle formulations were assessed for tumor accumulation after tail vein injection to xenograft tumor-bearing mice by non-invasive optical imaging. The mixed micelle formulation that facilitated the highest tumor accumulation was shown by cryo-electron microscopy to be filamentous in structure compared to spherical structures of pure PF-127 micelles. In addition, increased dye loading efficiency and dye stability was attained in this mixed micelle formulation compared to pure PEO-PHB-PEO micelles. Therefore, the optimized PEO-PHB-PEO/PF-127 mixed micelle formulation offers advantages for cancer delivery over micelles formed from the individual copolymer components. PMID:22118658

The effect of the hydrophilic/hydrophobic ratio of polymeric micelles on their endocytosis pathways into cells.

PubMed

Zhang, Zhao; Qu, Qianqian; Li, Jinrong; Zhou, Shaobing

2013-06-01

Fluorescein isothiocyanate (FITC), a fluorescent probe, is coupled to amphiphilic monomethoxy poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-PCL) copolymers. FITC-labeled mPEG-PCL copolymers self-assemble into micelles through the solvent evaporation method. The cellular internalization is examined using fluorescence microscopy on incubation of NIH-3T3 fibroblasts with micelles or free FITC solution. The effect of the hydrophilic/hydrophobic ratio on the endocytosis mechanisms is evaluated by fluorescence microscopy on culturing of human hepatoblastoma cells and human umbilical vein endothelial cells, individually, mixed with the micelles holding the same parameters including micelle size, shape, and surface charges. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reduction-Responsive Polymeric Micelles and Vesicles for Triggered Intracellular Drug Release

PubMed Central

Sun, Huanli; Cheng, Ru; Deng, Chao

2014-01-01

Abstract Significance: The therapeutic effects of current micellar and vesicular drug formulations are restricted by slow and inefficient drug release at the pathological site. The development of smart polymeric nanocarriers that release drugs upon arriving at the target site has received a tremendous amount of attention for cancer therapy. Recent Advances: Taking advantage of a high reducing potential in the tumor tissues and in particular inside the tumor cells, various reduction-sensitive polymeric micelles and vesicles have been designed and explored for triggered anticancer drug release. These reduction-responsive nanosystems have demonstrated several unique features, such as good stability under physiological conditions, fast response to intracellular reducing environment, triggering drug release right in the cytosol and cell nucleus, and significantly improved antitumor activity, compared to traditional reduction-insensitive counterparts. Critical Issues: Although reduction-sensitive micelles and polymersomes have accomplished rapid intracellular drug release and enhanced in vitro antitumor effect, their fate inside the cells including the mechanism, site, and rate of reduction reaction remains unclear. Moreover, the systemic fate and performance of reduction-sensitive polymeric drug formulations have to be investigated. Future Directions: Biophysical studies should be carried out to gain insight into the degradation and drug release behaviors of reduction-responsive nanocarriers inside the tumor cells. Furthermore, novel ligand-decorated reduction-sensitive nanoparticulate drug formulations should be designed and explored for targeted cancer therapy in vivo. Antioxid. Redox Signal. 21, 755–767. PMID:24279980

Polymeric micellar pH-sensitive drug delivery system for doxorubicin.

PubMed

Hrubý, Martin; Konák, Cestmír; Ulbrich, Karel

2005-03-02

A novel polymeric micellar pH-sensitive system for delivery of doxorubicin (DOX) is described. Polymeric micelles were prepared by self-assembly of amphiphilic diblock copolymers in aqueous solutions. The copolymers consist of a biocompatible hydrophilic poly(ethylene oxide) (PEO) block and a hydrophobic block containing covalently bound anthracycline antibiotic DOX. The starting block copolymers poly(ethylene oxide)-block-poly(allyl glycidyl ether) (PEO-PAGE) with a very narrow molecular weight distribution (Mw/Mn ca. 1.05) were prepared by anionic ring opening polymerization using sodium salt of poly(ethylene oxide) monomethyl ether as macroinitiator and allyl glycidyl ether as functional monomer. The copolymers were covalently modified via reactive double bonds by the addition of methyl sulfanylacetate. The resulting ester subsequently reacted with hydrazine hydrate yielding polymer hydrazide. The hydrazide was coupled with DOX yielding pH-sensitive hydrazone bonds between the drug and carrier. The resulting conjugate containing ca. 3 wt.% DOX forms micelles with Rh(a)=104 nm in phosphate-buffered saline. After incubation in buffers at 37 degrees C DOX was released faster at pH 5.0 (close to pH in endosomes; 43% DOX released within 24 h) than at pH 7.4 (pH of blood plasma; 16% DOX released within 24 h). Cleavage of hydrazone bonds between DOX and carrier continues even after plateau in the DOX release from micelles incubated in aqueous solutions is reached.

Synthesis and self-assembly of four-armed star copolymer based on poly(ethylene brassylate) hydrophobic block as potential drug carries

NASA Astrophysics Data System (ADS)

Chen, Jiucun; Li, Junzhi; Liu, Jianhua; Weng, Bo; Xu, Liqun

2016-05-01

A novel well-defined four-armed star poly(ethylene brassylate)- b-poly(poly(ethylene glycol)methyl ether methacrylate) (s-PEB- b-P(PEGMA)) was synthesized and self-assembled via the combination of ring-opening polymerization and reversible addition-fragmentation chain transfer polymerization (RAFT) in this work. It proceeded firstly with the synthesis of hydrophobic four-armed star homopolymer of ethylene brassylate (EB) via ROP with organic catalyst, followed by the esterification reaction of s-PEB with chain transfer agent. Afterward, RAFT polymerization of PEGMA monomer was initialed using PEB-based macro-RAFT agent, resulting in the target amphiphilic four-armed star copolymer. The obtained s-PEB- b-P(PEGMA) can assemble into micelles with PEB segments as core and P(PEGMA) segments as shell in aqueous solution. The self-assembly behavior was studied by dynamic light scattering and transmission electron microscope. The micelles of s-PEB- b-P(PEGMA) exhibited higher loading capacity of the anticancer drug doxorubicin (DOX). The investigation of DOX release from the micelles demonstrated that the release rate of the hydrophobic drug could be effectively controlled.

Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery

NASA Astrophysics Data System (ADS)

Cao, Yanwu; Gao, Min; Chen, Chao; Fan, Aiping; Zhang, Ju; Kong, Deling; Wang, Zheng; Peer, Dan; Zhao, Yanjun

2015-03-01

Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 ± 5.9 (nm) with a zeta potential of -10.6 ± 0.7 (mV). The critical micelle concentration was determined at 6.7 ± 0.4 (μg mL-1). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5 ± 1.4 (μg mL-1), whereas the IC50 of control micelles was 41.0 ± 2.4 (μg mL-1). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice.

Curcumin Delivery by Poly(Lactide)-Based Co-Polymeric Micelles: An In Vitro Anticancer Study.

PubMed

Kumari, Preeti; Swami, Muddineti Omkara; Nadipalli, Sravan Kumar; Myneni, Srividya; Ghosh, Balaram; Biswas, Swati

2016-04-01

This work describes the synthesis of block co-polymeric micelles, methoxy-poly(ethylene glycol)-poly(D,L-lactide) (mPEG-PLA) to encapsulate Curcumin (CUR), thereby improving the dispersibility and chemical stability of curcumin, prolonging its cellular uptake and enhancing its bioavailability. CUR-mPEG-PLA micelles, was prepared using the thin-film hydration method and evaluated in vitro. The preparation process was optimized with a central composite design (CCD). Micelles were characterized by size, transmission electron microscopy, loading capacity, and critical micelle concentration (CMC). The cytotoxicity of CUR-mPEG-PLA micelles was investigated against murine melanoma cells, B16F10 and human breast cancer cells, MDA-MB-231. The average size of the CUR-mPEG-PLA micelles was 110 ± 5 nm with polydispersity index in the range of 0.15-0.31, and the encapsulating efficiency for CUR was 91.89 ± 1.2, and 11.06 ± 0.8% for drug-loading. Sustained release of CUR from micelles was observed with 9.73% CUR release from micelles compared to 64.24% release of free curcumin in first 6 h under sink condition. The CUR-mPEG-PLA was efficiently taken up by the cancer cells, B16F10 and MDA-MB-231. Following 24 h incubation, CUR-mPEG-PLA induced higher cytotoxicity compared to free CUR in MDA-MB-231 cell lines indicating exposure of higher dose of free CUR to cells lead to up-regulation of drug efflux mechanisms leading to decreased cell death in case of free CUR administration. Our results indicate that the proposed micellar system has the potential to serve as an efficient carrier for CUR by effectively solubilizing, stabilizing and delivering the drug in a controlled manner to the cancer cells.

Synthesis and characterization of novel P(HEMA-LA-MADQUAT) micelles for co-delivery of methotrexate and Chrysin in combination cancer chemotherapy.

PubMed

Davaran, Soodabeh; Fazeli, Hamed; Ghamkhari, Aliyeh; Rahimi, Fariborz; Molavi, Ommoleila; Anzabi, Maryam; Salehi, Roya

2018-08-01

A Novel poly [2-hydroxyethyl methacrylate-Lactide-dimethylaminoethyl methacrylate quaternary ammonium alkyl halide] [P(HEMA-LA-MADQUAT)] copolymer was synthesized through combination of ring opening polymerization (ROP) and 'free' radical initiated polymerization methods. This newly developed copolymer was fully characterized by FT-IR, 1 HNMR and 13 CNMR spectroscopy. Micellization of the copolymer was performed by dialysis membrane method and obtained micelles were characterized by FESEM, dynamic light scattering (DLS), zeta potential (ξ), and critical micelle concentration (CMC) measurements. This copolymer was developed with the aim of co-delivering two different anticancer drugs: methotrexate (MTX) and chrysin. In vitro cytotoxicity effect of MTX@Chrysin-loaded P(HEMA-LA-MADQUAT) was also studied through assessing the survival rate of breast cancer cell line (MCF-7) and DAPI staining assays. Cationic micelle (and surface charge of + 7.6) with spherical morphology and an average diameter of 55 nm and CMC of 0.023 gL -1 was successfully obtained. Micelles showed the drug loaded capacity around 87.6 and 86.5% for MTX and Chrysin, respectively. The cytotoxicity assay of a drug-free nanocarrier on MCF-7 cell lines indicated that this developed micelles were suitable nanocarriers for anticancer drugs. Furthermore, the MTX@Chrysin-loaded micelle had more efficient anticancer performance than free dual anticancer drugs (MTX @ chrysin), confirmed by MTT assay and DAPI stainingmethods. Therefore, we envision that this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies. Therefore, this recently developed novel micelle can enhance the efficacy of chemotherapeutic agents, MTX and Chrysin, combination chemotherapy and has the potential to be used as an anticancer drug delivery system for in vivo studies.

Triggered-release polymeric conjugate micelles for on-demand intracellular drug delivery.

PubMed

Cao, Yanwu; Gao, Min; Chen, Chao; Fan, Aiping; Zhang, Ju; Kong, Deling; Wang, Zheng; Peer, Dan; Zhao, Yanjun

2015-03-20

Nanoscale drug delivery platforms have been developed over the past four decades that have shown promising clinical results in several types of cancer and inflammatory disorders. These nanocarriers carrying therapeutic payloads are maximizing the therapeutic outcomes while minimizing adverse effects. Yet one of the major challenges facing drug developers is the dilemma of premature versus on-demand drug release, which influences the therapeutic regiment, efficacy and potential toxicity. Herein, we report on redox-sensitive polymer-drug conjugate micelles for on-demand intracellular delivery of a model active agent, curcumin. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a disulfide bond or ester bond (control), respectively. The self-assembled redox-sensitive micelles exhibited a hydrodynamic size of 115.6 ± 5.9 (nm) with a zeta potential of -10.6 ± 0.7 (mV). The critical micelle concentration was determined at 6.7 ± 0.4 (μg mL(-1)). Under sink conditions with a mimicked redox environment (10 mM dithiothreitol), the extent of curcumin release at 48 h from disulfide bond-linked micelles was nearly three times higher compared to the control micelles. Such rapid release led to a lower half maximal inhibitory concentration (IC50) in HeLa cells at 18.5 ± 1.4 (μg mL(-1)), whereas the IC50 of control micelles was 41.0 ± 2.4 (μg mL(-1)). The cellular uptake study also revealed higher fluorescence intensity for redox-sensitive micelles. In conclusion, the redox-sensitive polymeric conjugate micelles could enhance curcumin delivery while avoiding premature release, and achieving on-demand release under the high glutathione concentration in the cell cytoplasm. This strategy opens new avenues for on-demand drug release of nanoscale intracellular delivery platforms that ultimately might be translated into pre-clinical and future clinical practice.

Preparation of multilocation reduction-sensitive core crosslinked folate-PEG-coated micelles for rapid release of doxorubicin and tariquidar to overcome drug resistance.

PubMed

Yi, Xiaoqing; Zhao, Dan; Zhang, Quan; Xu, Jiaqi; Yuan, Gongdao; Zhuo, Renxi; Li, Feng

2017-02-24

Herein, we prepared folate-targeting core crosslinked polymeric micelles (CCL/FA) containing multiple disulfide bonds located at the interface and core of the micelles to co-deliver doxorubicin (DOX) and the P-glycoprotein (P-gp) inhibitor tariquidar (TQR) for reversing drug resistance. The stability and redox-responsive behavior of the CCL/FA micelles was evaluated through the changes in morphology, molecular weight and hydrodynamic size. On the one hand, the micelles possessed good stability, which led to the suppression of drug release from the CCL micelles in the physiological environment. On the other hand, under reductive conditions, the CCL micelles collapsed rapidly and accelerated drug release markedly. In vitro cytotoxicity measurements, combined with confocal laser scanning microscopy (CLSM) and flow cytometry, confirmed that the dual-drug-loaded micelles exhibited obviously higher cytotoxicity to MCF-7/ADR-resistant cells than free DOX · HCl, single-drug loaded CCL micelles and nontargeted CCL micelles. The results imply that co-delivering DOX and TQR by CCL/FA micelles may be a promising way of overcoming multidrug resistance in tumor treatments.

Poly(2-(diethylamino)ethyl methacrylate)-based, pH-responsive, copolymeric mixed micelles for targeting anticancer drug control release.

PubMed

Chen, Quan; Li, Siheng; Feng, Zixiong; Wang, Meng; Cai, Chengzhi; Wang, Jufang; Zhang, Lijuan

2017-01-01

We have demonstrated a novel drug delivery system to improve the selectivity of the current chemotherapy by pH-responsive, polymeric micelle carriers. The micelle carriers were prepared by the self-assembly of copolymers containing the polybasic poly(2-(diethylamino) ethyl methacrylate) (PDEAEMA) block. The mixed copolymers exhibited a comparatively low critical micelle concentration (CMC; 1.95-5.25 mg/L). The resultant mixed micelles were found to be <100 nm and were used to encapsulate the anticancer drug doxorubicin (DOX) with pretty good drug-loading content (24%) and entrapment efficiency (55%). Most importantly, the micelle carrier exhibited a pH-dependent conformational conversion and promoted the DOX release at the tumorous pH. Our in vitro studies demonstrated the comparable level of DOX-loaded mixed micelle delivery into tumor cells with the free DOX (80% of the tumor cells were killed after 48 h incubation). The DOX-loaded mixed micelles were effective to inhibit the proliferation of tumor cells after prolonged incubation. Overall, the pH-responsive mixed micelle system provided desirable potential in the controlled release of anticancer therapeutics.

Thinking Outside the 'Block': Alternative Polymer Compositions for Micellar Drug Delivery.

PubMed

Jones, Marie-Christine

2015-01-01

With a number of formulations currently in clinical trials, the interest in polymer micelles as drug carriers in unlikely to subside. Historically, linear diblock copolymers have been used as the building blocks for micelle preparation. Yet, recent advances in polymer chemistry have meant that a wider variety of polymer architectures and compositions have become available and been trialed for pharmaceutical applications. This mini-review aims to provide an overview of recent, exciting developments in triblock, graft and hyperbranched polymer chemistries that may change the way polymeric micelles drug formulations are prepared.

Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs.

PubMed

Lukyanov, Anatoly N; Torchilin, Vladimir P

2004-05-07

Polymeric micelles have a whole set of unique characteristics, which make them very promising drug carriers, in particular, for poorly soluble drugs. Our review article focuses on micelles prepared from conjugates of water-soluble polymers, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone (PVP), with phospholipids or long-chain fatty acids. The preparation of micelles from certain polymer-lipid conjugates and the loading of these micelles with various poorly soluble anticancer agents are discussed. The data on the characterization of micellar preparations in terms of their morphology, stability, longevity in circulation, and ability to spontaneously accumulate in experimental tumors via the enhanced permeability and retention (EPR) effect are presented. The review also considers the preparation of targeted immunomicelles with specific antibodies attached to their surface. Available in vivo results on the efficiency of anticancer drugs incorporated into plain micelles and immunomicelles in animal models are also discussed.

Physicochemical properties of micelles of poly(styrene-b-[3-(methacryloylamino)propyl]trimethylammonium chloride-b-ethylene oxide) in aqueous solutions.

PubMed

Liu, Jingjing; Liu, Dian; Yokoyama, Yuuichi; Yusa, Shin-Ichi; Nakashima, Kenichi

2009-01-20

Polymeric micelles from a new triblock copolymer, polystyrene-block-poly[(3-(methacryloylamino)propyl)trimethylammonium chloride]-block-poly(ethylene oxide) (PS-b-PMAPTAC-b-PEO), were prepared in aqueous solutions and characterized by various techniques including dynamic light scattering (DLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and fluorescence spectroscopy. The micelle consists of a PS core, PMAPTAC shell, and PEO corona. It was revealed by SEM and DLS measurements that the micelles have a spherical structure with a hydrodynamic diameter about 75 nm. The addition of tungstate to the micellar solution caused a morphological change in the micelles from extended to shrunken spheres, which can be attributed to the fact that electrostatic repulsion among the cationic PMAPTAC blocks is canceled by the negative charge of the bound tungstate ions. Effective incorporation of tungstate ions into the micelles were confirmed by TEM and zeta-potential measurements.

Targeted polymeric micelles for siRNA treatment of experimental cancer by intravenous injection.

PubMed

Christie, R James; Matsumoto, Yu; Miyata, Kanjiro; Nomoto, Takahiro; Fukushima, Shigeto; Osada, Kensuke; Halnaut, Julien; Pittella, Frederico; Kim, Hyun Jin; Nishiyama, Nobuhiro; Kataoka, Kazunori

2012-06-26

Small interfering ribonucleic acid (siRNA) cancer therapies administered by intravenous injection require a delivery system for transport from the bloodstream into the cytoplasm of diseased cells to perform the function of gene silencing. Here we describe nanosized polymeric micelles that deliver siRNA to solid tumors and elicit a therapeutic effect. Stable multifunctional micelle structures on the order of 45 nm in size formed by spontaneous self-assembly of block copolymers with siRNA. Block copolymers used for micelle formation were designed and synthesized to contain three main features: a siRNA binding segment containing thiols, a hydrophilic nonbinding segment, and a cell-surface binding peptide. Specifically, poly(ethylene glycol)-block-poly(L-lysine) (PEG-b-PLL) comprising lysine amines modified with 2-iminothiolane (2IT) and the cyclo-Arg-Gly-Asp (cRGD) peptide on the PEG terminus was used. Modification of PEG-b-PLL with 2IT led to improved control of micelle formation and also increased stability in the blood compartment, while installation of the cRGD peptide improved biological activity. Incorporation of siRNA into stable micelle structures containing the cRGD peptide resulted in increased gene silencing ability, improved cell uptake, and broader subcellular distribution in vitro and also improved accumulation in both the tumor mass and tumor-associated blood vessels following intravenous injection into mice. Furthermore, stable and targeted micelles inhibited the growth of subcutaneous HeLa tumor models and demonstrated gene silencing in the tumor mass following treatment with antiangiogenic siRNAs. This new micellar nanomedicine could potentially expand the utility of siRNA-based therapies for cancer treatments that require intravenous injection.

Development and evaluation of vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate-mixed polymeric phospholipid micelles of berberine as an anticancer nanopharmaceutical

PubMed Central

Shen, Roger; Kim, Jane J; Yao, Mingyi; Elbayoumi, Tamer A

2016-01-01

Berberine (Brb) is an active alkaloid occurring in various common plant species, with well-recognized potential for cancer therapy. Brb not only augments the efficacy of antineoplastic chemotherapy and radiotherapy but also exhibits direct antimitotic and proapoptotic actions, along with distinct antiangiogenic and antimetastatic activities in a variety of tumors. Despite its low systemic toxicity, several pharmaceutical challenges limit the application of Brb in cancer therapy (ie, extremely low solubility and permeability, very poor pharmacokinetics (PKs), and oral bioavailability). Among lipid-based nanocarriers investigated recently for Brb, stealth amphiphilic micelles of polymeric phospholipid conjugates were studied here as a promising strategy to improve Brb delivery to tumors. Specifically, physicochemically stable micelles made of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (PEG-PE) mixed with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) (PEG-succinate ester of vitamin E), in a 3:1 M ratio, increased Brb solubilization by 300%. Our PEG-PE/TPGS-mixed micelles firmly retained the incorporated Brb, displaying extended-release profile in simulated media, with up to 30-fold projected improvement in simulated PKs of Brb. Owing to the markedly better uptake of Brb-containing mixed micelles in vitro, our Brb-mixed micelles nanoformulation significantly amplified apoptosis and overall cytotoxic effectiveness against monolayer and spheroid cultures of human prostate carcinomas (16- to 18-fold lower half-maximal inhibitory concentration values in PC3 and LNPaC, respectively), compared to free Brb. Mixed PEG-PE/TPGS micelles represent a promising delivery platform for the sparingly soluble anticancer agent, Brb, encouraging further pharmaceutical development of this drug for cancer therapy. PMID:27217747

Aripiprazole-Loaded Polymeric Micelles: Fabrication, Optimization and Evaluation using Response Surface Method.

PubMed

Patil, Payal Hasmukhlal; Wankhede, Pooja R; Mahajan, H S; Zawar, Laxmikant

2018-01-04

The fundamental objective of current study was to encapsulate Ari-piprazole (ARP) within Pluronic F127 micelles to improve its aqueous solubility. The recent patents on Ar-ipiprazole (JP2013136621) and micelles (WO2016004369A1) facilitated selection of drug and polymer. The drug-laden micelles were fabricated using thin-film hydration technique. Optimization of the micellar formulation was done by using response surface method (RSM). The Pluronic F127 concentration of 150 mg and 75 rpm rotational speed of rotary evaporator were found to be optimized conditions for formulating micelles. The prepared batches were further characterized for PDI (polydispersity index), zeta potential, % DLC (% Drug loading content), % EE (% Entrapment Efficiency) and % drug release study; results of these parameters were found to be 0.228, −4.04 mV and 76.50 % and 18.56 % respectively. It was observed from the In vitro release study that 97.37 ± 1.81 % drug had released from micelles after 20 hrs which were found about thrice as compared to that of pure drug. The optimized ARP micellar for-mulation was characterized using DSC (Differential Scanning Colorimetry), FT-IR (Fourier Trans-formed Infrared Spectroscopy), P-XRD (Powdered X-ray Diffraction Study) and TEM (Transmission Electronic Microscopy) studies. ARP-loaded micelles displayed a hydrodynamic diameter of 170.3 nm and a sphere-shaped morphology as determined by dynamic light scattering as well as TEM study. It is concluded that the prepared polymeric micellar system has an excellent potential to be used as a delivery carrier for Aripiprazole with increased solubility. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Self-assembly of BODIPY based pH-sensitive near-infrared polymeric micelles for drug controlled delivery and fluorescence imaging applications.

PubMed

Liu, Xiaodong; Chen, Bizheng; Li, Xiaojun; Zhang, Lifen; Xu, Yujie; Liu, Zhuang; Cheng, Zhenping; Zhu, Xiulin

2015-10-21

Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (∼7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells.

Micelles as Delivery Vehicles for Oligofluorene for Bioimaging

PubMed Central

Su, Fengyu; Alam, Ruhaniyah; Mei, Qian; Tian, Yanqing; Meldrum, Deirdre R.

2011-01-01

With the successful development of organic/polymeric light emitting diodes, many organic and polymeric fluorophores with high quantum efficiencies and optical stability were synthesized. However, most of these materials which have excellent optical properties are insoluble in water, limiting their applications in biological fields. Herein, we used micelles formed from an amino-group-containing poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL-b-PEG-NH2) to incorporate a hydrophobic blue emitter oligofluorene (OF) to enable its application in biological conditions. Although OF is completely insoluble in water, it was successfully transferred into aqueous solutions with a good retention of its photophysical properties. OF exhibited a high quantum efficiency of 0.84 in a typical organic solvent of tetrahydrofuran (THF). In addition, OF also showed a good quantum efficiency of 0.46 after being encapsulated into micelles. Two cells lines, human glioblastoma (U87MG) and esophagus premalignant (CP-A), were used to study the cellular internalization of the OF incorporated micelles. Results showed that the hydrophobic OF was located in the cytoplasm, which was confirmed by co-staining the cells with nucleic acid specific SYTO 9, lysosome specific LysoTracker Red®, and mitochondria specific MitoTracker Red. MTT assay indicated non-toxicity of the OF-incorporated micelles. This study will broaden the application of hydrophobic functional organic compounds, oligomers, and polymers with good optical properties to enable their applications in biological research fields. PMID:21915324

Micelles as delivery vehicles for oligofluorene for bioimaging.

PubMed

Su, Fengyu; Alam, Ruhaniyah; Mei, Qian; Tian, Yanqing; Meldrum, Deirdre R

2011-01-01

With the successful development of organic/polymeric light emitting diodes, many organic and polymeric fluorophores with high quantum efficiencies and optical stability were synthesized. However, most of these materials which have excellent optical properties are insoluble in water, limiting their applications in biological fields. Herein, we used micelles formed from an amino-group-containing poly(ε-caprolactone)-block-poly(ethylene glycol) (PCL-b-PEG-NH(2)) to incorporate a hydrophobic blue emitter oligofluorene (OF) to enable its application in biological conditions. Although OF is completely insoluble in water, it was successfully transferred into aqueous solutions with a good retention of its photophysical properties. OF exhibited a high quantum efficiency of 0.84 in a typical organic solvent of tetrahydrofuran (THF). In addition, OF also showed a good quantum efficiency of 0.46 after being encapsulated into micelles. Two cells lines, human glioblastoma (U87MG) and esophagus premalignant (CP-A), were used to study the cellular internalization of the OF incorporated micelles. Results showed that the hydrophobic OF was located in the cytoplasm, which was confirmed by co-staining the cells with nucleic acid specific SYTO 9, lysosome specific LysoTracker Red®, and mitochondria specific MitoTracker Red. MTT assay indicated non-toxicity of the OF-incorporated micelles. This study will broaden the application of hydrophobic functional organic compounds, oligomers, and polymers with good optical properties to enable their applications in biological research fields.

Preparation of thermo-responsive graft copolymer by using a novel macro-RAFT agent and its application for drug delivery.

PubMed

Song, Cunfeng; Yu, Shirong; Liu, Cheng; Deng, Yuanming; Xu, Yiting; Chen, Xiaoling; Dai, Lizong

2016-05-01

A methodology to prepare thermo-responsive graft copolymer by using a novel macro-RAFT agent was proposed. The macro-RAFT agent with pendant dithioester (ZC(S)SR) was facilely prepared via the combination of RAFT polymerization and esterification reaction. By means of ZC(S)SR-initiated RAFT polymerization, the thermo-responsive graft copolymer consisting of poly(methyl methacrylate-co-hydroxylethyl methacrylate) (P(MMA-co-HEMA)) backbone and hydrophilic poly(N-isopropylacrylamide) (PNIPAAm) side chains was constructed through the "grafting from" approach. The chemical compositions and molecular weight distributions of the synthesized polymers were respectively characterized by (1)H nuclear magnetic resonance ((1)H NMR) and gel permeation chromatography (GPC). Self-assembly behavior of the amphiphilic graft copolymers (P(MMA-co-HEMA)-g-PNIPAAm) was studied by transmission electron microscopy (TEM), dynamic light scattering (DLS) and spectrofluorimeter. The critical micelle concentration (CMC) value was 0.052 mg mL(-1). These micelles have thermo-responsibility and a low critical solution temperature (LCST) of 33.5°C. Further investigation indicated that the guest molecule release property of these micelles, which can be well described by a first-order kinetic model, was significantly affected by temperature. Besides, the micelles exhibited excellent biocompatibility and cellular uptake property. Hence, these micelles are considered to have potential application in controlled drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

Chemotherapeutic Effect of CD147 Antibody-labeled Micelles Encapsulating Doxorubicin Conjugate Targeting CD147-Expressing Carcinoma Cells.

PubMed

Asakura, Tadashi; Yokoyama, Masayuki; Shiraishi, Koichi; Aoki, Katsuhiko; Ohkawa, Kiyoshi

2018-03-01

CD147 (basigin/emmprin) is expressed on the surface of carcinoma cells. For studying the efficacy of CD147-targeting medicine on CD147-expressing cells, we studied the effect of anti-CD147-labeled polymeric micelles (CD147ab micelles) that encapsulated a conjugate of doxorubicin with glutathione (GSH-DXR), with specific accumulation and cytotoxicity against CD147-expressing A431 human epidermoid carcinoma cells, Ishikawa human endometrial adenocarcinoma cells, and PC3 human prostate carcinoma cells. By treatment of each cell type with CD147ab micelles for 1 h, a specific accumulation of CD147ab micelles in CD147-expressing cells was observed. In addition, the cytotoxicity of GSH-DXR-encapsulated micelles against each cell type was measured by treatment of the micelles for 1 h. The cytotoxic effect of CD147ab micelles carrying GSH-DXR was 3- to 10-fold higher for these cells than that of micelles without GSH-DXR. These results suggest that GSH-DXR-encapsulated CD147ab micelles could serve as an effective drug delivery system to CD147-expressing carcinoma cells. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Worm-like micelles of CTAB and sodium salicylate under turbulent flow.

PubMed

Rodrigues, Roberta K; da Silva, Marcelo A; Sabadini, Edvaldo

2008-12-16

Polymers with high molecular weight and worm-like micelles are drag-reducing agents under turbulent flow. However, in contrast to the polymeric systems, the worm-like micelles do not undergo mechanical degradation due to the turbulence, because their macromolecular structure can be spontaneously restored. This very favorable property, together with their drag-reduction capability, offer the possibility to use such worm-like micelles in heating and cooling systems to recirculate water while expending less energy. The formation, growth, and stability of worm-like micelles formed by cetyltrimethylammonium bromide (CTAB) and sodium salicylate (NaSal) were investigated using the self-fluorescence of salicylate ions and the ability of the giant micelles to promote hydrodynamic drag reduction under turbulent flow. The turbulence in solutions of CTAB-Sal was produced within the double-gap cell of a rotational rheometer. Detailed diagrams were obtained for different ratios of Sal and CTAB, which revealed transitions associated with the thermal stability of giant micelles under turbulent flow.

Novel biocompatible hydrogel nanoparticles: generation and size-tuning of nanoparticles by the formation of micelle templates obtained from thermo-responsive monomers mixtures

NASA Astrophysics Data System (ADS)

Khandadash, Raz; Machtey, Victoria; Shainer, Inbal; Gottlieb, Hugo E.; Gothilf, Yoav; Ebenstein, Yuval; Weiss, Aryeh; Byk, Gerardo

2014-12-01

Biocompatible hydrogel nanoparticles are prepared by polymerization and cross-linking of N-isopropyl acrylamide in a micelle template formed by block copolymers macro-monomers at high temperature. Different monomer ratios form, at high temperature, well-defined micelles of different sizes which are further polymerized leading to nanoparticles with varied sizes from 20 to 390 nm. Physico-chemical characterization of the nanoparticles demonstrates their composition and homogeneity. The NPs were tested in vitro and in vivo biocompatibility assays, and their lack of toxicity was proven. The NPs can be labeled with fluorescent probes, and their intracellular fate can be visualized and quantified using confocal microscopy. Their uptake by live stem cells and distribution in whole developing animals is reported. On the basis of our results, a mechanism of nanoparticle formation is suggested. The lack of toxicity makes these nanoparticles especially attractive for biological applications such as screening and bio-sensing.

Preparation and in vitro evaluation of folate-receptor-targeted SPION-polymer micelle hybrids for MRI contrast enhancement in cancer imaging

NASA Astrophysics Data System (ADS)

Mahajan, Shveta; Koul, Veena; Choudhary, Veena; Shishodia, Gauri; Bharti, Alok C.

2013-01-01

Polymer-SPION hybrids were investigated for receptor-mediated localization in tumour tissue. Superparamagnetic iron oxide nanoparticles (SPIONs) prepared by high-temperature decomposition of iron acetylacetonate were monodisperse (9.27 ± 3.37 nm), with high saturation magnetization of 76.8 emu g-1. Amphiphilic copolymers prepared from methyl methacrylate and PEG methacrylate by atom transfer radical polymerization were conjugated with folic acid (for folate-receptor specificity). The folate-conjugated polymer had a low critical micellar concentration (0.4 mg l-1), indicating stability of the micellar formulation. SPION-polymeric micelle clusters were prepared by desolvation of the SPION dispersion/polymer solution in water. Magnetic resonance imaging of the formulation revealed very good contrast enhancement, with transverse (T2) relaxivity of 260.4 mM-1 s-1. The biological evaluation of the SPION micelles included cellular viability assay (MTT) and uptake in HeLa cells. These studies demonstrated the potential use of these nanoplatforms for imaging and targeting.

Rifampicin-loaded 'flower-like' polymeric micelles for enhanced oral bioavailability in an extemporaneous liquid fixed-dose combination with isoniazid.

PubMed

Moretton, Marcela A; Hocht, Christian; Taira, Carlos; Sosnik, Alejandro

2014-08-01

Coadministration of rifampicin (RIF)/isoniazid (INH) is clinically recommended to improve the treatment of tuberculosis. Under gastric conditions, RIF undergoes fast hydrolysis (a pathway hastened by INH) and oral bioavailability loss. We aimed to assess the chemical stabilization and the oral pharmacokinetics of RIF nanoencapsulated within poly(ε-caprolactone)-b-PEG-b-poly(ε-caprolactone) 'flower-like' polymeric micelles. The chemical stability of RIF was evaluated in vitro under acid conditions with and without INH, and the oral pharmacokinetics of RIF-loaded micelles in rats was compared with those of a suspension coded by the US Pharmacopeia. Nanoencapsulation decreased the degradation rate of RIF with respect to the free drug. Moreover, in vivo data showed a statistically significant increase of RIF oral bioavailability (up to 3.3-times) with respect to the free drug in the presence of INH. Overall results highlight the potential of this nanotechnology platform to develop an extemporaneous liquid RIF/INH fixed-dose combination suitable for pediatric administration.

The role of non-covalent interactions in anticancer drug loading and kinetic stability of polymeric micelles.

PubMed

Yang, Chuan; Attia, Amalina B Ebrahim; Tan, Jeremy P K; Ke, Xiyu; Gao, Shujun; Hedrick, James L; Yang, Yi-Yan

2012-04-01

A new series of acid- and urea-functionalized polycarbonate block copolymers were synthesized via organocatalytic living ring-opening polymerization using methoxy poly(ethylene glycol) (PEG) as a macroinitiator to form micelles as drug delivery carriers. The micelles were characterized for critical micelle concentration, particle size and size distribution, kinetic stability and loading capacity for a model anticancer drug, doxorubicin (DOX) having an amine group. The acid/urea groups were placed in block forms (i.e. acid as the middle block or the end block) or randomly distributed in the polycarbonate block to investigate molecular structure effect. The micelles formed from the polymers in both random and block forms provided high drug loading capacity due to strong ionic interaction between the acid in the polymer and the amine in DOX. However, the polymers with acid and urea groups placed in the block forms formed micelles with wider size distribution (two size populations), and their DOX-loaded micelles were less stable. The number of acid/urea groups in the random form was further varied from 5 to 8, 13 and 19 to study its effects on self-assembly behaviors and DOX loading. An increased number of acid/urea groups yielded DOX-loaded micelles with smaller size and enhanced kinetic stability because of improved inter-molecular polycarbonate-polycarbonate (urea-urea and urea-acid) hydrogen-bonding and polycarbonate-DOX (acid-amine) ionic interactions. However, when the number of acid/urea groups was 13 or higher, micelles aggregated in a serum-containing medium, and freeze-dried DOX-loaded micelles were unable to re-disperse in an aqueous solution. Among all the polymers synthesized in this study, 1b with 8 acid/urea groups in the random form had the optimum properties. In vitro release studies showed that DOX release from 1b micelles was sustained over 7 h without significant initial burst release. MTT assays demonstrated that the polymer was not toxic towards HepG2 and HEK293 cells. Importantly, DOX-loaded micelles were potent against HepG2 cells with IC(50) of 0.26 mg/L, comparable to that of free DOX (IC(50): 0.20 mg/L). In addition, DOX-loaded 1b micelles yielded lower DOX content in the heart tissue of the tested mice as compared to free DOX formulation after i.v. injection. These findings signify that 1b micelles may be a promising carrier for delivery of anticancer drugs that contain amine groups. Copyright © 2011 Elsevier Ltd. All rights reserved.

Bioflavonoid Fisetin Loaded α-Tocopherol-Poly(lactic acid)-Based Polymeric Micelles for Enhanced Anticancer Efficacy in Breast Cancers.

PubMed

Wang, Lei; Zhang, De-Zhong; Wang, Yu-Xia

2017-02-01

In this study, tocopherol based polymeric micelles were successfully prepared to enhance the anticancer effect of fisetin (FIS) in breast cancer cells. The drug-loaded carrier was characterized in terms of physicochemical and in vivo parameters. Compared to FIS, FIS-TPN showed higher cellular uptake in MCF-7 breast cancer cells as revealed by CLSM and flow cytometry. The cytotoxicity assay results clearly showed that the free FIS and FIS-TPN exhibited a typical dose-dependent toxic effect in MCF-7 breast cancer cells. Especially, enhanced cytotoxic effect of FIS was observed when loaded in a nanocarrier. Free FIS induced a ~11% apoptosis whereas FIS-TPN induced a significantly greater apoptosis of ~20% by the end of 24 h. At 48 h, similar trend continued and free FIS showed ~30% of apoptosis whereas ~42% cell apoptosis was observed in FIS-TPN treated group. Notably, migration of cancer cell was significantly inhibited when treated with FIS-TPN formulations. The FIS-TPN significantly reduced to tumor burden and H&E staining showed the lowest tumor volume and higher cell apoptosis. All the findings suggest that the fisetin-loaded TPGS-PLA polymeric micelles serve as a potential candidate and promising alternative for the effective treatment of breast cancers.

In vivo pharmacokinetic studies and intracellular delivery of methotrexate by means of glycine-tethered PLGA-based polymeric micelles.

PubMed

Madhwi; Kumar, Rajendra; Kumar, Pramod; Singh, Bhupinder; Sharma, Gajanand; Katare, Om Prakash; Raza, Kaisar

2017-03-15

Methotrexate (MTX) is a widely used drug for the management of various kinds of cancers. However, numerous challenges are associated with MTX like poor aqueous solubility, dose-dependent side effects and poor-bioavailability. With an aim to explore the potential benefits in drug delivery of MTX, it was intended to fabricate glycine-PLGA-based polymeric micelles. Glycine was chemically linked to PLGA and the linkage was confirmed by FT-IR, and NMR-Spectroscopy. The developed polymeric micelles offered substantial loading to MTX with a pH-dependent drug release profile. The drug was released maximally at the cancer cell pH vis-à-vis blood plasma pH. The cytotoxicity of drug against MDA-MB-231 cell lines was enhanced by approx. 100% and the confocal laser scanning microscopy confirmed the localization of dye-tagged nanocarriers in the interiors of cancer cells. The bioavailable fraction of the drug was increased by approx. 4-folds, whereas elimination half-life was enhanced by around two-folds in Wistar rats. The novel approach offers a biodegradable and promising carrier for the better delivery of anticancer agents with immense promises of efficacy enhancement, improved delivery and better pharmacokinetic profile. Copyright © 2017 Elsevier B.V. All rights reserved.

Cellular uptake and intracellular trafficking of PEG-b-PLA polymeric micelles.

PubMed

Zhang, Zhen; Xiong, Xiaoqin; Wan, Jiangling; Xiao, Ling; Gan, Lu; Feng, Youmei; Xu, Huibi; Yang, Xiangliang

2012-10-01

Besides as an inert carrier for hydrophobic anticancer agents, polymeric micelles composed of di-block copolymer poly(ethylene glycol)-poly(lactic acid) (PEG-b-PLA) function as biological response modifiers including reversal of multidrug resistance in cancer. However, the uptake mechanisms and the subsequent intracellular trafficking remain to be elucidated. In this paper, we found that the uptake of PEG-b-PLA polymeric micelles incorporating nile red (M-NR) was significantly inhibited by both dynamin inhibitor dynasore and dynamin-2 dominant negative mutant (dynamin-2 K44A). Exogenously expressed caveolin-1 colocalized with M-NR and upregulated M-NR internalization in HepG2 cells expressing low level of endogenous caveolin-1, while caveolin-1 dominant negative mutant (caveolin-1 Y14F) significantly downregulated M-NR internalization in C6 cells expressing high level of endogenous caveolin-1. Exogenously expressed clathrin light chain A (clathrin LCa) did not mainly colocalize with the internalized M-NR and had no effect on M-NR uptake. These results suggested that dynamin- and caveolin-dependent but clathrin-independent endocytosis was involved in M-NR cellular uptake. We further found that M-NR colocalized with lysosome and microtubulin after internalization. Copyright © 2012 Elsevier Ltd. All rights reserved.

Amphiphilic multiarm star block copolymer-based multifunctional unimolecular micelles for cancer targeted drug delivery and MR imaging.

PubMed

Li, Xiaojie; Qian, Yinfeng; Liu, Tao; Hu, Xianglong; Zhang, Guoying; You, Yezi; Liu, Shiyong

2011-09-01

We report on the fabrication of multifunctional polymeric unimolecular micelles as an integrated platform for cancer targeted drug delivery and magnetic resonance imaging (MRI) contrast enhancement under in vitro and in vivo conditions. Starting from a fractionated fourth-generation hyperbranched polyester (Boltorn H40), the ring-opening polymerization of ɛ-caprolactone (CL) from the periphery of H40 and subsequent terminal group esterification with 2-bromoisobutyryl bromide afforded star copolymer-based atom transfer radical polymerization (ATRP) macroinitiator, H40-PCL-Br. Well-defined multiarm star block copolymers, H40-PCL-b-P(OEGMA-co-AzPMA), were then synthesized by the ATRP of oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) and 3-azidopropyl methacrylate (AzPMA). This was followed by the click reaction of H40-PCL-b-P(OEGMA-co-AzPMA) with alkynyl-functionalized cancer cell-targeting moieties, alkynyl-folate, and T(1)-type MRI contrast agents, alkynyl-DOTA-Gd (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakisacetic acid), affording H40-PCL-b-P(OEGMA-Gd-FA). In aqueous solution, the amphiphilic multiarm star block copolymer exists as structurally stable unimolecular micelles possessing a hyperbranched polyester core, a hydrophobic PCL inner layer, and a hydrophilic P(OEGMA-Gd-FA) outer corona. H40-PCL-b-P(OEGMA-Gd-FA) unimolecular micelles are capable of encapsulating paclitaxel, a well-known hydrophobic anticancer drug, with a loading content of 6.67 w/w% and exhibiting controlled release of up to 80% loaded drug over a time period of ∼120 h. In vitro MRI experiments demonstrated considerably enhanced T(1) relaxivity (18.14 s(-1) mM(-1)) for unimolecular micelles compared to 3.12 s(-1) mM(-1) for that of the small molecule counterpart, alkynyl-DOTA-Gd. Further experiments of in vivo MR imaging in rats revealed good accumulation of unimolecular micelles within rat liver and kidney, prominent positive contrast enhancement, and relatively long duration of blood circulation. The reported unimolecular micelles-based structurally stable nanocarriers synergistically integrated with cancer targeted drug delivery and controlled release and MR imaging functions augur well for their potential applications as theranostic systems. Copyright © 2011 Elsevier Ltd. All rights reserved.

pH-responsive unimolecular micelle-gold nanoparticles-drug nanohybrid system for cancer theranostics.

PubMed

Lin, Wenjing; Yao, Na; Qian, Long; Zhang, Xiaofang; Chen, Quan; Wang, Jufang; Zhang, Lijuan

2017-08-01

The development of an in situ formed pH-responsive theranostic nanocomposite for anticancer drug delivery and computed tomography (CT) imaging was reported. β-cyclodextrin-{poly(lactide)-poly(2-(dimethylamino) ethyl methacrylate)-poly[oligo(2-ethyl-2-oxazoline)methacrylate]} 21 [β-CD-(PLA-PDMAEMA-PEtOxMA) 21 ] unimolecular micelles served as a template for the in situ formation of gold nanoparticles (GNPs) and the subsequent encapsulation of doxorubicin (DOX). The formation of unimolecular micelles, microstructures and the distributions of GNPs and DOX were investigated through the combination of experiments and dissipative particle dynamics (DPD) simulations. β-CD-(PLA-PDMAEMA-PEtOxMA) 21 formed spherical unimolecular micelles in aqueous solution within a certain range of polymer concentrations. GNPs preferentially distributed in the PDMAEMA area. The maximum wavelength (λ max ) and the size of GNPs increased with increasing concentration of HAuCl 4 . DOX preferentially distributed in the PDMAEMA mesosphere, but penetrated the inner PLA core with increasing DOX concentration. DOX-loaded micelles with 41-61% entrapment efficiency showed fast release (88% after 102h) under acidic tumor conditions. Both in vitro and in vivo experiments revealed superior anticancer efficacy and effective CT imaging properties for β-CD-(PLA-PDMAEMA-PEtOxMA) 21 /Au/DOX. We conclude that the reported unimolecular micelles represent a class of versatile smart nanocarriers for theranostic application. Developing polymeric nanoplatforms as integrated theranostic vehicles for improving cancer diagnostics and therapy is an emerging field of much importance. This article aims to develop an in situ formed pH-responsive theranostic nanocomposite for anticancer drug delivery and computed tomography (CT) imaging. Specific emphases is on structure-properties relationship. There is a sea of literature on polymeric drug nanocarriers, and a couple of polymer-stabilized gold nanoparticles (GNPs) systems for cancer diagnosis are also known. However, to our knowledge, there has been no report on polymeric unimolecular micelles capable of dual loading of GNPs without external reducing agents and anticancer drugs for cancer diagnosis and treatment. To this end, the target of the current work was to develop an in situ formed nanocarrier, which actively dual wrapped CT contrast agent GNPs and hydrophobic anticancer drug doxorubicin (DOX), achieving high CT imaging and antitumor efficacy under in vitro and in vivo acid tumor condition. Meanwhile, by taking advantage of dissipative particle dynamics (DPD) simulation, we further obtained the formation process and mechanism of unimolecular micelles, and detailed distributions and microstructures of GNPs and DOX on unimolecular micelles. Taken together, our results here provide insight and guidance for the design of more effective nanocarriers for cancer theranostic application. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Biodegradable polymeric micelle-encapsulated doxorubicin suppresses tumor metastasis by killing circulating tumor cells

NASA Astrophysics Data System (ADS)

Deng, Senyi; Wu, Qinjie; Zhao, Yuwei; Zheng, Xin; Wu, Ni; Pang, Jing; Li, Xuejing; Bi, Cheng; Liu, Xinyu; Yang, Li; Liu, Lei; Su, Weijun; Wei, Yuquan; Gong, Changyang

2015-03-01

Circulating tumor cells (CTCs) play a crucial role in tumor metastasis, but it is rare for any chemotherapy regimen to focus on killing CTCs. Herein, we describe doxorubicin (Dox) micelles that showed anti-metastatic activity by killing CTCs. Dox micelles with a small particle size and high encapsulation efficiency were obtained using a pH-induced self-assembly method. Compared with free Dox, Dox micelles exhibited improved cytotoxicity, apoptosis induction, and cellular uptake. In addition, Dox micelles showed a sustained release behavior in vitro, and in a transgenic zebrafish model, Dox micelles exhibited a longer circulation time and lower extravasation from blood vessels into surrounding tissues. Anti-tumor and anti-metastatic activities of Dox micelles were investigated in transgenic zebrafish and mouse models. In transgenic zebrafish, Dox micelles inhibited tumor growth and prolonged the survival of tumor-bearing zebrafish. Furthermore, Dox micelles suppressed tumor metastasis by killing CTCs. In addition, improved anti-tumor and anti-metastatic activities were also confirmed in mouse tumor models, where immunofluorescent staining of tumors indicated that Dox micelles induced more apoptosis and showed fewer proliferation-positive cells. There were decreased side effects in transgenic zebrafish and mice after administration of Dox micelles. In conclusion, Dox micelles showed stronger anti-tumor and anti-metastatic activities and decreased side effects both in vitro and in vivo, which may have potential applications in cancer therapy.

A polymeric micelle magnetic resonance imaging (MRI) contrast agent reveals blood-brain barrier (BBB) permeability for macromolecules in cerebral ischemia-reperfusion injury.

PubMed

Shiraishi, Kouichi; Wang, Zuojun; Kokuryo, Daisuke; Aoki, Ichio; Yokoyama, Masayuki

2017-05-10

Blood-brain barrier (BBB) opening is a key phenomenon for understanding ischemia-reperfusion injuries that are directly linked to hemorrhagic transformation. The recombinant human tissue-type plasminogen activator (rtPA) increases the risk of symptomatic intracranial hemorrhages. Recent imaging technologies have advanced our understanding of pathological BBB disorders; however, an ongoing challenge in the pre-"rtPA treatment" stage is the task of developing a rigorous method for hemorrhage-risk assessments. Therefore, we examined a novel method for assessment of rtPA-extravasation through a hyper-permeable BBB. To examine the image diagnosis of rtPA-extravasation for a rat transient occlusion-reperfusion model, in this study we used a polymeric micelle MRI contrast-agent (Gd-micelles). Specifically, we used two MRI contrast agents at 1h after reperfusion. Gd-micelles provided very clear contrast images in 15.5±10.3% of the ischemic hemisphere at 30min after i.v. injection, whereas a classic gadolinium chelate MRI contrast agent provided no satisfactorily clear images. The obtained images indicate both the hyper-permeable BBB area for macromolecules and the distribution area of macromolecules in the ischemic hemisphere. Owing to their large molecular weight, Gd-micelles remained in the ischemic hemisphere through the hyper-permeable BBB. Our results indicate the feasibility of a novel clinical diagnosis for evaluating rtPA-related hemorrhage risks. Copyright © 2017 Elsevier B.V. All rights reserved.

Fluorescent polymeric assemblies as stimuli-responsive vehicles for drug controlled release and cell/tissue imaging

NASA Astrophysics Data System (ADS)

Chang, Ying; Li, Yang; Yu, Shirong; Mao, Jie; Liu, Cheng; Li, Qi; Yuan, Conghui; He, Ning; Luo, Weiang; Dai, Lizong

2015-01-01

Polymer assemblies with good biocompatibility, stimuli-responsive properties and clinical imaging capability are desirable carriers for future biomedical applications. Herein, we report on the synthesis of a novel anthracenecarboxaldehyde-decorated poly(N-(4-aminophenyl) methacryl amide-oligoethyleneglycolmonomethylether methacrylate) (P(MAAPAC-MAAP-MAPEG)) copolymer, comprising fluorescent chromophore and acid-labile moiety. This copolymer can assemble into micelles in aqueous solution and shows a spherical shape with well-defined particle size and narrow particle size distribution. The pH-responsive property of the micelles has been evaluated by the change of particle size and the controlled release of guest molecules. The intrinsic fluorescence property endows the micelles with excellent cell/tissue imaging capability. Cell viability evaluation with human hepatocellular carcinoma BEL-7402 cells demonstrates that the micelles are nontoxic. The cellular uptake of the micelles indicates a time-dependent behavior. The H22-tumor bearing mice treated with the micelles clearly exhibits the tumor accumulation. These multi-functional nanocarriers may be of great interest in the application of drug delivery.

Synergistic Combinations of Multiple Chemotherapeutic Agents in High Capacity Poly(2-oxazoline) Micelles

PubMed Central

Han, Yingchao; He, Zhijian; Schulz, Anita; Bronich, Tatiana K.; Jordan, Rainer; Luxenhofer, Robert; Kabanov, Alexander V.

2012-01-01

Many effective drugs for cancer treatment are poorly water-soluble. In combination chemotherapy, needed excipients in additive formulations are often toxic and restrict their applications in clinical intervention. Here, we report on amphiphilic poly(2-oxazoline)s (POx) micelles as a promising high capacity delivery platform for multi-drug cancer chemotherapy. A variety of binary and ternary drugs combinations of paclitaxel (PTX), docetaxel (DTX), 17-allylamino-17-demethoxygeldanamycin (17-AAG), etoposide (ETO) and bortezomib (BTZ) were solubilized in defined polymeric micelles achieving unprecedented high total loading capacities of up to 50 wt.% drug per final formulation. Multi-drug loaded POx micelles showed enhanced stability in comparison to single-drug loaded micelles. Drug ratio dependent synergistic cytotoxicity of micellar ETO/17-AAG was observed in MCF-7 cancer cells and of micellar BTZ/17-AAG in MCF-7, PC3, MDA-MB-231 and HepG2 cells. PMID:22681126

Therapeutic and scintigraphic applications of polymeric micelles: combination of chemotherapy and radiotherapy in hepatocellular carcinoma

PubMed Central

Shih, Ying-Hsia; Peng, Cheng-Liang; Chiang, Ping-Fang; Lin, Wuu-Jyh; Luo, Tsai-Yueh; Shieh, Ming-Jium

2015-01-01

This study evaluated a multifunctional micelle simultaneously loaded with doxorubicin (Dox) and labeled with radionuclide rhenium-188 (188Re) as a combined radiotherapy and chemotherapy treatment for hepatocellular carcinoma. We investigated the single photon emission computed tomography, biodistribution, antitumor efficacy, and pathology of 188Re-Dox micelles in a murine orthotopic luciferase-transfected BNL tumor cells hepatocellular carcinoma model. The single photon emission computed tomography and computed tomography images showed high radioactivity in the liver and tumor, which was in agreement with the biodistribution measured by γ-counting. In vivo bioluminescence images showed the smallest size tumor (P<0.05) in mice treated with the combined micelles throughout the experimental period. In addition, the combined 188Re-Dox micelles group had significantly longer survival compared with the control, 188ReO4 alone (P<0.005), and Dox micelles alone (P<0.01) groups. Pathohistological analysis revealed that tumors treated with 188Re-Dox micelles had more necrotic features and decreased cell proliferation. Therefore, 188Re-Dox micelles may enable combined radiotherapy and chemotherapy to maximize the effectiveness of treatment for hepatocellular carcinoma. PMID:26719687

Nano-sized Soluplus® polymeric micelles enhance the induction of tetanus toxin neutralising antibody response following transcutaneous immunisation with tetanus toxoid.

PubMed

Saydam, Manolya; Cheng, Woei Ping; Palmer, Nathan; Tierney, Robert; Francis, Robert; MacLellan-Gibson, Kirsty; Khan, Ambreen; Mawas, Fatme

2017-04-25

The use of Soluplus® polymeric micelles as a novel adjuvant for tetanus toxoid (TTxd) in transcutaneous immunisation was evaluated. TTxd was added to Soluplus® polymeric micelles to form TTxd-Soluplus® nano-aggregates with a size of 68nm. Non-adjuvanted TTxd commonly induces very poor antibody response by the transcutaneous route. However, in this study, the use of TTxd-Soluplus® resulted in a significant increase in the antibody response to TTxd, which was similar to that induced in the presence of CPG-oligodeoxynucleotides (CPG-ODNs) adjuvant. The toxin neutralising potency of the immune sera induced by TTxd-Soluplus® was also much stronger than that from TTxd alone, in a passive transfer experiment in mice. Soluplus® also enhanced the immunogenicity of the toxoid when TTxd-Soluplus® was stored at 4°C for 4weeks, but not at higher temperatures. Confocal microscopy imaging showed a much higher uptake of TTxd in the epidermis and dermis layers of the skin when it was associated with Soluplus®, suggesting that the mechanism for Soluplus® adjuvanticity is through enhanced uptake of the TTxd through the skin. Overall, our findings demonstrated that Soluplus® is an effective novel adjuvant for transcutaneous immunisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis of poly(N-isopropylacrylamide)-co-poly(phenylboronate ester) acrylate and study on their glucose-responsive behavior.

PubMed

Yao, Yuan; Shen, Heyun; Zhang, Guanghui; Yang, Jing; Jin, Xu

2014-10-01

We introduced thermo-sensitive poly(N-isopropylacrylamide) (PNIPAM) into the polymer structure of poly(ethylene glycol)-block-poly(phenylboronate ester) acrylate (MPEG-block-PPBDEMA) by block and random polymerization pathways in order to investigate the effect of polymer architecture on the glucose-responsiveness and enhance their insulin release controllability. By following the structure, the continuous PNIPAM shell of the triblock polymer MPEG-block-PNIPAM-block-PPBDEMA collapsing on the glucose-responsive PPBDEMA core formed the polymeric micelles with a core-shell-corona structure, and MPEG-block-(PNIPAM-rand-PPBDEMA) exhibited core-corona micelles in which the hydrophobic core consisted of PNIPAM and PPBDEMA segments when the environmental temperature was increased above low critical solution temperature (LCST) of PNIPAM. The micellar morphologies can be precisely controlled by temperature change between 15 and 37°C. As a result, the introduction of PNIPAM greatly enhanced the overall stability of insulin encapsulated in the polymeric micelles in the absence of glucose over incubation 80 h at 37°C. Comparing to MPEG-block-PNIPAM-block-PPBDEMA, the nanocarriers from MPEG-block-(PNIPAM-rand-PPBDEMA) showed great insulin release behavior which is zero insulin release without glucose, low release at normal blood glucose concentration (1.0 mg/mL). Therefore, these nanocarriers may be served as promising self-regulated insulin delivery system for diabetes treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of Micellization on the Adsorption Kinetics of Polymeric Surfactants to the Solid/Water Interface

NASA Astrophysics Data System (ADS)

Toomey, Ryan; Tirrell, Matthew

2002-03-01

We have studied the adsorption kinetics of two classes of hydrophobic/ionic diblock copolymer surfactants in aqueous environments to understand the role that micellization plays in the adsorption process. The two systems studied were poly(t-butyl styrene)-block-poly(styrene sulfonate) (PtBS-b-PSS) and polystyrene-block-poly(acrylic acid) (PS-b-PAA). It is found that by changing the hydrophobicity of the adsorbing surface, micelle adsorption can be turned on or off. When micelle adsorption occurs, the initial adsorption rate is always slower than the supply rate of micelles to the surface, indicating “reaction-limited” adsorption. Since these micelles have essentially frozen cores, the adsorption cannot be explained by the release of unimers from the micelles. Rather, micelles directly adsorb, and they have to overcome the potential barrier imposed by their corona. Due to micellization, the adsorption rate can also be a complex function of ionic strength. A regime was found where the initial adsorption rate decreased with increasing ionic strength. This anomaly can be explained by the onset of micellization. As the salt concentration is increased, more micelles are formed. However micelles adsorb roughly an order of magnitude slower than free chains. Therefore, if increasing the ionic strength produces more micelles, the adsorption rate will simultaneously decrease.

Improving anticancer activity and reducing systemic toxicity of doxorubicin by self-assembled polymeric micelles

NASA Astrophysics Data System (ADS)

Gou, MaLing; Shi, HuaShan; Guo, Gang; Men, Ke; Zhang, Juan; Zheng, Lan; Li, ZhiYong; Luo, Feng; Qian, ZhiYong; Zhao, Xia; Wei, YuQuan

2011-03-01

In an attempt to improve anticancer activity and reduce systemic toxicity of doxorubicin (Dox), we encapsulated Dox in monomethoxy poly(ethylene glycol)-poly(ɛ-caprolactone) (MPEG-PCL) micelles by a novel self-assembly procedure without using surfactants, organic solvents or vigorous stirring. These Dox encapsulated MPEG-PCL (Dox/MPEG-PCL) micelles with drug loading of 4.2% were monodisperse and ~ 20 nm in diameter. The Dox can be released from the Dox/MPEG-PCL micelles; the Dox-release at pH 5.5 was faster than that at pH 7.0. Encapsulation of Dox in MPEG-PCL micelles enhanced the cellular uptake and cytotoxicity of Dox on the C-26 colon carcinoma cell in vitro, and slowed the extravasation of Dox in the transgenic zebrafish model. Compared to free Dox, Dox/MPEG-PCL micelles were more effective in inhibiting tumor growth in the subcutaneous C-26 colon carcinoma and Lewis lung carcinoma models, and prolonging survival of mice bearing these tumors. Dox/MPEG-PCL micelles also induced lower systemic toxicity than free Dox. In conclusion, incorporation of Dox in MPEG-PCL micelles enhanced the anticancer activity and decreased the systemic toxicity of Dox; these Dox/MPEG-PCL micelles are an interesting formulation of Dox and may have potential clinical applications in cancer therapy.

Preparation and evaluation of novel mixed micelles as nanocarriers for intravenous delivery of propofol

NASA Astrophysics Data System (ADS)

Li, Xinru; Zhang, Yanhui; Fan, Yating; Zhou, Yanxia; Wang, Xiaoning; Fan, Chao; Liu, Yan; Zhang, Qiang

2011-12-01

Novel mixed polymeric micelles formed from biocompatible polymers, poly(ethylene glycol)-poly(lactide) (mPEG-PLA) and polyoxyethylene-660-12-hydroxy stearate (Solutol HS15), were fabricated and used as a nanocarrier for solubilizing poorly soluble anesthetic drug propofol. The solubilization of propofol by the mixed micelles was more efficient than those made of mPEG-PLA alone. Micelles with the optimized composition of mPEG-PLA/Solutol HS15/propofol = 10/1/5 by weight had particle size of about 101 nm with narrow distribution (polydispersity index of about 0.12). Stability analysis of the mixed micelles in bovine serum albumin (BSA) solution indicated that the diblock copolymer mPEG efficiently protected the BSA adsorption on the mixed micelles because the hydrophobic groups of the copolymer were efficiently screened by mPEG, and propofol-loaded mixed micelles were stable upon storage for at least 6 months. The content of free propofol in the aqueous phase for mixed micelles was lower by 74% than that for the commercial lipid emulsion. No significant differences in times to unconsciousness and recovery of righting reflex were observed between mixed micelles and commercial lipid formulation. The pharmacological effect may serve as pharmaceutical nanocarriers with improved solubilization capacity for poorly soluble drugs.

Intravitreal injection of rapamycin-loaded polymeric micelles for inhibition of ocular inflammation in rat model.

PubMed

Wu, Wei; He, Zhifen; Zhang, Zhaoliang; Yu, Xinxin; Song, Zongming; Li, Xingyi

2016-11-20

The therapeutic efficacy of rapamycin conjugated monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles (rapamycin micelles) was evaluated in a rat experimental autoimmune uveitis (EAU) model. Rapamycin micelles exhibited spherical morphology and had a mean particle size of 40nm and a zeta-potential of -0.89mv. The water solubility of rapamycin improved by more than 1000-fold in a micellar formulation. Intravitreal injection of MPEG-PCL micelles did not result in vitreous hemorrhage or retinal detachment. Fluorescence microscopy demonstrated that labeled micelles localized to the retinal pigment epithelium for at least 14 days following injection and the drug concentration of rapamycin micelles in the retinal tissue was significantly higher than unconjugated rapamycin over this period. At the optimal concentration of rapamycin micelles (9μg/eye), clinical signs of EAU were abolished via the downregulation of the Th1 and Th17 response. There were no significant difference in T cell proliferation and delayed-type hypersensitivity between the treatment and control groups, suggesting that the therapeutic effect of rapamycin manifested locally in the eye and not systemically. These results indicate that intravitreal injection of rapamycin micelles is a promising therapy for controlling sterile intraocular inflammation. Copyright © 2016 Elsevier B.V. All rights reserved.

Glucose-installed, SPIO-loaded PEG- b-PCL micelles as MR contrast agents to target prostate cancer cells

NASA Astrophysics Data System (ADS)

Theerasilp, Man; Sunintaboon, Panya; Sungkarat, Witaya; Nasongkla, Norased

2017-11-01

Polymeric micelles of poly(ethylene glycol)- block-poly(ɛ-caprolactone) bearing glucose analog encapsulated with superparamagnetic iron oxide nanoparticles (Glu-SPIO micelles) were synthesized as an MRI contrast agent to target cancer cells based on high-glucose metabolism. Compared to SPIO micelles (non-targeting SPIO micelles), Glu-SPIO micelles demonstrated higher toxicity to human prostate cancer cell lines (PC-3) at high concentration. Atomic absorption spectroscopy was used to determine the amount of iron in cells. It was found that the iron in cancer cells treated by Glu-SPIO micelles were 27-fold higher than cancer cells treated by SPIO micelles at the iron concentration of 25 ppm and fivefold at the iron concentration of 100 ppm. To implement Glu-SPIO micelles as a MR contrast agent, the 3-T clinical MRI was applied to determine transverse relaxivities ( r 2*) and relaxation rate (1/ T 2*) values. In vitro MRI showed different MRI signal from cancer cells after cellular uptake of SPIO micelles and Glu-SPIO micelles. Glu-SPIO micelles was highly sensitive with the r 2* in agarose gel at 155 mM-1 s-1. Moreover, the higher 1/ T 2* value was found for cancer cells treated with Glu-SPIO micelles. These results supported that glucose ligand increased the cellular uptake of micelles by PC-3 cells with over-expressing glucose transporter on the cell membrane. Thus, glucose can be used as a small molecule ligand for targeting prostate cancer cells overexpressing glucose transporter.

Glutathione-responsive core cross-linked micelles for controlled cabazitaxel delivery

NASA Astrophysics Data System (ADS)

Han, Xiaoxiong; Gong, Feirong; Sun, Jing; Li, Yueqi; Liu, XiaoFei; Chen, Dan; Liu, Jianwen; Shen, Yaling

2018-02-01

Stimulus-responsive polymeric micelles (PMs) have recently received attention due to the controlled delivery of drug or gene for application in cancer diagnosis and treatment. In this work, novel glutathione-responsive PMs were prepared to encapsulate hydrophobic antineoplastic drug, cabazitaxel (CTX), to improve its solubility and toxicity. These CTX-loaded micelles core cross-linked by disulfide bonds (DCL-CTX micelles) were prepared by a novel copolymer, lipoic acid grafted mPEG-PLA. These micelles had regular spherical shape, homogeneous diameter of 18.97 ± 0.23 nm, and a narrow size distribution. The DCL-CTX micelles showed high encapsulation efficiency of 98.65 ± 1.77%, and the aqueous solubility of CTX was improved by a factor of 1:1200. In vitro release investigation showed that DCL-CTX micelles were stable in the medium without glutathione (GSH), whereas the micelles had burst CTX release in the medium with 10 mM GSH. Cell uptake results implied that DCL-CTX micelles were internalized into MCF-7 cells through clathrin-mediated endocytosis and released cargo more effectively than Jevtana (commercially available CTX) owing to GSH-stimulated degradation. In MTT assay against MCF-7 cells, these micelles inhibited tumor cell proliferation more effectively than Jevtana due to their GSH-responsive CTX release. All results revealed the potency of GSH-responsive DCL-CTX micelles for stable delivery in blood circulation and for intracellular GSH-trigged release of CTX. Therefore, DCL-CTX micelles show potential as safe and effective CTX delivery carriers and as a cancer chemotherapy formulation.

Polymeric micelle assembly for the smart synthesis of mesoporous platinum nanospheres with tunable pore sizes.

PubMed

Li, Yunqi; Bastakoti, Bishnu Prasad; Malgras, Victor; Li, Cuiling; Tang, Jing; Kim, Jung Ho; Yamauchi, Yusuke

2015-09-14

A facile method for the fabrication of well-dispersed mesoporous Pt nanospheres involves the use of a polymeric micelle assembly. A core-shell-corona type triblock copolymer [poly(styrene-b-2-vinylpyridine-b-ethylene oxide), PS-b-P2VP-b-PEO] is employed as the pore-directing agent. Negatively charged PtCl4 (2-) ions preferably interact with the protonated P2VP(+) blocks while the free PEO chains prevent the aggregation of the Pt nanospheres. The size of the mesopores can be finely tuned by varying the length of the PS chain. Furthermore, it is demonstrated that the metallic mesoporous nanospheres thus obtained are promising candidates for applications in electrochemistry. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Passive targeting of thermosensitive diblock copolymer micelles to the lungs: synthesis and characterization of poly(N-isopropylacrylamide)-block-poly(ε-caprolactone).

PubMed

Lee, Ren-Shen; Lin, Chih-Hung; Aljuffali, Ibrahim A; Hu, Kai-Yin; Fang, Jia-You

2015-06-18

Amphiphilic poly(N-isopropylacrylamide)-block-poly(ε-caprolactone) (PNiPAAm-b-PCL) copolymers were synthesized by ring-opening polymerization to form thermosensitive micelles as nanocarriers for bioimaging and carboplatin delivery. The critical micelle concentration increased from 1.8 to 3.5 mg/l following the decrease of the PNiPAAm chain length. The copolymers revealed a lower critical solution temperature (LCST) between 33 and 40°C. The copolymers self-assembled to form spherical particles of 146-199 nm in diameter. Carboplatin in micelles exhibited a slower release at 37°C relative to that at 25°C due to the gel layer formation on the micellar shell above the LCST. The micelles containing dye or carboplatin were intravenously injected into the rats for in vivo bioimaging and drug biodistribution. The bioimaging profiles showed a significant accumulation of micelles in the lungs. The micelles could minimize the reticuloendothelial system (RES) recognition of the dye. In vivo biodistribution demonstrated an improved pulmonary accumulation of carboplatin from 2.5 to 3.4 μg/mg by the micelles as compared to the control solution. Carboplatin accumulation in the heart and kidneys was reduced after encapsulation by the micelles. This study supports the potential of PNiPAAm-b-PCL micelles to passively target the lungs and attenuate RES uptake and possible side effects.

Solubilization of docetaxel in poly(ethylene oxide)-block-poly(butylene/styrene oxide) micelles.

PubMed

Elsabahy, Mahmoud; Perron, Marie-Eve; Bertrand, Nicolas; Yu, Ga-Er; Leroux, Jean-Christophe

2007-07-01

Poly(ethylene oxide)-block-poly(styrene oxide) (PEO-b-PSO) and PEO-b-poly(butylene oxide) (PEO-b-PBO) of different chain lengths were synthesized and characterized for their self-assembling properties in water by dynamic/static light scattering, spectrofluorimetry, and transmission electron microscopy. The resulting polymeric micelles were evaluated for their ability to solubilize and protect the anticancer drug docetaxel (DCTX) from degradation. The drug release kinetics as well as the cytotoxicity of the loaded micelles were assessed in vitro. All polymers formed micelles with a highly viscous core at low critical association concentrations (<10 mg/L). Micelle morphology depended on the nature of the hydrophobic block, with PBO- and PSO-based micelles yielding monodisperse spherical and cylindrical nanosized aggregates, respectively. The maximum solubilization capacity for DCTX ranged from 0.7 to 4.2% and was the highest for PSO micelles exhibiting the longest hydrophobic segment. Despite their high affinity for DCTX, PEO-b-PSO micelles were not able to efficiently protect DCTX against hydrolysis under accelerated stability testing conditions. Only PEO-b-PBO bearing 24 BO units afforded significant protection against degradation. In vitro, DCTX was released slower from the latter micelles, but all formulations possessed a similar cytotoxic effect against PC-3 prostate cancer cells. These data suggest that PEO-b-P(SO/BO) micelles could be used as alternatives to conventional surfactants for the solubilization of taxanes.

Sugar-based amphiphilic polymers for biomedical applications: from nanocarriers to therapeutics.

PubMed

Gu, Li; Faig, Allison; Abdelhamid, Dalia; Uhrich, Kathryn

2014-10-21

Various therapeutics exhibit unfavorable physicochemical properties or stability issues that reduce their in vivo efficacy. Therefore, carriers able to overcome such challenges and deliver therapeutics to specific in vivo target sites are critically needed. For instance, anticancer drugs are hydrophobic and require carriers to solubilize them in aqueous environments, and gene-based therapies (e.g., siRNA or pDNA) require carriers to protect the anionic genes from enzymatic degradation during systemic circulation. Polymeric micelles, which are self-assemblies of amphiphilic polymers (APs), constitute one delivery vehicle class that has been investigated for many biomedical applications. Having a hydrophobic core and a hydrophilic shell, polymeric micelles have been used as drug carriers. While traditional APs are typically comprised of nondegradable block copolymers, sugar-based amphiphilic polymers (SBAPs) synthesized by us are comprised of branched, sugar-based hydrophobic segments and a hydrophilic poly(ethylene glycol) chain. Similar to many amphiphilic polymers, SBAPs self-assemble into polymeric micelles. These nanoscale micelles have extremely low critical micelle concentrations offering stability against dilution, which occurs with systemic administration. In this Account, we illustrate applications of SBAPs for anticancer drug delivery via physical encapsulation within SBAP micelles and chemical conjugation to form SBAP prodrugs capable of micellization. Additionally, we show that SBAPs are excellent at stabilizing liposomal delivery systems. These SBAP-lipid complexes were developed to deliver hydrophobic anticancer therapeutics, achieving preferential uptake in cancer cells over normal cells. Furthermore, these complexes can be designed to electrostatically complex with gene therapies capable of transfection. Aside from serving as a nanocarrier, SBAPs have also demonstrated unique bioactivity in managing atherosclerosis, a major cause of cardiovascular disease. The atherosclerotic cascade is usually triggered by the unregulated uptake of oxidized low-density lipoprotein, a cholesterol carrier, in macrophages of the blood vessel wall; SBAPs can significantly inhibit oxidized low-density lipoprotein uptake in macrophages and abrogate the atherosclerotic cascade. By modification of various functionalities (e.g., branching, stereochemistry, hydrophobicity, and charge) in the SBAP chemical structure, SBAP bioactivity was optimized, and influential structural components were identified. Despite the potential of SBAPs as atherosclerotic therapies, blood stability of the SBAP micelles was not ideal for in vivo applications, and means to stabilize them were pursued. Using kinetic entrapment via flash nanoprecipitation, SBAPs were formulated into nanoparticles with a hydrophobic solute core and SBAP shell. SBAP nanoparticles exhibited excellent physiological stability and enhanced bioactivity compared with SBAP micelles. Further, this method enables encapsulation of additional hydrophobic drugs (e.g., vitamin E) to yield a stable formulation that releases two bioactives. Both as nanoscale carriers and as polymer therapeutics, SBAPs are promising biomaterials for medical applications.

Self-assembly of BODIPY based pH-sensitive near-infrared polymeric micelles for drug controlled delivery and fluorescence imaging applications

NASA Astrophysics Data System (ADS)

Liu, Xiaodong; Chen, Bizheng; Li, Xiaojun; Zhang, Lifen; Xu, Yujie; Liu, Zhuang; Cheng, Zhenping; Zhu, Xiulin

2015-10-01

Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (~7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells.Responsive block copolymer micelles emerging as promising imaging and drug delivery systems show high stability and on-demand drug release activities. Herein, we developed self-assembled pH-responsive NIR emission micelles entrapped with doxorubicin (DOX) within the cores by the electrostatic interactions for fluorescence imaging and chemotherapy applications. The block copolymer, poly(methacrylic acid)-block-poly[(poly(ethylene glycol) methyl ether methacrylate)-co-boron dipyrromethene derivatives] (PMAA-b-P(PEGMA-co-BODIPY)), was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, and the molecular weight distribution of this copolymer was narrow (Mw/Mn = 1.31). The NIR fluorescence enhancement induced by the phenol/phenolate interconversion equilibrium works as a switch in response to the intracellular pH fluctuations. DOX-loaded PMAA-b-P(PEGMA-co-BODIPY) micelles can detect the physiological pH fluctuations with a pKa near physiological conditions (~7.52), and showed pH-responsive collapse and an obvious acid promoted anticancer drug release behavior (over 58.8-62.8% in 10 h). Real-time imaging of intracellular pH variations was performed and a significant chemotherapy effect was demonstrated against HeLa cells. Electronic supplementary information (ESI) available: GPC, UV/vis, fluorescence, and MTT data of the as-prepared polymers; 1H NMR, 13C NMR, HRMS and FT-IR of organic molecules and polymers. See DOI: 10.1039/c5nr04655f

pH-responsive polymeric micelles of poly(ethylene glycol)-b-poly(alkyl(meth)acrylate-co-methacrylic acid): influence of the copolymer composition on self-assembling properties and release of candesartan cilexetil.

PubMed

Satturwar, Prashant; Eddine, Mohamad Nasser; Ravenelle, François; Leroux, Jean-Christophe

2007-03-01

The objective of the present study was to investigate the influence of chemical structure and molecular weight of pH-sensitive block copolymers on their self-assembling properties, the loading and the release of candesartan cilexetil (CDN). Block copolymers of poly(ethylene glycol) and t-butyl methacrylate, iso-butyl acrylate, n-butyl acrylate or propyl methacrylate were synthesized by atom transfer radical polymerization. pH-sensitivity was obtained by hydrolysis of t-butyl groups. The poorly water-soluble drug CDN was incorporated in the micelles and the in vitro drug release was evaluated as a function of pH. The critical aggregation concentration of hydrolyzed copolymers (pK(a)=6.2-6.6) was higher compared to the unhydrolyzed ones. Dynamic light scattering studies and atomic force microscopy images revealed uniform size micelles with aggregation numbers ranging from 60 to 160. The entrapment efficiency of CDN was generally found to be above 90%, with drug loading levels reaching approximately 20% (w/w). Differential scanning calorimetry studies showed the amorphous nature of entrapped CDN. The release of CDN from pH-sensitive micelles was triggered upon an increase in pH from 1.2 to 7.2. These findings suggest that the PEG-b-poly(alkyl(meth)acrylate-co-methacrylic acid)s can self-assemble to form micelles which exhibit high loading capacities for CDN and release the drug in a pH-dependent fashion.

A stapled peptide antagonist of MDM2 carried by polymeric micelles sensitizes glioblastoma to temozolomide treatment through p53 activation

PubMed Central

Chen, Xishan; Tai, Lingyu; Gao, Jie; Qian, Jianchang; Zhang, Mingfei; Li, Beibei; Xie, Cao; Lu, Linwei; Lu, Wuyuan; Lu, Weiyue

2017-01-01

Antagonizing MDM2 and MDMX to activate the tumor suppressor protein p53 is an attractive therapeutic paradigm for the treatment of glioblastoma multiforme (GBM). However, challenges remain with respect to the poor ability of p53 activators to efficiently cross the blood–brain barrier and/or blood–brain tumor barrier and to specifically target tumor cells. To circumvent these problems, we developed a cyclic RGD peptide-conjugated poly(-ethylene glycol)-co-poly(lactic acid) polymeric micelle (RGD-M) that carried a stapled peptide antagonist of both MDM2 and MDMX (sPMI). The peptide-carrying micelle RGD-M/sPMI was prepared via film-hydration method with high encapsulation efficiency and loading capacity as well as ideal size distribution. Micelle encapsulation dramatically increased the solubility of sPMI, thus alleviating its serum sequestration. In vitro studies showed that RGD-M/sPMI efficiently inhibited the proliferation of glioma cells in the presence of serum by activating the p53 signaling pathway. Further, RGD-M/sPMI exerted potent tumor growth inhibitory activity against human glioblastoma in nude mouse xenograft models. Importantly, the combination of RGD-M/sPMI and temozolomide — a standard chemotherapy drug for GBM increased antitumor efficacy against glioblastoma in experimental animals. Our results validate a combination therapy using p53 activators with temozolomide as a more effective treatment for GBM. PMID:26428461

Dynamics of micelle-nanoparticle systems undergoing shear. A coarse-grained molecular dynamics approach

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rolfe, Bryan A.; Chun, Jaehun; Joo, Yong L.

2013-09-05

Recent experimental work has shown that polymeric micelles can template nanoparticles via interstitial sites in shear-ordered micelle solutions. In the current study, we report simulation results based on a coarse-grained molecular dynamics (CGMD) model of a solvent/polymer/nanoparticle system. Our results demonstrate the importance of polymer concentration and the micelle corona length in 2D shear-ordering of neat block copolymer solutions. Although our results do not show strong 3D ordering during shear, we find that cessation of shear allows the system to relax into a 3D configuration of greater order than without shear. It is further shown that this post-shear relaxation ismore » strongly dependent on the length of the micelle corona. For the first time, we demonstrate the presence and importance of a flow disturbance surrounding micelles in simple shear flow at moderate Péclet numbers. This disturbance is similar to what is observed around simulated star polymers and ellipsoids. The extent of the flow disturbance increases as expected with a longer micelle corona length. It is further suggested that without proper consideration of these dynamics, a stable nanoparticle configuration would be difficult to obtain.« less

Dual pH-sensitive supramolecular micelles from star-shaped PDMAEMA based on β-cyclodextrin for drug release.

PubMed

Zhou, Zaishuai; Guo, Feng; Wang, Nairong; Meng, Meng; Li, Guiying

2018-05-23

Star-shaped poly(2-(dimethylamino)ethyl methacrylate) based on β-cyclodextrin (β-CD-(PDMAEMA) 7 ) was synthesized by means of atomic transfer radical polymerization (ATRP). Dual pH-sensitive supramolecular micelles were formed from β-CD-(PDMAEMA) 7 and benzimidazole modified poly(ε-caprolactone) (BM-PCL) through the host-guest interactions between β-CD and benzimidazole. The supramolecular micelles have regular spherical structure with hydrophobic β-CD/BM-PCL as the core and pH-sensitive PDMAEMA as the shell. The hydrophobic PCL as well as the hydrophobic cavity of β-CD can efficiently encapsulate doxorubicin (DOX) with the drug-loading content and entrapment efficiency up to 40% and 86%. The drug release from micelles accelerated when the pH decreased from 7.0 to 2.0 and the temperature increased from 25 °C to 45 °C. MTT assay showed that drug loaded supramolecular micelles exhibited excellent anti-cancer activity than free DOX. These supramolecular micelles have promising potential applications as intelligent nanocarriers in drug delivery system. Copyright © 2018 Elsevier B.V. All rights reserved.

Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo.

PubMed

Yang, Xi; Li, Zhaojun; Wang, Ning; Li, Ling; Song, Linjiang; He, Tao; Sun, Lu; Wang, Zhihan; Wu, Qinjie; Luo, Na; Yi, Cheng; Gong, Changyang

2015-05-18

To develop injectable formulation and improve the stability of curcumin (Cur), Cur was encapsulated into monomethyl poly (ethylene glycol)-poly (ε-caprolactone)-poly (trimethylene carbonate) (MPEG-P(CL-co-TMC)) micelles through a single-step solid dispersion method. The obtained Cur micelles had a small particle size of 27.6 ± 0.7 nm with polydisperse index (PDI) of 0.11 ± 0.05, drug loading of 14.07 ± 0.94%, and encapsulation efficiency of 96.08 ± 3.23%. Both free Cur and Cur micelles efficiently suppressed growth of CT26 colon carcinoma cells in vitro. The results of in vitro anticancer studies confirmed that apoptosis induction and cellular uptake on CT26 cells had completely increased in Cur micelles compared with free Cur. Besides, Cur micelles were more effective in suppressing the tumor growth of subcutaneous CT26 colon in vivo, and the mechanisms included the inhibition of tumor proliferation and angiogenesis and increased apoptosis of tumor cells. Furthermore, few side effects were found in Cur micelles. Overall, our findings suggested that Cur micelles could be a stabilized aqueous formulation for intravenous application with improved antitumor activity, which may be a potential treatment strategy for colon cancer in the future.

Bioinspired Coordination Micelles Integrating High Stability, Triggered Cargo Release, and Magnetic Resonance Imaging.

PubMed

Xin, Keting; Li, Man; Lu, Di; Meng, Xuan; Deng, Jun; Kong, Deling; Ding, Dan; Wang, Zheng; Zhao, Yanjun

2017-01-11

Catechol-Fe 3+ coordinated micelles show the potential for achieving on-demand drug delivery and magnetic resonance imaging in a single nanoplatform. Herein, we developed bioinspired coordination-cross-linked amphiphilic polymeric micelles loaded with a model anticancer agent, doxorubicin (Dox). The nanoscale micelles could tolerate substantial dilution to a condition below the critical micelle concentration (9.4 ± 0.3 μg/mL) without sacrificing the nanocarrier integrity due to the catechol-Fe 3+ coordinated core cross-linking. Under acidic conditions (pH 5.0), the release rate of Dox was significantly faster compared to that at pH 7.4 as a consequence of coordination collapse and particle de-cross-linking. The cell viability study in 4T1 cells showed no toxicity regarding placebo cross-linked micelles. The micelles with improved stability showed a dramatically increased Dox accumulation in tumors and hence the enhanced suppression of tumor growth in a 4T1 tumor-bearing mouse model. The presence of Fe 3+ endowed the micelles T 1 -weighted MRI capability both in vitro and in vivo without the incorporation of traditional toxic paramagnetic contrast agents. The current work presented a simple "three birds with one stone" approach to engineer the robust theranostic nanomedicine platform.

Synthesis of amphiphilic tadpole-shaped linear-cyclic diblock copolymers via ring-opening polymerization directly initiating from cyclic precursors and their application as drug nanocarriers.

PubMed

Wan, Xuejuan; Liu, Tao; Liu, Shiyong

2011-04-11

We report on the facile synthesis of well-defined amphiphilic and thermoresponsive tadpole-shaped linear-cyclic diblock copolymers via ring-opening polymerization (ROP) directly initiating from cyclic precursors, their self-assembling behavior in aqueous solution, and the application of micellar assemblies as controlled release drug nanocarriers. Starting from a trifunctional core molecule containing alkynyl, hydroxyl, and bromine moieties, alkynyl-(OH)-Br, macrocyclic poly(N-isopropylacrylamide) (c-PNIPAM) bearing a single hydroxyl functionality was prepared by atom transfer radical polymerization (ATRP), the subsequent end group transformation into azide functionality, and finally the intramacromolecular ring closure reaction via click chemistry. The target amphiphilic tadpole-shaped linear-cyclic diblock copolymer, (c-PNIPAM)-b-PCL, was then synthesized via the ROP of ε-caprolactone (CL) by directly initiating from the cyclic precursor. In aqueous solution at 20 °C, (c-PNIPAM)-b-PCL self-assembles into spherical micelles consisting of hydrophobic PCL cores and well-solvated coronas of cyclic PNIPAM segments. For comparison, linear diblock copolymer with comparable molecular weight and composition, (l-PNIPAM)-b-PCL, was also synthesized. It was found that the thermoresponsive coronas of micelles self-assembled from (c-PNIPAM)-b-PCL exhibit thermoinduced collapse and aggregation at a lower critical thermal phase transition temperature (T(c)) compared with those of (l-PNIPAM)-b-PCL. Temperature-dependent drug release profiles from the two types of micelles of (c-PNIPAM)-b-PCL and (l-PNIPAM)-b-PCL loaded with doxorubicin (Dox) were measured, and the underlying mechanism for the observed difference in releasing properties was proposed. Moreover, MTT assays revealed that micelles of (c-PNIPAM)-b-PCL are almost noncytotoxic up to a concentration of 1.0 g/L, whereas at the same polymer concentration, micelles loaded with Dox lead to ∼60% cell death. Overall, chain topologies of thermoresponsive block copolymers, that is, (c-PNIPAM)-b-PCL versus (l-PNIPAM)-b-PCL, play considerable effects on the self-assembling and thermal phase transition properties and their functions as controlled release drug nanocarriers.

Novel micelle formulation of curcumin for enhancing antitumor activity and inhibiting colorectal cancer stem cells

PubMed Central

Wang, Ke; Zhang, Tao; Liu, Lina; Wang, Xiaolei; Wu, Ping; Chen, Zhigang; Ni, Chao; Zhang, Junshu; Hu, Fuqiang; Huang, Jian

2012-01-01

Background and methods: Curcumin has extraordinary anticancer properties but has limited use due to its insolubility in water and instability, which leads to low systemic bioavailability. We have developed a novel nanoparticulate formulation of curcumin encapsulated in stearic acid-g-chitosan oligosaccharide (CSO-SA) polymeric micelles to overcome these hurdles. Results: The synthesized CSO-SA copolymer was able to self-assemble to form nanoscale micelles in aqueous medium. The mean diameter of the curcumin-loaded CSO-SA micelles was 114.7 nm and their mean surface potential was 18.5 mV. Curcumin-loaded CSO-SA micelles showed excellent internalization ability that increased curcumin accumulation in cancer cells. Curcumin-loaded CSO-SA micelles also had potent antiproliferative effects on primary colorectal cancer cells in vitro, resulting in about 6-fold greater inhibition compared with cells treated with a solution containing an equivalent concentration of free curcumin. Intravenous administration of curcumin-loaded CSO-SA micelles marginally suppressed tumor growth but did not increase cytotoxicity to mice, as confirmed by no change in body weight. Most importantly, curcumin-loaded CSO-SA micelles were effective for inhibiting subpopulations of CD44+/CD24+ cells (putative colorectal cancer stem cell markers) both in vitro and in vivo. Conclusion: The present study identifies an effective and safe means of using curcumin-loaded CSO-SA micelles for cancer therapy. PMID:22927762

Let there be light: photo-cross-linked block copolymer nanoparticles.

PubMed

Roy, Debashish; Sumerlin, Brent S

2014-01-01

Polymeric nanoparticles are prepared by selectively cross-linking a photo-sensitive dimethylmaleimide-containing block of a diblock copolymer via UV irradiation. A well-defined photo-cross-linkable block copolymer is prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization of a dimethylmaleimide-functional acrylamido monomer containing photoreactive pendant groups with a poly(N,N-dimethylacrylamide) (PDMA) macro-chain transfer agent. The resulting amphiphilic block copolymers form micelles in water with a hydrophilic PDMA shell and a hydrophobic photo-cross-linkable dimethylmaleimide-containing core. UV irradiation results in photodimerization of the dimethylmaleimide groups within the micelle cores to yield core-cross-linked aggregates. Alternatively, UV irradiation of homogeneous solutions of the block copolymer in a non-selective solvent leads to in situ nanoparticle formation. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Methotrexate-Loaded Four-Arm Star Amphiphilic Block Copolymer Elicits CD8+ T Cell Response against a Highly Aggressive and Metastatic Experimental Lymphoma.

PubMed

Hira, Sumit Kumar; Ramesh, Kalyan; Gupta, Uttam; Mitra, Kheyanath; Misra, Nira; Ray, Biswajit; Manna, Partha Pratim

2015-09-16

We have synthesized a well-defined four-arm star amphiphilic block copolymer [poly(DLLA)-b-poly(NVP)]4 [star-(PDLLA-b-PNVP)4] that consists of D,L-lactide (DLLA) and N-vinylpyrrolidone (NVP) via the combination of ring-opening polymerization (ROP) and xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization. Synthesis of the polymer was verified by 1H NMR spectroscopy and gel permeation chromatography (GPC). The amphiphilic four-arm star block copolymer forms spherical micelles in water as demonstrated by transmission electron microscopy (TEM) and 1H NMR spectroscopy. Pyrene acts as a probe to ascertain the critical micellar concentration (cmc) by using fluorescence spectroscopy. Methotrexate (MTX)-loaded polymeric micelles of star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer were prepared and characterized by fluorescence and TEM studies. Star-(PDLLA15-b-PNVP10)4 copolymer was found to be significantly effective with respect to inhibition of proliferation and lysis of human and murine lymphoma cells. The amphiphilic block copolymer causes cell death in parental and MTX-resistant Dalton lymphoma (DL) and Raji cells. The formulation does not cause hemolysis in red blood cells and is tolerant to lymphocytes compared to free MTX. Therapy with MTX-loaded star-(PDLLA15-b-PNVP10)4 amphiphilic block copolymer micelles prolongs the life span of animals with neoplasia by reducing the tumor load, preventing metastasis and augmenting CD8+ T cell-mediated adaptive immune responses.

Stable curcumin-loaded polymeric micellar formulation for enhancing cellular uptake and cytotoxicity to FLT3 overexpressing EoL-1 leukemic cells.

PubMed

Tima, Singkome; Anuchapreeda, Songyot; Ampasavate, Chadarat; Berkland, Cory; Okonogi, Siriporn

2017-05-01

The present study aims to develop a stable polymeric micellar formulation of curcumin (CM) with improved solubility and stability, and that is suitable for clinical applications in leukemia patients. CM-loaded polymeric micelles (CM-micelles) were prepared using poloxamers. The chemical structure of the polymers influenced micellar properties. The best formulation of CM-micelles, namely CM-P407, was obtained from poloxamer 407 at drug to polymer ratio of 1:30 and rehydrated with phosphate buffer solution pH 7.4. CM-P407 exhibited the smallest size of 30.3±1.3nm and highest entrapment efficiency of 88.4±4.1%. When stored at -80°C for 60days, CM-P407 retained high protection of CM and had no significant size change. In comparison with CM solution in dimethyl sulfoxide (CM-DMSO), CM kinetic degradation in both formulations followed a pseudo-first-order reaction, but the half-life of CM in CM-P407 was approx. 200 times longer than in CM-DMSO. Regarding the activity against FLT3 overexpressing EoL-1 leukemic cells, CM-P407 showed higher cytotoxicity than CM-DMSO. Moreover, intracellular uptake to leukemic cells of CM-P407 was 2-3 times greater than that of CM-DMSO. These promising results for CM-P407 will be further investigated in rodents and in clinical studies for leukemia treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

Stereocomplex micelle from nonlinear enantiomeric copolymers efficiently transports antineoplastic drug

NASA Astrophysics Data System (ADS)

Wang, Jixue; Shen, Kexin; Xu, Weiguo; Ding, Jianxun; Wang, Xiaoqing; Liu, Tongjun; Wang, Chunxi; Chen, Xuesi

2015-05-01

Nanoscale polymeric micelles have attracted more and more attention as a promising nanocarrier for controlled delivery of antineoplastic drugs. Herein, the doxorubicin (DOX)-loaded poly(D-lactide)-based micelle (PDM/DOX), poly(L-lactide)-based micelle (PLM/DOX), and stereocomplex micelle (SCM/DOX) from the equimolar mixture of the enantiomeric four-armed poly(ethylene glycol)-polylactide (PEG-PLA) copolymers were successfully fabricated. In phosphate-buffered saline (PBS) at pH 7.4, SCM/DOX exhibited the smallest hydrodynamic diameter ( D h) of 90 ± 4.2 nm and the slowest DOX release compared with PDM/DOX and PLM/DOX. Moreover, PDM/DOX, PLM/DOX, and SCM/DOX exhibited almost stable D hs of around 115, 105, and 90 nm at above normal physiological condition, respectively, which endowed them with great potential in controlled drug delivery. The intracellular DOX fluorescence intensity after the incubation with the laden micelles was different degrees weaker than that incubated with free DOX · HCl within 12 h, probably due to the slow DOX release from micelles. As the incubation time reached to 24 h, all the cells incubated with the laden micelles, especially SCM/DOX, demonstrated a stronger intracellular DOX fluorescence intensity than free DOX · HCl-cultured ones. More importantly, all the DOX-loaded micelles, especially SCM/DOX, exhibited potent antineoplastic efficacy in vitro, excellent serum albumin-tolerance stability, and satisfactory hemocompatibility. These encouraging data indicated that the loading micelles from nonlinear enantiomeric copolymers, especially SCM/DOX, might be promising in clinical systemic chemotherapy through intravenous injection.

Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo

NASA Astrophysics Data System (ADS)

Gou, Maling; Men, Ke; Shi, Huashan; Xiang, Mingli; Zhang, Juan; Song, Jia; Long, Jianlin; Wan, Yang; Luo, Feng; Zhao, Xia; Qian, Zhiyong

2011-04-01

Curcumin is an effective and safe anticancer agent, but its hydrophobicity inhibits its clinical application. Nanotechnology provides an effective method to improve the water solubility of hydrophobic drug. In this work, curcumin was encapsulated into monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles through a single-step nano-precipitation method, creating curcumin-loaded MPEG-PCL (Cur/MPEG-PCL) micelles. These Cur/MPEG-PCL micelles were monodisperse (PDI = 0.097 +/- 0.011) with a mean particle size of 27.3 +/- 1.3 nm, good re-solubility after freeze-drying, an encapsulation efficiency of 99.16 +/- 1.02%, and drug loading of 12.95 +/- 0.15%. Moreover, these micelles were prepared by a simple and reproducible procedure, making them potentially suitable for scale-up. Curcumin was molecularly dispersed in the PCL core of MPEG-PCL micelles, and could be slow-released in vitro. Encapsulation of curcumin in MPEG-PCL micelles improved the t1/2 and AUC of curcuminin vivo. As well as free curcumin, Cur/MPEG-PCL micelles efficiently inhibited the angiogenesis on transgenic zebrafish model. In an alginate-encapsulated cancer cell assay, intravenous application of Cur/MPEG-PCL micelles more efficiently inhibited the tumor cell-induced angiogenesisin vivo than that of free curcumin. MPEG-PCL micelle-encapsulated curcumin maintained the cytotoxicity of curcumin on C-26 colon carcinoma cellsin vitro. Intravenous application of Cur/MPEG-PCL micelle (25 mg kg-1curcumin) inhibited the growth of subcutaneous C-26 colon carcinoma in vivo (p < 0.01), and induced a stronger anticancer effect than that of free curcumin (p < 0.05). In conclusion, Cur/MPEG-PCL micelles are an excellent intravenously injectable aqueous formulation of curcumin; this formulation can inhibit the growth of colon carcinoma through inhibiting angiogenesis and directly killing cancer cells.

Neutron scattering characterization of homopolymers and graft-copolymer micelles in supercritical carbon dioxide

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chillura-Martino, D; Triolo, R.; McClain, J.B.

1995-12-31

Supercritical fluids are becoming an attractive alternative to the liquid solvents traditionally used as polymerization media. As the synthesis proceeds, a wide range of colloidal aggregates form, but there has hitherto been no way to measure such structures directly. We have applied small-angle neutron scattering (SANS) to characterize such systems, and although SCF polymerizations are carried out at high pressures, the penetrating power of the neutron beam means that typical cell windows are virtually transparent. Systems studied include molecules soluble in CO{sub 2} (e.g. polyfluoro-octyl acrylate or PFOA) and this polymer has previously been shown to exhibit a positive secondmore » virial coefficient (A{sub 2}). Other CO{sub 2}-soluble polymers include hexafluoro-polypropylene oxide (HFPPO), which appears to have a second virial coefficient which is close to zero (10{sup 4}A{sub 2} {approx_equal} 0 +{+-} 0.2 cm{sup 3} g{sup -2} mol). Polydimethylsiloxane (PDMS), is soluble on the molecular level only in the limit of dilute solution and seems to form aggregates as the concentration increases (c > 0.01 g cm{sup -3}). Other polymers (e.g. polystyrene) are insoluble in CO{sub 2}, though polymerizations may be accomplished via the use of PS-PFOA blockcopolymer stabilizers, which are also amenable to SANS characterization, and have been shown to form micelles in CO{sub 2}. Other amphiphilic surfactant molecules that form micelles include PFOA-polyethylene oxide (PFOA-PEO) graft copolymers, which swell as the CO{sub 2} medium is saturated with water. These systems have been characterized by SANS, by taking advantage of the different contrast options afforded by substituting D{sub 2}O for H{sub 2}O. This paper illustrates the utility of SANS to measure molecular dimensions, thermodynamic variables, molecular weights, micelle structures etc. in supercritical CO{sub 2}.« less

Dextran based Polymeric Micelles as Carriers for Delivery of Hydrophobic Drugs.

PubMed

Mocanu, Georgeta; Nichifor, Marieta; Sacarescu, Liviu

2017-01-01

The improvement of drugs bioavailability, especially of the hydrophobic ones, by using various nanoparticles is a very exciting field of the modern research. The applicability of nano-sized shell crosslinked micelles based on dextran as supports for controlled release of several hydrophobic drugs (nystatin, rifampicin, resveratrol, and curcumin) was investigated by in vitro drug loading/release experiments. The synthesized crosslinked micelles were loaded with drugs of various hydrophobicities and their retention/release behavior was followed by dialysis procedure. Crosslinked micelles obtained from dextran with octadecyl end groups, with or without N-(2- hydroxypropyl)-N,N-dimethyl-N-benzylammonium chloride groups attached to the main dextran chains, could retain the drugs in amounts which increased with increasing drug hydrophobicity (water insolubility), as follows: 30-60 mg rifampicin/g, 70-100 mg nystatin/g, 120-144 mg resveratrol/g and 146-260 mg curcumin/g. The rate of drug release from the loaded micelles was also dependent on the drug hydrophobicity and was always slower than the free drug recovery. Antioxidant activity of curcumin and resveratrol released from the loaded micelles was preserved. The results highlighted the potential of the new nano-sized micelles as carriers for prolonged and controlled delivery of various hydrophobic drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Stimuli-responsive magnetic nanomicelles as multifunctional heat and cargo delivery vehicles.

PubMed

Kim, Dong-Hyun; Vitol, Elina A; Liu, Jing; Balasubramanian, Shankar; Gosztola, David J; Cohen, Ezra E; Novosad, Valentyn; Rozhkova, Elena A

2013-06-18

Hybrid nanoarchitectures are among the most promising nanotechnology-enabled materials for biomedical applications. Interfacing of nanoparticles with active materials gives rise to the structures with unique multiple functionality. Superparamagnetic iron oxide nanoparticles particles SPION are widely employed in the biology and in developing of advanced medical technologies. Polymeric micelles offer the advantage of multifunctional carriers which can serve as delivery vehicles carrying nanoparticles, hydrophobic chemotherapeutics and other functional materials and molecules. Stimuli-responsive polymers are especially attractive since their properties can be modulated in a controlled manner. Here we report on multifunctional thermo-responsive poly(N-isopropylacrylamide-co-acrylamide)-block-poly(ε-caprolactone) random block copolymer micelles as magnetic hyperthermia-mediated payload release and imaging agents. The combination of copolymers, nanoparticles and doxorubicin drug was tailored the way that the loaded micelles were cable to respond to magnetic heating at physiologically-relevant temperatures. A surface functionalization of the micelles with the integrin β4 antibody and consequent interfacing of the resulting nanobio hybrid with squamous head and neck carcinoma cells which is known to specifically over-express the A9 antigen resulted in concentration of the micelles on the surface of cells. No inherent cytotoxicity was detected for the magnetic micelles without external stimuli application. Furthermore, SPION-loaded micelles demonstrate significant MRI contrast enhancement abilities.

Anti-CD22 Antibody Targeting of pH-responsive Micelles Enhances Small Interfering RNA Delivery and Gene Silencing in Lymphoma Cells

PubMed Central

Palanca-Wessels, Maria C; Convertine, Anthony J; Cutler-Strom, Richelle; Booth, Garrett C; Lee, Fan; Berguig, Geoffrey Y; Stayton, Patrick S; Press, Oliver W

2011-01-01

The application of small interfering RNA (siRNA) for cancer treatment is a promising strategy currently being explored in early phase clinical trials. However, efficient systemic delivery limits clinical implementation. We developed and tested a novel delivery system comprised of (i) an internalizing streptavidin-conjugated monoclonal antibody (mAb-SA) directed against CD22 and (ii) a biotinylated diblock copolymer containing both a positively charged siRNA condensing block and a pH-responsive block to facilitate endosome release. The modular design of the carrier facilitates the exchange of different targeting moieties and siRNAs to permit its usage in a variety of tumor types. The polymer was synthesized using the reversible addition fragmentation chain transfer (RAFT) technique and formed micelles capable of binding siRNA and mAb-SA. A hemolysis assay confirmed the predicted membrane destabilizing activity of the polymer under acidic conditions typical of the endosomal compartment. Enhanced siRNA uptake was demonstrated in DoHH2 lymphoma and transduced HeLa-R cells expressing CD22 but not in CD22 negative HeLa-R cells. Gene knockdown was significantly improved with CD22-targeted vs. nontargeted polymeric micelles. Treatment of DoHH2 cells with CD22-targeted polymeric micelles containing 15 nmol/l siRNA produced 70% reduction of gene expression. This CD22-targeted polymer carrier may be useful for siRNA delivery to lymphoma cells. PMID:21629223

Anti-CD22 antibody targeting of pH-responsive micelles enhances small interfering RNA delivery and gene silencing in lymphoma cells.

PubMed

Palanca-Wessels, Maria C; Convertine, Anthony J; Cutler-Strom, Richelle; Booth, Garrett C; Lee, Fan; Berguig, Geoffrey Y; Stayton, Patrick S; Press, Oliver W

2011-08-01

The application of small interfering RNA (siRNA) for cancer treatment is a promising strategy currently being explored in early phase clinical trials. However, efficient systemic delivery limits clinical implementation. We developed and tested a novel delivery system comprised of (i) an internalizing streptavidin-conjugated monoclonal antibody (mAb-SA) directed against CD22 and (ii) a biotinylated diblock copolymer containing both a positively charged siRNA condensing block and a pH-responsive block to facilitate endosome release. The modular design of the carrier facilitates the exchange of different targeting moieties and siRNAs to permit its usage in a variety of tumor types. The polymer was synthesized using the reversible addition fragmentation chain transfer (RAFT) technique and formed micelles capable of binding siRNA and mAb-SA. A hemolysis assay confirmed the predicted membrane destabilizing activity of the polymer under acidic conditions typical of the endosomal compartment. Enhanced siRNA uptake was demonstrated in DoHH2 lymphoma and transduced HeLa-R cells expressing CD22 but not in CD22 negative HeLa-R cells. Gene knockdown was significantly improved with CD22-targeted vs. nontargeted polymeric micelles. Treatment of DoHH2 cells with CD22-targeted polymeric micelles containing 15 nmol/l siRNA produced 70% reduction of gene expression. This CD22-targeted polymer carrier may be useful for siRNA delivery to lymphoma cells.

Actively targeted delivery of anticancer drug to tumor cells by redox-responsive star-shaped micelles.

PubMed

Shi, Chunli; Guo, Xing; Qu, Qianqian; Tang, Zhaomin; Wang, Yi; Zhou, Shaobing

2014-10-01

In cancer therapy nanocargos based on star-shaped polymer exhibit unique features such as better stability, smaller size distribution and higher drug capacity in comparison to linear polymeric micelles. In this study, we developed a multifunctional star-shaped micellar system by combination of active targeting ability and redox-responsive behavior. The star-shaped micelles with good stability were self-assembled from four-arm poly(ε-caprolactone)-poly(ethylene glycol) copolymer. The redox-responsive behaviors of these micelles triggered by glutathione were evaluated from the changes of micellar size, morphology and molecular weight. In vitro drug release profiles exhibited that in a stimulated normal physiological environment, the redox-responsive star-shaped micelles could maintain good stability, whereas in a reducing and acid environment similar with that of tumor cells, the encapsulated agent was promptly released. In vitro cellular uptake and subcellular localization of these micelles were further studied with confocal laser scanning microscopy and flow cytometry against the human cervical cancer cell line HeLa. In vivo and ex vivo DOX fluorescence imaging displayed that these FA-functionalized star-shaped micelles possessed much better specificity to target solid tumor. Both the qualitative and quantitative results of the antitumor effect in 4T1 tumor-bearing BALB/c mice demonstrated that these redox-responsive star-shaped micelles have a high therapeutic efficiency to artificial solid tumor. Therefore, the multifunctional star-shaped micelles are a potential platform for targeted anticancer drug delivery. Copyright © 2014 Elsevier Ltd. All rights reserved.

Multifunctional hybrid micelles with tunable active targeting and acid/phosphatase-stimulated drug release for enhanced tumor suppression.

PubMed

Liu, Xuhan; Li, Yinghuan; Tan, Xi; Rao, Rong; Ren, Yuanyuan; Liu, Lingyan; Yang, Xiangliang; Liu, Wei

2018-03-01

Therapeutic efficacy of conventional single PEGylated polymeric micelles is significantly reduced by limited endocytosis and intracellular drug release. To improve drug delivery efficiency, poly (ethylene glycol)-block-poly (l-lactic acid)/(Arg-Gly-Asp-Phe)-poly (aminoethyl ethylene phosphate)-block-poly (l-lactic acid) (PEG-PLLA/RGDF-PAEEP-PLLA) hybrid micelles with tunable active targeting and acid/phosphatase-stimulated drug release are developed. The optimized hybrid micelles with 6 wt % of RGDF have favorable in vitro and in vivo activities. The hybrid micelles could temporarily shield the targeting efficacy of RGDF at pH 7.4 due to the steric effect exerted by concealment of RGDF peptides in the PEG corona, which strongly decreases the clearance by mononuclear phagocyte system and consequently improves the tumor accumulation. Inside the solid tumor with a lower acidic pH, the hybrid micelles restore the active tumor targeting property with exposed RGDF on the surface of the micelles because of the increased protonation and stretching degree of PAEEP blocks. RGDF-mediated endocytosis improves the tumor cell uptake. The hybrid micelles would also enhance intracellular drug release because of the hydrolysis of the acid/phosphatase-sensitivity of PAEEP blocks in endo/lysosome. Systemic administration of the hybrid micelles significantly inhibits tumor growth by 96% due to the integration of enhanced circulation time, tumor accumulation, cell uptake and intracellular drug release. Copyright © 2017 Elsevier Ltd. All rights reserved.

Patchy micelles based on coassembly of block copolymer chains and block copolymer brushes on silica particles.

PubMed

Zhu, Shuzhe; Li, Zhan-Wei; Zhao, Hanying

2015-04-14

Patchy particles are a type of colloidal particles with one or more well-defined patches on the surfaces. The patchy particles with multiple compositions and functionalities have found wide applications from the fundamental studies to practical uses. In this research patchy micelles with thiol groups in the patches were prepared based on coassembly of free block copolymer chains and block copolymer brushes on silica particles. Thiol-terminated and cyanoisopropyl-capped polystyrene-block-poly(N-isopropylacrylamide) block copolymers (PS-b-PNIPAM-SH and PS-b-PNIPAM-CIP) were synthesized by reversible addition-fragmentation chain transfer polymerization and chemical modifications. Pyridyl disulfide-functionalized silica particles (SiO2-SS-Py) were prepared by four-step surface chemical reactions. PS-b-PNIPAM brushes on silica particles were prepared by thiol-disulfide exchange reaction between PS-b-PNIPAM-SH and SiO2-SS-Py. Surface micelles on silica particles were prepared by coassembly of PS-b-PNIPAM-CIP and block copolymer brushes. Upon cleavage of the surface micelles from silica particles, patchy micelles with thiol groups in the patches were obtained. Dynamic light scattering, transmission electron microscopy, and zeta-potential measurements demonstrate the preparation of patchy micelles. Gold nanoparticles can be anchored onto the patchy micelles through S-Au bonds, and asymmetric hybrid structures are formed. The thiol groups can be oxidized to disulfides, which results in directional assembly of the patchy micelles. The self-assembly behavior of the patchy micelles was studied experimentally and by computer simulation.

Tuneable enhancement of the salt and thermal stability of polymeric micelles by cyclized amphiphiles

PubMed Central

Honda, Satoshi; Yamamoto, Takuya; Tezuka, Yasuyuki

2013-01-01

Cyclic molecules provide better stability for their aggregates. Typically in nature, the unique cyclic cell membrane lipids allow thermophilic archaea to inhabit extreme conditions. By mimicking the biological design, the robustness of self-assembled synthetic nanostructures is expected to be improved. Here we report topology effects by cyclized polymeric amphiphiles against their linear counterparts, demonstrating a drastic enhancement in the thermal, as well as salt stability of self-assembled micelles. Furthermore, through coassembly of the linear and cyclic amphiphiles, the stability was successfully tuned for a wide range of temperatures and salt concentrations. The enhanced thermal/salt stability was exploited in a halogen exchange reaction to stimulate the catalytic activity. The mechanism for the enhancement was also investigated. These topology effects by the cyclic amphiphiles offer unprecedented opportunities in polymer materials design unattainable by traditional means. PMID:23481382

Amphiphilic conjunct of methyl cellulose and well-defined polyvinyl acetate.

PubMed

Xiao, Congming; Xia, Cunping

2013-01-01

Tailor-made conjunct of methyl cellulose (MC) and polyvinyl acetate (PVAc) was synthesized through the combination of reversible addition-fragmentation chain transfer (RAFT) polymerization and thiol-ene click reaction. MC was firstly transferred into unsaturated MC (UMC), and then covalently connected with well-defined PVAc obtained by RAFT polymerization of vinyl acetate. The structure of the conjunct polymer (MCV) was confirmed with Fourier transform infrared spectra (FTIR) and proton nuclear magnetic resonance ((1)H NMR). Well-defined MCV was amphiphilic and able to self-assemble into size controllable micelles, which was verified with transmission electron microscopy (TEM) and size distribution analysis. It was found that the mean diameters of the micelles in aqueous solution were 105.6, 96.0 and 75.9 nm when the number average molecular weights of PVAc segments of MCV were 49,300, 32,500 and 18,200, respectively. Copyright © 2012 Elsevier B.V. All rights reserved.

Molecular organization and dynamics of micellar phase of polyelectrolyte-surfactant complexes: ESR spin probe study

NASA Astrophysics Data System (ADS)

Wasserman, A. M.; Kasaikin, V. A.; Zakharova, Yu. A.; Aliev, I. I.; Baranovsky, V. Yu.; Doseva, V.; Yasina, L. L.

2002-04-01

Molecular dynamics and organization of the micellar phase of complexes of linear polyelectrolytes with ionogenic and non-ionogenic surfactants was studied by the ESR spin probe method. Complexes of polyacrylic acid (PAA) and sodium polystyrenesulfonate (PSS) with alkyltrimethylammonium bromides (ATAB), as well as complexes of poly- N, N'-dimethyldiallylammonium chloride (PDACL) with sodium dodecylsulfate (SDS) were studied. The micellar phase of such complexes is highly organized molecular system, molecular ordering of which near the polymeric chain is much higher than in the 'center' of the micelle, it depends on the polymer-detergent interaction, flexibility of polymeric chain and length of carbonic part of the detergent molecule. Complexes of polymethacrylic acid (PMAA) with non-ionic detergent (dodecyl-substituted polyethyleneglycol), show that the local mobility of surfactant in such complexes is significantly lower than in 'free' micelles and depends on the number of micellar particles participating in formation of complexes.

Formation of Polymeric Nanocubes by Self-Assembly and Crystallization of Dithiolane-Containing Triblock Copolymers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Margulis, Katherine; Zhang, Xiangyi; Joubert, Lydia -Marie

Template–free fabrication of non–spherical polymeric nanoparticles is desirable for various applications, but has had limited success owing to thermodynamic favorability of sphere formation. Herein we present a simple way to prepare cubic nanoparticles of block copolymers by self–assembly from aqueous solutions at room temperature. Nanocubes with edges of 40–200 nm are formed spontaneously on different surfaces upon water evaporation from micellar solutions of triblock copolymers containing a central poly(ethylene oxide) block and terminal trimethylene carbonate/dithiolane blocks. These polymers self–assemble into 28±5 nm micelles in water. Upon drying, micelle aggregation and a kinetically controlled crystallization of central blocks evidently induce solidmore » cubic particle formation. An approach for preserving the structures of these cubes in water by thiol– or photo–induced crosslinking was developed. In conclusion, the ability to solubilize a model hydrophobic drug, curcumin, was also explored.« less

Formation of Polymeric Nanocubes by Self-Assembly and Crystallization of Dithiolane-Containing Triblock Copolymers

DOE PAGES

Margulis, Katherine; Zhang, Xiangyi; Joubert, Lydia -Marie; ...

2017-10-27

Template–free fabrication of non–spherical polymeric nanoparticles is desirable for various applications, but has had limited success owing to thermodynamic favorability of sphere formation. Herein we present a simple way to prepare cubic nanoparticles of block copolymers by self–assembly from aqueous solutions at room temperature. Nanocubes with edges of 40–200 nm are formed spontaneously on different surfaces upon water evaporation from micellar solutions of triblock copolymers containing a central poly(ethylene oxide) block and terminal trimethylene carbonate/dithiolane blocks. These polymers self–assemble into 28±5 nm micelles in water. Upon drying, micelle aggregation and a kinetically controlled crystallization of central blocks evidently induce solidmore » cubic particle formation. An approach for preserving the structures of these cubes in water by thiol– or photo–induced crosslinking was developed. In conclusion, the ability to solubilize a model hydrophobic drug, curcumin, was also explored.« less

TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors.

PubMed

Sethuraman, Vijay A; Bae, You Han

2007-04-02

A novel drug targeting system for acidic solid tumors has been developed based on ultra pH-sensitive polymer and cell penetrating TAT. The delivery system consisted of two components: 1) A polymeric micelle that has a hydrophobic core made of poly(l-lactic acid) (PLLA) and a hydrophilic shell consisting of polyethylene glycol (PEG) conjugated to TAT (TAT micelle), 2) an ultra pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and PEG (PSD-b-PEG). The anionic PSD is complexed with cationic TAT of the micelles to achieve the final carrier, which could systemically shield the micelles and expose them at slightly acidic tumor pH. TAT micelles had particle sizes between 20 and 45 nm and their critical micelle concentrations were 3.5 mg/l to 5.5 mg/l. The TAT micelles, upon mixing with pH-sensitive PSD-b-PEG, showed a slight increase in particle size between pH 8.0 and 6.8 (60-90 nm), indicating complexation. As the pH was decreased (pH 6.6 to 6.0) two populations were observed, one that of normal TAT micelles (45 nm) and the other of aggregated hydrophobic PSD-b-PEG. Zeta potential measurements showed similar trend substantiating the shielding/deshielding process. Flow cytometry and confocal microscopy showed significantly higher uptake of TAT micelles at pH 6.6 compared to pH 7.4 indicating shielding at normal pH and deshielding at tumor pH. The confocal microscopy indicated that the TAT not only translocates into the cells but is also seen on the surface of the nucleus. These results strongly indicate that the above micelles would be able to target any hydrophobic drug near the nucleus.

In vivo evaluation of folate decorated cross-linked micelles for the delivery of platinum anticancer drugs.

PubMed

Eliezar, Jeaniffer; Scarano, Wei; Boase, Nathan R B; Thurecht, Kristofer J; Stenzel, Martina H

2015-02-09

The biodistribution of micelles with and without folic acid targeting ligands were studied using a block copolymer consisting of acrylic acid (AA) and polyethylene glycol methyl ether acrylate (PEGMEA) blocks. The polymers were prepared using RAFT polymerization in the presence of a folic acid functionalized RAFT agent. Oxoplatin was conjugated onto the acrylic acid block to form amphiphilic polymers which, when diluted in water, formed stable micelles. In order to probe the in vivo stability, a selection of micelles were cross-linked using 1,8-diamino octane. The sizes of the micelles used in this study range between 75 and 200 nm, with both spherical and worm-like conformation. The effects of cross-linking, folate conjugation and different conformation on the biodistribution were studied in female nude mice (BALB/c) following intravenous injection into the tail vein. Using optical imaging to monitor the fluorophore-labeled polymer, the in vivo biodistribution of the micelles was monitored over a 48 h time-course after which the organs were removed and evaluated ex vivo. These experiments showed that both cross-linking and conjugation with folic acid led to increased fluorescence intensities in the organs, especially in the liver and kidneys, while micelles that are not conjugated with folate and not cross-linked are cleared rapidly from the body. Higher accumulation in the spleen, liver, and kidneys was also observed for micelles with worm-like shapes compared to the spherical micelles. While the various factors of cross-linking, micelle shape, and conjugation with folic acid all contribute separately to prolong the circulation time of the micelle, optimization of these parameters for drug delivery devices could potentially overcome adverse effects such as liver and kidney toxicity.

Ultrasound-enhanced localized chemotherapy of drug-sensitive and multidrug resistant tumors

NASA Astrophysics Data System (ADS)

Rapoport, Natalya Y.; Gao, Zhonggao; Kamaev, Pavel; Christensen, Douglas A.

2006-05-01

A new modality of targeted tumor chemotherapy is based on the drug encapsulation in polymeric nanoparticles followed by a localized release at the tumor site triggered by focused ultrasound. Effect of 1 MHz and 3 MHz unfocused ultrasound applied locally to the tumor on the Doxorubicin (DOX) biodistribution and tumor growth rates was measured for ovarian carcinoma tumors in nu/nu mice. The bioeffects of ultrasound were investigated on the systemic and cellular levels. Growth rates of A2780 ovarian carcinoma tumors were substantially reduced by combining micellar drug delivery with tumor irradiation. Ultrasound effect was not thermal as manifested by intratumoral temperature measurements during sonication. Biodistribution studies showed that ultrasound did not enhance micelle extravasation. Main mechanisms of the ultrasound-enhanced chemotherapy included (i) passive targeting of drug-loaded micelles to the tumor interstitium; (ii) ultrasound-triggered localized drug release from micelles in the tumor volume; (iii) enhanced micelle and drug diffusion through the tumor interstitium; and (iv) ultrasound-triggered cell membrane damage resulting in the enhanced micelle and drug uptake by tumor cells.

Polymeric micelles based on poly(methacrylic acid) block-containing copolymers with different membrane destabilizing properties for cellular drug delivery.

PubMed

Mebarek, Naila; Aubert-Pouëssel, Anne; Gérardin, Corine; Vicente, Rita; Devoisselle, Jean-Marie; Bégu, Sylvie

2013-10-01

Poly(methacrylic acid)-b-poly(ethylene oxide) are double hydrophilic block copolymers, which are able to form micelles by complexation with a counter-polycation, such as poly-l-lysine. A study was carried out on the ability of the copolymers to interact with model membranes as a function of their molecular weights and as a function of pH. Different behaviors were observed: high molecular weight copolymers respect the membrane integrity, whereas low molecular weight copolymers with a well-chosen asymmetry degree can induce a membrane alteration. Hence by choosing the appropriate molecular weight, micelles with distinct membrane interaction behaviors can be obtained leading to different intracellular traffics with or without endosomal escape, making them interesting tools for cell engineering. Especially micelles constituted of low molecular weight copolymers could exhibit the endosomal escape property, which opens vast therapeutic applications. Moreover micelles possess a homogeneous nanometric size and show variable properties of disassembly at acidic pH, of stability in physiological conditions, and finally of cyto-tolerance. Copyright © 2013 Elsevier B.V. All rights reserved.

Gelling Mechanism of Aluminum Di-Soaps in Oils

NASA Astrophysics Data System (ADS)

Wang, Xiaorong; Rackaitis, Mindaugas

2009-03-01

This work demonstrates that aluminum di-soaps form nano-sized spherical micelles in the oils and that the aggregation of these micelles forms a network that gives rise to a gel formation -- thereby refuting a long-held belief that the gel formation was the result of linear polymeric chains of aluminum association. The discovery of such aluminum nano-particles could expand application of these materials to new technologies because these materials are chemically inert, odorless and nontoxic, and have been widely used in greases, paints, gels, cosmetics, drugs and foods.

Fabrication and biological imaging of polyhedral oligomeric silsesquioxane cross-linked fluorescent polymeric nanoparticles with aggregation-induced emission feature

NASA Astrophysics Data System (ADS)

Mao, Liucheng; Liu, Meiying; Xu, Dazhuang; Wan, Qing; Huang, Qiang; Jiang, Ruming; Shi, Yingge; Deng, Fengjie; Zhang, Xiaoyong; Wei, Yen

2017-11-01

Aggregation-induced emission (AIE) dyes based fluorescent polymeric nanoparticles (FNPs) have been intensively explored for biomedical applications. However, many of these AIE-active FNPs are relied on the self-assembly of amphiphilic copolymers, which are not stable in diluted solution. Therefore, the introduction of cross-linkages into these micelles has demonstrated to be an efficient route to overcome this stability problem and endow ultra-low critical micelle concentrations (CMC) of these AIE-active FNPs. In this work, we reported the fabrication of cross-linked AIE-active FNPs through controllable reversible addition fragmentation chain transfer polymerization by using commercially available octavinyl-T8-silsesquioxane (8-vinyl POSS) as the cross-linkage for the first time. The resultant cross-linked amphiphilic copolymers (named as PEG-POSS-PhE) are prone to self-assemble into stable core-shell nanoparticles with well water dispersity, strong red fluorescence and low CMC (0.0069 mg mL-1) in aqueous solution. More importantly, PEG-POSS-PhE FNPs possess some other properties such as high water dispersity, uniform morphology and small size, excellent biocompatibility and cellular internalization, providing great potential of PEG-POSS-PhE FNPs for biological imaging application.

Nanoscale elastic modulus variation in loaded polymeric micelle reactors.

PubMed

Solmaz, Alim; Aytun, Taner; Deuschle, Julia K; Ow-Yang, Cleva W

2012-07-17

Tapping mode atomic force microscopy (TM-AFM) enables mapping of chemical composition at the nanoscale by taking advantage of the variation in phase angle shift arising from an embedded second phase. We demonstrate that phase contrast can be attributed to the variation in elastic modulus during the imaging of zinc acetate (ZnAc)-loaded reverse polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) diblock co-polymer micelles less than 100 nm in diameter. Three sample configurations were characterized: (i) a 31.6 μm thick polystyrene (PS) support film for eliminating the substrate contribution, (ii) an unfilled PS-b-P2VP micelle supported by the same PS film, and (iii) a ZnAc-loaded PS-b-P2VP micelle supported by the same PS film. Force-indentation (F-I) curves were measured over unloaded micelles on the PS film and over loaded micelles on the PS film, using standard tapping mode probes of three different spring constants, the same cantilevers used for imaging of the samples before and after loading. For calibration of the tip geometry, nanoindentation was performed on the bare PS film. The resulting elastic modulus values extracted by applying the Hertz model were 8.26 ± 3.43 GPa over the loaded micelles and 4.17 ± 1.65 GPa over the unloaded micelles, confirming that phase contrast images of a monolayer of loaded micelles represent maps of the nanoscale chemical and mechanical variation. By calibrating the tip geometry indirectly using a known soft material, we are able to use the same standard tapping mode cantilevers for both imaging and indentation.

Micelle-like Nanoparticles as Carriers for DNA and siRNA

PubMed Central

Navarro, Gemma; Pan, Jiayi; Torchilin, Vladimir P.

2015-01-01

Gene therapy represents a potential efficient approach of disease prevention and therapy. However, due to their poor in vivo stability, gene molecules need to be associated with delivery systems to overcome extracellular and intracellular barriers and allow access to the site of action. Cationic polymeric nanoparticles are popular carriers for small interfering RNA (siRNA) and DNA-based therapeutics for which efficient and safe delivery are important factors that need to be optimized. Micelle-like nanoparticles (MNP) (half micelles, half polymeric nanoparticles) can overcome some of the disadvantages of such cationic carriers by unifying in one single carrier the best of both delivery systems. In this review, we will discuss how the unique properties of MNP including self-assembly, condensation and protection of nucleic acids, improved cell association and gene transfection, and low toxicity may contribute to the successful application of siRNA- and DNA-based therapeutics into the clinic. Recent developments of MNP involving the addition of stimulus-sensitive functions to respond specifically to pathological or externally applied “triggers” (e.g., temperature, pH or enzymatic catalysis, light, or magnetic fields) will be discussed. Finally, we will overview the use of MNP as two-in-one carriers for the simultaneous delivery of different agents (small molecules, imaging agents) and nucleic acid combinations. PMID:25557580

A new class of dual responsive self-healable hydrogels based on a core crosslinked ionic block copolymer micelle prepared via RAFT polymerization and Diels-Alder "click" chemistry.

PubMed

Banerjee, Sovan Lal; Singha, Nikhil K

2017-12-06

Amphiphilic diblock copolymers of poly(furfuryl methacrylate) (PFMA) with cationic poly(2-(methacryloyloxy)ethyltrimethyl ammonium chloride) (PFMA-b-PMTAC) and anionic poly(sodium 4-vinylbenzenesulfonate) (PFMA-b-PSS) were prepared via reversible addition fragmentation chain-transfer (RAFT) polymerization by using PFMA as a macro-RAFT agent. The formation of the block copolymer was confirmed by FTIR and 1 H NMR analyses. In water, the amphiphilic diblock copolymers, (PFMA-b-PMTAC) and (PFMA-b-PSS), formed micelles with PFMA in the core and the rest of the hydrophilic polymers like PMTAC and PSS in the corona. The PFMA core was crosslinked by using Diels-Alder (DA) "Click" chemistry in water at 60 °C where bismaleimide acted as a crosslinker. Afterwards, both the core crosslinked micelles were mixed at an almost equal charge ratio which was determined by zeta potential analysis to prepare the self-assembled hydrogel. The de-crosslinking of the hydrophobic PFMA core in the self-assembled hydrogel via rDA reaction took place at 165 °C as determined from DSC analysis. This hydrogel showed self-healing behavior using ionic interaction (in the presence of water) and DA chemistry (in the presence of heat).

Gold-Loaded Polymeric Micelles for Computed Tomography-Guided Radiation Therapy Treatment and Radiosensitization

PubMed Central

2013-01-01

Gold nanoparticles (AuNPs) have generated interest as both imaging and therapeutic agents. AuNPs are attractive for imaging applications since they are nontoxic and provide nearly three times greater X-ray attenuation per unit weight than iodine. As therapeutic agents, AuNPs can sensitize tumor cells to ionizing radiation. To create a nanoplatform that could simultaneously exhibit long circulation times, achieve appreciable tumor accumulation, generate computed tomography (CT) image contrast, and serve as a radiosensitizer, gold-loaded polymeric micelles (GPMs) were prepared. Specifically, 1.9 nm AuNPs were encapsulated within the hydrophobic core of micelles formed with the amphiphilic diblock copolymer poly(ethylene glycol)-b-poly(ε-capralactone). GPMs were produced with low polydispersity and mean hydrodynamic diameters ranging from 25 to 150 nm. Following intravenous injection, GPMs provided blood pool contrast for up to 24 h and improved the delineation of tumor margins via CT. Thus, GPM-enhanced CT imaging was used to guide radiation therapy delivered via a small animal radiation research platform. In combination with the radiosensitizing capabilities of gold, tumor-bearing mice exhibited a 1.7-fold improvement in the median survival time, compared with mice receiving radiation alone. It is envisioned that translation of these capabilities to human cancer patients could guide and enhance the efficacy of radiation therapy. PMID:24377302

Characteristics and cytotoxicity of folate-modified curcumin-loaded PLA-PEG micellar nano systems with various PLA:PEG ratios.

PubMed

Phan, Quoc Thong; Le, Mai Huong; Le, Thi Thu Huong; Tran, Thi Hong Ha; Xuan, Phuc Nguyen; Ha, Phuong Thu

2016-06-30

Targeting delivery system use natural drugs for tumor cells is an appealing platform help to reduce the side effects and enhance the therapeutic effects of the drug. In this study, we synthesized curcumin (Cur) loaded (D, L Poly lactic - Poly ethylenglycol) micelle (Cur/PLA-PEG) with the ratio of PLA/PEG of 3:1 2:1 1:1 1:2 and 1:3 (w/w) and another micelle modified by folate (Cur/PLA-PEG-Fol) for targeting cancer therapy. The PLA-PEG copolymer was synthesized by ring opening polymerization method. After loading onto the micelle, solubility of Cur increased from 0.38 to 0.73mgml(-1). The average size of prepared Cur/PLA-PEG micelles was from 60 to 69nm (corresponding to the ratio difference of PLA/PEG) and the drug encapsulating efficiency was from 48.8 to 91.3%. Compared with the Cur/PLA-PEG micelles, the size of Cur/PLA-PEG-Fol micelles were from 80 to 86nm and showed better in vitro cellular uptake and cytotoxicity towards HepG2 cells. The cytotoxicity of the NPs however depends much on the PEG component. The results demonstrated that Folate-modified micelles could serve as a potential nano carrier to improve solubility, anti-cancer activity of Cur and targeting ability of the system. Copyright © 2016 Elsevier B.V. All rights reserved.

A study of properties of "micelle-enhanced" polyelectrolyte capsules: Structure, encapsulation and in vitro release.

PubMed

Li, Xiaodong; Lu, Tian; Zhang, Jianxiang; Xu, Jiajie; Hu, Qiaoling; Zhao, Shifang; Shen, Jiacong

2009-07-01

"Micelle-enhanced" polyelectrolyte capsules were fabricated via a layer-by-layer technique, templated on hybrid calcium carbonate particles with built-in polymeric micelles based on polystyrene-b-poly(acrylic acid). Due to the presence of a large number of negatively charged micelles inside the polyelectrolyte capsule, which were liberated from templates, the capsule wall was reconstructed and had properties different to those of conventional polyelectrolyte capsules. This type of capsule could selectively entrap positively charged water-soluble substances. The encapsulation efficiency of positively charged substances was dependent on their molecular weight or size. For some positively charged compounds, such as rhodamine B and lysozyme, the concentration in the capsules was orders of magnitude higher than that in the incubation solution. In addition, in vitro release study suggested that the encapsulated compounds could be released through a sustained manner to a certain degree. All these results point to the fact that these capsules might be used as novel delivery systems for some water-soluble compounds.

Curcumin-loaded biodegradable polymeric micelles for colon cancer therapy in vitro and in vivo.

PubMed

Gou, MaLing; Men, Ke; Shi, HuaShan; Xiang, MingLi; Zhang, Juan; Song, Jia; Long, JianLin; Wan, Yang; Luo, Feng; Zhao, Xia; Qian, ZhiYong

2011-04-01

Curcumin is an effective and safe anticancer agent, but its hydrophobicity inhibits its clinical application. Nanotechnology provides an effective method to improve the water solubility of hydrophobic drug. In this work, curcumin was encapsulated into monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelles through a single-step nano-precipitation method, creating curcumin-loaded MPEG-PCL (Cur/MPEG-PCL) micelles. These Cur/MPEG-PCL micelles were monodisperse (PDI = 0.097 ± 0.011) with a mean particle size of 27.3 ± 1.3 nm, good re-solubility after freeze-drying, an encapsulation efficiency of 99.16 ± 1.02%, and drug loading of 12.95 ± 0.15%. Moreover, these micelles were prepared by a simple and reproducible procedure, making them potentially suitable for scale-up. Curcumin was molecularly dispersed in the PCL core of MPEG-PCL micelles, and could be slow-released in vitro. Encapsulation of curcumin in MPEG-PCL micelles improved the t(1/2) and AUC of curcumin in vivo. As well as free curcumin, Cur/MPEG-PCL micelles efficiently inhibited the angiogenesis on transgenic zebrafish model. In an alginate-encapsulated cancer cell assay, intravenous application of Cur/MPEG-PCL micelles more efficiently inhibited the tumor cell-induced angiogenesis in vivo than that of free curcumin. MPEG-PCL micelle-encapsulated curcumin maintained the cytotoxicity of curcumin on C-26 colon carcinoma cells in vitro. Intravenous application of Cur/MPEG-PCL micelle (25 mg kg(-1) curcumin) inhibited the growth of subcutaneous C-26 colon carcinoma in vivo (p < 0.01), and induced a stronger anticancer effect than that of free curcumin (p < 0.05). In conclusion, Cur/MPEG-PCL micelles are an excellent intravenously injectable aqueous formulation of curcumin; this formulation can inhibit the growth of colon carcinoma through inhibiting angiogenesis and directly killing cancer cells.

Doxorubicin-loaded micelles of reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers as efficient "active" chemotherapeutic agents.

PubMed

Cambón, A; Rey-Rico, A; Mistry, D; Brea, J; Loza, M I; Attwood, D; Barbosa, S; Alvarez-Lorenzo, C; Concheiro, A; Taboada, P; Mosquera, V

2013-03-10

Five reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) block copolymers, BOnEOmBOn, with BO ranging from 8 to 21 units and EO from 90 to 411 were synthesized and evaluated as efficient chemotherapeutic drug delivery nanocarriers and inhibitors of the P-glycoprotein (P-gp) efflux pump in a multidrug resistant (MDR) cell line. The copolymers were obtained by reverse polymerization of poly(butylene oxide), which avoids transfer reaction and widening of the EO block distribution, commonly found in commercial poly(ethylene oxide)-poly(propylene oxide) block copolymers (poloxamers). BOnEOmBOn copolymers formed spherical micelles of 10-40 nm diameter at lower concentrations (one order of magnitude) than those of equivalent poloxamers. The influence of copolymer block lengths and BO/EO ratios on the solubilization capacity and protective environment for doxorubicin (DOXO) was investigated. Micelles showed drug loading capacity ranging from ca. 0.04% to 1.5%, more than 150 times the aqueous solubility of DOXO, and protected the cargo from hydrolysis for more than a month due to their greater colloidal stability in solution. Drug release profiles at various pHs, and the cytocompatibility and cytotoxicity of the DOXO-loaded micelles were assessed in vitro. DOXO loaded in the polymeric micelles accumulated more slowly inside the cells than free DOXO due to its sustained release. All copolymers were found to be cytocompatible, with viability extents larger than 95%. In addition, the cytotoxicity of DOXO-loaded micelles was higher than that observed for free drug solutions in a MDR ovarian NCI-ADR-RES cell line which overexpressed P-gp. The inhibition of the P-gp efflux pump by some BOnEOmBOn copolymers, similar to that measured for the common P-gp inhibitor verapamil, favored the retention of DOXO inside the cell increasing its cytotoxic activity. Therefore, poly(butylene oxide)-poly(ethylene oxide) block copolymers offer interesting features as cell response modifiers to complement their role as efficient nanocarriers for cancer chemotherapy. Copyright © 2013 Elsevier B.V. All rights reserved.

Core-shell-corona polymeric micelles as a versatile template for synthesis of inorganic hollow nanospheres.

PubMed

Sasidharan, Manickam; Nakashima, Kenichi

2014-01-21

Hollow, inorganic nanoscale capsules have many applications, from the delivery of encapsulated products for cosmetic and medicinal purposes to use as lightweight composite materials. Early methods for producing inorganic hollow nanospheres using hard templates suffered from low product yield and shell weakness upon template removal. In the past decade, researchers have turned to amphiphilic copolymers to synthesize hollow nanostructures and ordered mesoporous materials. Amphiphilic molecules self-assemble into well-defined nanostructures including spherical micelles. Micelles formed from simple, two-component AB diblock and ABA triblock copolymers, however, have been difficult to work with to construct inorganic hollow nanoparticles, because the corona of the micelle, which serves as the template for the shell, becomes unstable as it absorbs inorganic shell precursors, causing aggregates to form. Newly developed, three-component ABC triblock copolymers may solve this problem. They provide nanoassemblies with more diverse morphological and functional features than AB diblock and ABA triblock copolymers. Micelles formed from ABC triblock copolymers in selective solvents that dissolve only one or two of the blocks provide templates for these improved nanoassemblies. By manipulating individual polymer blocks, one can "encode" additional features at the molecular level. For instance, modifying the functional groups or substitution patterns of the blocks allows better morphological and size control. Insights into polymer self-assembly gained over years of work in our group have set the stage to systematically engineer inorganic spherical hollow nanoparticles using ABC triblock copolymers. In this Account, we report our recent progress in producing diverse, inorganic hollow spherical nanospheres from asymmetric triblock copolymeric micelles with core-shell-corona architecture as templates. We discuss three classes of polymeric micelles-with neutral, cationic, and anionic shell structures-that allow fabrication of a variety of hollow nanoparticles. Importantly, we synthesized all of these particles in water, avoiding use of hazardous organic solvents. We have designed the precursor of the inorganic material to be selectively sorbed into the shell domain, leaving the corona free from the inorganic precursors that would destabilize the micelle. The core, meanwhile, is the template for the formation of the hollow void. By rationally tailoring experimental parameters, we readily and selectively obtained a variety of hollow nanoparticles including silica, hybrid silicas, metal-oxides, metal-carbonates, metal-sulfates, metal-borates, and metal-phosphates. Finally, we highlight the state-of-the-art techniques we used to characterize these nanoparticles, and describe experiments that demonstrate the potential of these hollow particles in drug delivery, and as anode and cathode materials for lithium-ion batteries.

Chiral separation of norlaudanosoline, laudanosoline, laudanosine, chlorthalidone, and three benzoin derivatives using amino acid based molecular micelles.

PubMed

Billiot, Fereshteh H; Billiot, Eugene J; Ng, Yuen Kwun; Warner, Isiah M

2006-02-01

In this study, 18 polymeric single amino acid and dipeptide surfactants are examined, and their performances, in terms of enantioselectivity, are compared for norlaudanosoline, laudanosoline, laudanosine, chlorthalidone, benzoin, benzoin methyl, and benzoin ethyl enantiomers. Several aspects of amino acid-based polymeric surfactants including comparison of single amino acid versus dipeptide, amino acid order, steric effect, and effect of the position of the chiral center of dipeptide surfactants on the chiral selectivity of these optically active compounds are discussed.

Mechanisms of pH-Sensitivity and Cellular Internalization of PEOz-b-PLA Micelles with Varied Hydrophilic/Hydrophobic Ratios and Intracellular Trafficking Routes and Fate of the Copolymer.

PubMed

Wang, Dishi; Zhou, Yanxia; Li, Xinru; Qu, Xiaoyou; Deng, Yunqiang; Wang, Ziqi; He, Chuyu; Zou, Yang; Jin, Yiguang; Liu, Yan

2017-03-01

pH-responsive polymeric micelles have shown promise for the targeted and intracellular delivery of antitumor agents. The present study aimed to elucidate the possible mechanisms of pH-sensitivity and cellular internalization of PEOz-b-PLA micelles in detail, further unravel the effect of hydrophilic/hydrophobic ratio of the micelles on their cellular internalization, and examine the intracellular trafficking routes and fate of PEOz-b-PLA after internalization of the micelles. The results of variations in the size and Zeta potential of PEOz-b-PLA micelles and cross-sectional area of PEOz-b-PLA molecules with pH values suggested that electrostatic repulsion between PEOz chains resulting from ionization of the tertiary amide groups along PEOz chain at pH lower than its pK a was responsible for pH-sensitivity of PEOz-b-PLA micelles. Furthermore, the studies on internalization of PEOz-b-PLA micelles by MCF-7 cells revealed that the uptake of PEOz-b-PLA micelles was strongly influenced by their structural features, and showed that PEOz-b-PLA micelles with hydrophilic/hydrophobic ratio of 1.7-2.0 exhibited optimal cellular uptake. No evident alteration in cellular uptake of PEOz-b-PLA micelles was detected by flow cytometry upon the existence of EIPA and chlorpromazine. However, the intracellular uptake of the micelles in the presence of MβCD and genistein was effectively inhibited. Hence, the internalization of such micelles by MCF-7 cells appeared to proceed mainly through caveolae/lipid raft-mediated endocytosis without being influenced by their hydrophilic/hydrophobic ratio. Confocal micrographs revealed that late endosomes, mitochondria and endoplasmic reticulum were all involved in the intracellular trafficking of PEOz-b-PLA copolymers following their internalization via endocytosis, and then part of them was excreted from tumor cells to extracellular medium. These findings provided valuable information for developing desired PEOz-b-PLA micelles to improve their therapeutic efficacy and reducing the potential safety risks associated with their intracellular accumulation.

A prodrug micellar carrier assembled from polymers with pendant farnesyl thiosalicylic acid moieties for improved delivery of paclitaxel.

PubMed

Sun, Jingjing; Chen, Yichao; Li, Ke; Huang, Yixian; Fu, Xiaofeng; Zhang, Xiaolan; Zhao, Wenchen; Wei, Yuan; Xu, Liang; Zhang, Peijun; Venkataramanan, Raman; Li, Song

2016-10-01

In order to achieve enhanced and synergistic delivery of paclitaxel (PTX), a hydrophobic anticancer agent, two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks, were synthesized. Both POEG-b-PFTS polymers were able to form micelles with intrinsic antitumor activity in vitro and in vivo. Employing these micelles as a carrier to load PTX, their drug loading capacity, stability, in vivo biodistribution and tumor inhibition effect were evaluated. PTX/POEG15-b-PFTS16 mixed micelles exhibited an excellent stability of 9days at 4°C with a PTX loading capacity of 8.2%, which was more effective than PTX/POEG15-b-PFTS6 mixed micelles. In vivo biodistribution data showed that DiR-loaded POEG-b-PFTS micelles were more effectively localized in the tumor than in other organs. Moreover, both PTX/POEG-b-PFTS micelles showed significantly higher antitumor activity than Taxol in a 4T1.2 murine breast tumor model, and the tumor inhibition and animal survival followed the order of PTX/POEG15-b-PFTS16>PTX/POEG15-b-PFTS6>POEG15-b-PFTS16>Taxol≈POEG15-b-PFTS6. Our data suggest that POEG-b-PFTS micelles are a promising anticancer drug carrier that warrants more studies in the future. Polymerization of drug-based monomer represents a facile and precise method to obtain well-defined polymeric prodrug amphiphiles. Currently, most reports largely focus on the synthesis methods and the biophysical properties. There is limited information about their anti-tumor activity and delivery function as prodrug carriers in vitro and in vivo. In this manuscript, we report the development of two novel prodrug copolymers, POEG15-b-PFTS6 and POEG15-b-PFTS16 composed of hydrophilic poly(oligo(ethylene glycol) methacrylate) (POEG) and hydrophobic farnesylthiosalicylate (FTS, a nontoxic Ras antagonist) blocks. Both POEG-b-PFTS polymers were able to self-assemble into nano-sized micelles with intrinsic antitumor activity in vitro and in vivo. More importantly, POEG-b-PFTS polymers were effective in forming stable mixed micelles with various anticancer agents including PTX, DOX, docetaxel, gefitinib, and imatinib. Delivery of PTX via our new carrier led to significantly improved antitumor activity, suggesting effective PTX/FTS combination therapy. We believe that our study shall be of broad interest to the readers in the fields of biomaterials and drug delivery. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Location of Varying Hydrophobicity Zinc(II) Phthalocyanine-Type Photosensitizers in Methoxy Poly(ethylene oxide) and Poly(l-lactide) Block Copolymer Micelles Using 1H NMR and XPS Techniques.

PubMed

Lamch, Łukasz; Tylus, Włodzimierz; Jewgiński, Michał; Latajka, Rafał; Wilk, Kazimiera A

2016-12-15

Hydrophobic zinc(II) phthalocyanine-type derivatives, solubilized in polymeric micelles (PMs), provide a befitting group of so-called nanophotosensitizers, suitable for a variety of photodynamic therapy (PDT) protocols. The factors that influence the success of such products in PDT are the location of the active cargo in the PMs and the nanocarrier-enhanced ability to safely interact with biological systems and fulfill their therapeutic functions. Therefore, the aim of this work was to determine the solubilization loci of three phthalocyanines of varying hydrophobicity, i.e., zinc(II) phthalocyanine (ZnPc), along with its tetrasulfonic acid (ZnPc-sulfo 4 ) and perfluorinated (ZnPcF 16 ) derivatives, loaded in polymeric micelles of methoxy poly(ethylene oxide)-b-poly(l-lactide) (mPEG-b-PLLA), by means of 1 H nuclear magnetic resonance (NMR) and X-ray photoelectron spectroscopy (XPS) combined with ion sputtering. Furthermore, the microenvironment influence upon the chemical and physical status of the solubilized cargo in PMs, expressed by photobleaching and reactive oxygen species (ROS) generation comparing to the same properties of native cargoes in solution, was also evaluated and discussed in regards to the probing location data. The studied phthalocyanine-loaded PMs exhibited good physical stability, high drug-loading efficiency, and a size of less than ca. 150 nm with low polydispersity indices. The formation of polymeric micelles and the solubilization locus were investigated by 1 H NMR and XPS. ZnPc localized within the PM core, whereas both ZnPcF 16 and ZnPc-sulfo 4 - in the corona of PMs. We proved that the cargo locus is crucial for the photochemical properties of the studied phthalocyanines; the increase in photostability and ability to generate ROS in micellar solution compared to free photosensitizer was most significant for the photosensitizer in the PM core. Our results indicate the role of the cargo location in the PM microenvironment and demonstrate that such attempts are fundamental for improving the properties of photosensitizers and their assumed efficiency as nanophotosensitizers in PDT.

Folic acid Targeted Polymeric Micelles Based on Tocopherol Succinate- Pulluan as an Effective Carrier for Epirubicin: Preparation, Characterization and In-vitro Cytotoxicity Assessment.

PubMed

Hassanzadeh, Farshid; Mehdifar, Mozhdeh; Varshosaz, Jaleh; Khodarahmi, Ghadam Ali; Rostami, Mahboubeh

2018-02-14

Chemotherapy still encounters a serious drawback, the lack of selectivity of anticancer drugs toward neoplastic cells, thus, the normal cells are affected by the cytotoxic action of the drugs. This causes a narrow therapeutic index in most anticancer drugs. We describe the preparation of pullulan-tocopherol succinate-folic acid (Pu-TS-FA) micelles for the first time to targeted delivery of Epirubicin (EPI) to Hela and MCF-7 cell lines. We confirmed the structure of conjugate using spectroscopic methods. The degree of substitution for both folic acid and tocopherol succinate was calculated using 1HNMR. We prepared the micelles via direct dissolution method. All the physicochemical properties of micelles including size, zeta potential, polydispersity index (PDI), critical micelle concentration (CMC), entrapment efficiency (EE %) and release efficiency (RE24%) were determined. The morphology of particles was studied using transmission electron microscopy (TEM), and the in-vitro cell cytotoxicity of EPI loaded micelles was studied using MTT assay on MCF-7 and Hela cell lines. The optimized micelles showed the particle size of 149.5 nm, the zeta potential of -6.49 mV, a polydispersity index of 0.259 ± 0.07, LE% of 88 %, and RE24% of 63 ± 2.45 % with a relatively low CMC 194.87 µg/ml. TEM showed the relatively uniform spherical structure for particles and in vitro MTT assay showed that EPI loaded micelles were more toxic on Hela cell line than MCF7 as expected. Since the Pu-TS-FA micelle could improve the anticancer activity of epirubicin and would be a promising candidate for EPI treatment of cancers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Phenformin-loaded polymeric micelles for targeting both cancer cells and cancer stem cells in vitro and in vivo.

PubMed

Krishnamurthy, Sangeetha; Ng, Victor W L; Gao, Shujun; Tan, Min-Han; Yang, Yi Yan

2014-11-01

Conventional cancer chemotherapy often fails as most anti-cancer drugs are not effective against drug-resistant cancer stem cells. These surviving cancer stem cells lead to relapse and metastasis. In this study, an anti-diabetic drug, phenformin, capable of eliminating cancer stem cells was loaded into micelles via self-assembly using a mixture of a diblock copolymer of poly(ethylene glycol) (PEG) and urea-functionalized polycarbonate and a diblock copolymer of PEG and acid-functionalized polycarbonate through hydrogen bonding. The phenformin-loaded micelles, having an average diameter of 102 nm with narrow size distribution, were stable in serum-containing solution over 48 h and non-cytotoxic towards non-cancerous cells. More than 90% of phenformin was released from the micelles over 96 h. Lung cancer stem cells (side population cells, i.e. SP cells) and non-SP cells were sorted from H460 human lung cancer cell line, and treated with free phenformin and phenformin-loaded micelles. The results showed that the drug-loaded micelles were more effective in inhibiting the growth of both SP and non-SP cells. In vivo studies conducted in an H460 human lung cancer mouse model demonstrated that the drug-loaded micelles had greater anti-tumor efficacy, and reduced the population of SP cells in the tumor tissues more effectively than free phenformin. Liver function analysis was performed following drug treatments, and the results indicated that the drug-loaded micelles did not cause liver damage, a harmful side-effect of phenformin when used clinically. These phenformin-loaded micelles may be used to target both cancer cells and cancer stem cells in chemotherapy for the prevention of relapse and metastasis. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nanomedicines for Inflammatory Arthritis: Head-To-Head Comparison of Glucocorticoid-Containing Polymers, Micelles and Liposomes

PubMed Central

Crielaard, Bart J.; Dusad, Anand; Lele, Subodh M.; Rijcken, Cristianne J. F.; Metselaar, Josbert M; Kostková, Hana; Etrych, Tomáš; Ulbrich, Karel; Kiessling, Fabian; Mikuls, Ted R.; Hennink, Wim E.; Storm, Gert; Lammers, Twan; Wang, Dong

2014-01-01

As an emerging research direction, nanomedicine has been increasingly utilized to treat inflammatory diseases. In this head-to-head comparison study, four established nanomedicine formulations of dexamethasone, including liposomes (L-Dex), core-crosslinked micelles (M-Dex), slow releasing polymeric prodrugs (P-Dex-slow) and fast releasing polymeric prodrugs (P-Dex-fast), were evaluated in an adjuvant-induced arthritis rat model with an equivalent dose treatment design. It was found that after a single i.v. injection, the formulations with the slower drug release kinetics (i.e. M-Dex and P-Dex-slow) maintained longer duration of therapeutic activity than those with relatively faster drug release kinetics, resulting in better joint protection. This finding will be instructional in the future development and optimization of nanomedicines for the clinical management of rheumatoid arthritis. The outcome of this study also illustrates the value of such head-to-head comparison studies in translational nanomedicine research. PMID:24341611

Polymeric Nano-Micelles as Novel Cargo-Carriers for LY2157299 Liver Cancer Cells Delivery.

PubMed

Hanafy, Nemany Abdelhamid Nemany; Quarta, Alessandra; Ferraro, Marzia Maria; Dini, Luciana; Nobile, Concetta; De Giorgi, Maria Luisa; Carallo, Sonia; Citti, Cinzia; Gaballo, Antonio; Cannazza, Giuseppe; Rinaldi, Rosaria; Giannelli, Gianluigi; Leporatti, Stefano

2018-03-06

LY2157299 (LY), which is very small molecule bringing high cancer diffusion, is a pathway antagonist against TGFβ. LY dosage can be diluted by blood plasma, can be captured by immune system or it might be dissolved during digestion in gastrointestinal tract. The aim of our study is to optimize a "nano-elastic" carrier to avoid acidic pH of gastrointestinal tract, colon alkaline pH, and anti-immune recognition. Polygalacturonic acid (PgA) is not degradable in the gastrointestinal tract due to its insolubility at acidic pH. To avoid PgA solubility in the colon, we have designed its conjugation with Polyacrylic acid (PAA). PgA-PAA conjugation has enhanced their potential use for oral and injected dosage. Following these pre-requisites, novel polymeric nano-micelles derived from PgA-PAA conjugation and loading LY2157299 are developed and characterized. Efficacy, uptake and targeting against a hepatocellular carcinoma cell line (HLF) have also been demonstrated.

Dual soft-template system based on colloidal chemistry for the synthesis of hollow mesoporous silica nanoparticles.

PubMed

Li, Yunqi; Bastakoti, Bishnu Prasad; Imura, Masataka; Tang, Jing; Aldalbahi, Ali; Torad, Nagy L; Yamauchi, Yusuke

2015-04-20

A new dual soft-template system comprising the asymmetric triblock copolymer poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-b-P2VP-b-PEO) and the cationic surfactant cetyltrimethylammonium bromide (CTAB) is used to synthesize hollow mesoporous silica (HMS) nanoparticles with a center void of around 17 nm. The stable PS-b-P2VP-b-PEO polymeric micelle serves as a template to form the hollow interior, while the CTAB surfactant serves as a template to form mesopores in the shells. The P2VP blocks on the polymeric micelles can interact with positively charged CTA(+) ions via negatively charged hydrolyzed silica species. Thus, dual soft-templates clearly have different roles for the preparation of the HMS nanoparticles. Interestingly, the thicknesses of the mesoporous shell are tunable by varying the amounts of TEOS and CTAB. This study provides new insight on the preparation of mesoporous materials based on colloidal chemistry. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Design and evaluation of mPEG-PLA micelles functionalized with drug-interactive domains as improved drug carriers for docetaxel delivery.

PubMed

Qi, Dingqing; Gong, Feirong; Teng, Xin; Ma, Mingming; Wen, Huijing; Yuan, Weihao; Cheng, Yi; Lu, Chong

2017-10-01

Polymeric micelles are very attractive drug delivery systems for hydrophobic agents, owing to their readily tailorable chemical structure and ease for scale-up preparation. However, the intrinsic poor stability of drug-loaded micelles presents one of the major challenges for most micellar systems in the translation to clinical applications. In this study, a simple, well-defined, and easy-to-scale up 9-Fluorenylmethoxycarbonyl (Fmoc) and tert-butoxycarbonyl (Boc) containing lysine dendronized mPEG-PLA (mPEG-PLA-Lys(FB) 2 ) micellar formulation was designed and prepared for docetaxel (DTX) delivery, in an effort to improve the stability of the micelles, and its physicochemical properties, pharmacokinetics, and anti-tumor efficacy against SKOV-3 ovarian cancer were evaluated. MPEG-PLA-Lys(FB) 2 was synthesized via a three-step synthetic route, and it actively interacted with DTX in aqueous media to form stable micelles with small particle sizes (~17-19 nm) and narrow size distribution (PI < 0.1), which can be lyophilized and easily reconstituted in saline without significant change in particle size distribution. In vitro drug-release study demonstrated that mPEG-PLA-Lys(FB) 2 micelles achieved delayed and sustained release manner of DTX in comparison with mPEG-PLA micelles. Further in vivo xenograft tumor model in nude mice DTX/mPEG-PLA-Lys(FB) 2 micelles demonstrated significantly higher inhibitory effect on tumor growth than the marketed formulation Taxotere. Thus, our system may hold promise as a simple and effective delivery system for DTX with a potential for translation into clinical study.

Targeting Mast Cells and Basophils with Anti-FcεRIα Fab-Conjugated Celastrol-Loaded Micelles Suppresses Allergic Inflammation.

PubMed

Peng, Xia; Wang, Juan; Li, Xianyang; Lin, Lihui; Xie, Guogang; Cui, Zelin; Li, Jia; Wang, Yuping; Li, Li

2015-12-01

Mast cells and basophils are effector cells in the pathophysiology of allergic diseases. Targeted elimination of these cells may be a promising strategy for the treatment of allergic disorders. Our present study aims at targeted delivery of anti-FcεRIα Fab-conjugated celastrol-loaded micelles toward FcεRIα receptors expressed on mast cells and basophils to have enhanced anti-allergic effect. To achieve this aim, we prepared celastrol-loaded (PEO-block-PPO-block-PEO, Pluronic) polymeric nanomicelles using thin-film hydration method. The anti-FcεRIα Fab Fragment was then conjugated to carboxyl groups on drug-loaded micelles via EDC amidation reaction. The anti-FcεRIα Fab-conjugated celastrol-loaded micelles revealed uniform particle size (93.43 ± 12.93 nm) with high loading percentage (21.2 ± 1.5% w/w). The image of micelles showed oval and rod like. The anti-FcεRIα Fab-conjugated micelles demonstrated enhanced cellular uptake and cytotoxity toward target KU812 cells than non-conjugated micelles in vitro. Furthermore, diffusion of the drug into the cells allowed an efficient induction of cell apoptosis. In mouse model of allergic asthma, treatment with anti-FcεRIα Fab-conjugated micelles increased lung accumulation of micelles, and significantly reduced OVA-sIgE, histamine and Th2 cytokines (IL-4, IL-5, TNF-α) levels, eosinophils infiltration and mucus production. In addition, in mouse model of passive cutaneous anaphylaxis, anti-FcεRIα Fab-conjugated celastrol-loaded micelles treatment significantly decreased extravasated evan's in the ear. These results indicate that anti-FcεRIα Fab-conjugated celastrol-loaded micelles can target and selectively kill mast cells and basophils which express FcεRIα, and may be efficient reagents for the treatment of allergic disorders and mast cell related diseases.

Covalent and non-covalent curcumin loading in acid-responsive polymeric micellar nanocarriers

NASA Astrophysics Data System (ADS)

Gao, Min; Chen, Chao; Fan, Aiping; Zhang, Ju; Kong, Deling; Wang, Zheng; Zhao, Yanjun

2015-07-01

Poor aqueous solubility, potential degradation, rapid metabolism and elimination lead to low bioavailability of pleiotropic impotent curcumin. Herein, we report two types of acid-responsive polymeric micelles where curcumin was encapsulated via both covalent and non-covalent modes for enhanced loading capacity and on-demand release. Biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) copolymer (mPEG-PLA) was conjugated with curcumin via a hydrazone linker, generating two conjugates differing in architecture (single-tail versus double-tail) and free curcumin was encapsulated therein. The two micelles exhibited similar hydrodynamic size at 95 ± 3 nm (single-tail) and 96 ± 3 nm (double-tail), but their loading capacities differed significantly at 15.0 ± 0.5% (w/w) (single-tail) and 4.8 ± 0.5% (w/w) (double-tail). Under acidic sink conditions (pH 5.0 and 6.0), curcumin displayed a faster release from the single-tail nanocarrier, which was correlated to a low IC50 of 14.7 ± 1.6 (μg mL-1) compared to the value of double-tail micelle (24.9 ± 1.3 μg mL-1) in HeLa cells. The confocal imaging and flow cytometry analysis demonstrated a superior capability of single-tail micelle for intracellular curcumin delivery, which was a consequence of the higher loading capacity and lower degree of mPEG surface coverage. In conclusion, the dual loading mode is an effective means to increase the drug content in the micellar nanocarriers whose delivery efficiency is highly dependent on its polymer-drug conjugate architecture. This strategy offers an alternative nanoplatform for intracellularly delivering impotent hydrophobic agents (i.e. curcumin) in an efficient stimuli-triggered way, which is valuable for the enhancement of curcumin’s efficacy in managing a diverse range of disorders.

Enhanced Antitumor Effects of Epidermal Growth Factor Receptor Targetable Cetuximab-Conjugated Polymeric Micelles for Photodynamic Therapy.

PubMed

Chang, Ming-Hsiang; Pai, Chin-Ling; Chen, Ying-Chen; Yu, Hsiu-Ping; Hsu, Chia-Yen; Lai, Ping-Shan

2018-02-22

Nanocarrier-based delivery systems are promising strategies for enhanced therapeutic efficacy and safety of toxic drugs. Photodynamic therapy (PDT)-a light-triggered chemical reaction that generates localized tissue damage for disease treatments-usually has side effects, and thus patients receiving photosensitizers should be kept away from direct light to avoid skin phototoxicity. In this study, a clinically therapeutic antibody cetuximab (C225) was conjugated to the surface of methoxy poly(ethylene glycol)- b -poly(lactide) (mPEG- b -PLA) micelles via thiol-maleimide coupling to allow tumor-targetable chlorin e6 (Ce6) delivery. Our results demonstrate that more C225-conjugated Ce6-loaded polymeric micelles (C225-Ce6/PM) were selectively taken up than Ce6/PM or IgG conjugated Ce6/PM by epidermal growth factor receptor (EGFR)-overexpressing A431 cells observed by confocal laser scanning microscopy (CLSM), thereby decreasing the IC 50 value of Ce6-mediated PDT from 0.42 to 0.173 μM. No significant differences were observed in cellular uptake study or IC 50 value between C225-Ce6/PM and Ce6/PM groups in lower EGFR expression HT-29 cells. For antitumor study, the tumor volumes in the C225-Ce6/PM-PDT group (percentage of tumor growth inhibition, TGI% = 84.8) were significantly smaller than those in the Ce6-PDT (TGI% = 38.4) and Ce6/PM-PDT groups (TGI% = 53.3) ( p < 0.05) at day 21 through reduced cell proliferation in A431 xenografted mice. These results indicated that active EGFR targeting of photosensitizer-loaded micelles provides a possible way to resolve the dose-limiting toxicity of conventional photosensitizers and represents a potential delivery system for PDT in a clinical setting.

Mechanistic insights for block copolymer morphologies: how do worms form vesicles?

PubMed

Blanazs, Adam; Madsen, Jeppe; Battaglia, Giuseppe; Ryan, Anthony J; Armes, Steven P

2011-10-19

Amphiphilic diblock copolymers composed of two covalently linked, chemically distinct chains can be considered to be biological mimics of cell membrane-forming lipid molecules, but with typically more than an order of magnitude increase in molecular weight. These macromolecular amphiphiles are known to form a wide range of nanostructures (spheres, worms, vesicles, etc.) in solvents that are selective for one of the blocks. However, such self-assembly is usually limited to dilute copolymer solutions (<1%), which is a significant disadvantage for potential commercial applications such as drug delivery and coatings. In principle, this problem can be circumvented by polymerization-induced block copolymer self-assembly. Here we detail the synthesis and subsequent in situ self-assembly of amphiphilic AB diblock copolymers in a one pot concentrated aqueous dispersion polymerization formulation. We show that spherical micelles, wormlike micelles, and vesicles can be predictably and efficiently obtained (within 2 h of polymerization, >99% monomer conversion) at relatively high solids in purely aqueous solution. Furthermore, careful monitoring of the in situ polymerization by transmission electron microscopy reveals various novel intermediate structures (including branched worms, partially coalesced worms, nascent bilayers, "octopi", "jellyfish", and finally pure vesicles) that provide important mechanistic insights regarding the evolution of the particle morphology during the sphere-to-worm and worm-to-vesicle transitions. This environmentally benign approach (which involves no toxic solvents, is conducted at relatively high solids, and requires no additional processing) is readily amenable to industrial scale-up, since it is based on commercially available starting materials.

Enzyme-Cleavable Polymeric Micelles for the Intracellular Delivery of Proapoptotic Peptides.

PubMed

Kern, Hanna B; Srinivasan, Selvi; Convertine, Anthony J; Hockenbery, David; Press, Oliver W; Stayton, Patrick S

2017-05-01

Peptides derived from the third Bcl-2 homology domain (BH3) renormalize apoptotic signaling by antagonizing prosurvival Bcl-2 family members. These potential peptide drugs exhibit therapeutic activities but are limited by barriers including short circulation half-lives and poor penetration into cells. A diblock polymeric micelle carrier for the BIM BH3 peptide was recently described that demonstrated antitumor activity in a B-cell lymphoma xenograft model [Berguig et al., Mol. Ther. 2015, 23, 907-917]. However, the disulfide linkage used to conjugate the BIM peptide was shown to have nonoptimal blood stability. Here we describe a peptide macromonomer composed of BIM capped with a four amino acid cathepsin B substrate (FKFL) that possesses high blood stability and is cleaved to release the drug inside of target cells. Employing RAFT polymerization, the peptide macromonomer was directly integrated into a multifunctional diblock copolymer tailored for peptide delivery. The first polymer block was made as a macro-chain transfer agent (CTA) and composed of a pH-responsive endosomolytic formulation of N,N-diethylaminoethyl methacrylate (DEAEMA) and butyl methacrylate (BMA). The second polymer block was a copolymer of the peptide and polyethylene glycol methacrylate (PEGMA). PEGMA monomers of two sizes were investigated (300 Da and 950 Da). Protein gel analysis, high performance liquid chromatography, and coupled mass spectrometry (MS) showed that incubation with cathepsin B specifically cleaved the FKFL linker and released active BIM peptide with PEGMA 300 but not with PEGMA 950 . MALDI-TOF MS showed that incubation of the peptide monomers alone in human serum resulted in partial cleavage at the FKFL linker after 12 h. However, formulation of the peptides into polymers protected against serum-mediated peptide degradation. Dynamic light scattering (DLS) demonstrated pH-dependent micelle disassembly (25 nm polymer micelles at pH 7.4 versus 6 nm unimers at pH 6.6), and a red blood cell lysis assay showed a corresponding increase in membrane destabilizing activity (<1% lysis at pH 7.4 versus 95% lysis at pH 6.6). The full carrier-drug system successfully induced apoptosis in SKOV3 ovarian cancer cells in a dose-dependent manner, in comparison to a control polymer containing a scrambled BIM peptide sequence. Mechanistic analysis verified target-dependent activation of caspase 3/7 activity (8.1-fold increase), and positive annexin V staining (72% increase). The increased blood stability of this enzyme-cleavable peptide polymer design, together with the direct polymerization approach that eliminated postsynthetic conjugation steps, suggests that this new carrier design could provide important benefits for intracellular peptide drug delivery.

Biological assessment of self-assembled polymeric micelles for pulmonary administration of insulin.

PubMed

Andrade, Fernanda; das Neves, José; Gener, Petra; Schwartz, Simó; Ferreira, Domingos; Oliva, Mireia; Sarmento, Bruno

2015-10-01

Pulmonary delivery of drugs for both local and systemic action has gained new attention over the last decades. In this work, different amphiphilic polymers (Soluplus®, Pluronic® F68, Pluronic® F108 and Pluronic® F127) were used to produce lyophilized formulations for inhalation of insulin. Development of stimuli-responsive, namely glucose-sensitive, formulations was also attempted with the addition of phenylboronic acid (PBA). Despite influencing the in vitro release of insulin from micelles, PBA did not confer glucose-sensitive properties to formulations. Lyophilized powders with aerodynamic diameter (<6 μm) compatible with good deposition in the lungs did not present significant in vitro toxicity for respiratory cell lines. Additionally, some formulations, in particular Pluronic® F127-based formulations, enhanced the permeation of insulin through pulmonary epithelial models and underwent minimal internalization by macrophages in vitro. Overall, formulations based on polymeric micelles presenting promising characteristics were developed for the delivery of insulin by inhalation. The ability to deliver other systemic drugs via inhalation has received renewed interests in the clinical setting. This is especially true for drugs which usually require injections for delivery, like insulin. In this article, the authors investigated their previously developed amphiphilic polymers for inhalation of insulin in an in vitro model. The results should provide basis for future in vivo studies. Copyright © 2015 Elsevier Inc. All rights reserved.

Fisetin and polymeric micelles encapsulating fisetin exhibit potent cytotoxic effects towards ovarian cancer cells.

PubMed

Xiao, Xue; Zou, Juan; Fang, Yin; Meng, Yibo; Xiao, Chao; Fu, Jiaxin; Liu, Shiyu; Bai, Peng; Yao, Yuan

2018-03-15

The anti-tumor activities of Natural compounds and their derivatives are of great interest to pharmaceutical industries. Fisetin is one of prospective natural compounds in this regard but unfortunately with poor hydrophilicity. The effects of unmodified and modified fisetin in cultured ovarian cancer cells were compared by transmission electronmicroscopy to determine apoptotic bodies, MTT assay to quantitate cell numbers, and fluorescence activated cell sorting analyse of various markers to determine the apoptotic state. In addition, the efficacy of fisetin and fisetin-micelles in vivo was determined by using immunocompromised mice. Apoptosis was measured by established markers using both western blot analysis and immunochemistry. Angiogenesis in a xenograft mouse model carring SKOV3 cells was evaluated by color Doppler ultrasound and immunohistochemistry. Multiple lines of evidence indicated that fisetin and fisetin micelles induce apoptosis in ovarian cancer cells in a dose-dependent manner. Histological analysis, terminal deoxynucleotidyltransferase-mediated nick-end labeling assay, western blot, immunohistochemical detection and microvessel density detection demonstrated that fisetin and fisetin micelles induced increased tumor apoptosis, proliferation suppression and antiangiogenesis activities. As far as we know, the present study is the first time to demonstrate the potency of both fisetin and fisetin micelles inducing apoptosis in ovarian cancer cells. Further studies will be needed to validate the therapeutic potential of fisetin and fisetin micelles in ovarian cancer treatment.

Investigation of a new thermosensitive block copolymer micelle: hydrolysis, disruption, and release.

PubMed

Pelletier, Maxime; Babin, Jérôme; Tremblay, Luc; Zhao, Yue

2008-11-04

Thermosensitive polymer micelles are generally obtained with block copolymers in which one block exhibits a lower critical solution temperature in aqueous solution. We investigate a different design that is based on the use of one block bearing a thermally labile side group, whose hydrolysis upon heating shifts the hydrophilic-hydrophobic balance toward the destabilization of block copolymer micelles. Atom transfer radical polymerization was utilized to synthesize a series of diblock copolymers composed of hydrophilic poly(ethylene oxide) (PEO) and hydrophobic poly(2-tetrahydropyranyl methacrylate) (PTHPMA). We show that micelles of PEO-b-PTHPMA in aqueous solution can be destabilized as a result of the thermosensitive hydrolytic cleavage of tetrahydropyranyl (THP) groups that transforms PTHPMA into hydrophilic poly(methacrylic acid). The three related processes occurring in aqueous solution, namely, hydrolytic cleavage of THP, destabilization of micelles, and release of loaded Nile Red (NR), were investigated simultaneously using 1H NMR, dynamic light scattering, and fluorescence spectroscopy, respectively. At 80 degrees C, the results suggest that the three events proceed with a similar kinetics. Although slower than at elevated temperatures, the disruption of PEO-b-PTHPMA micelles can take place at the body temperature (approximately 37 degrees C), and the release kinetics of NR can be adjusted by changing the relative lengths of the two blocks or the pH of the solution.

Formation of cage-like particles by poly(amino acid)-based block copolymers in aqueous solution.

PubMed Central

Cudd, A; Bhogal, M; O'Mullane, J; Goddard, P

1991-01-01

When dissolved in N,N-dimethylformamide and then dialyzed against phosphate-buffered saline, A-B-A block copolymers composed of poly [N5-(2-hydroxyethyl)-L-glutamine]-block-poly(gamma-benzyl-L-glutamate)- block-poly [N5-(2-hydroxyethyl)-L-glutamine] form particles. The particles are cage-like structures with average diameters of 300 nm (average polydispersity, 0.3-0.5). They are stable in aqueous solution at 4 degrees C for up to 3 weeks, at which time flocculation becomes apparent. Negative staining and freeze-fracture electron microscopy suggest that cage-like particles are formed by selective association of segregated micelle populations. A model of particle formation is presented in which B blocks form micelles in dimethylformamide. On dialysis against an aqueous solution, the extended A blocks then associate intermolecularly to form rod-shaped micelles, which connect the B block micelles. The result is a meshed cage-like particle. The implications of these observations on the aggregation behavior of polymeric surfactants in dilute solution are discussed. Images PMID:11607245

Synthesis of a large-sized mesoporous phosphosilicate thin film through evaporation-induced polymeric micelle assembly.

PubMed

Li, Yunqi; Bastakoti, Bishnu Prasad; Imura, Masataka; Suzuki, Norihiro; Jiang, Xiangfen; Ohki, Shinobu; Deguchi, Kenzo; Suzuki, Madoka; Arai, Satoshi; Yamauchi, Yusuke

2015-01-01

A triblock copolymer, poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-b-P2VP-b-PEO) was used as a soft template to synthesize large-sized mesoporous phosphosilicate thin films. The kinetically frozen PS core stabilizes the micelles. The strong interaction of the inorganic precursors with the P2VP shell enables the fabrication of highly robust walls of phosphosilicate and the PEO helps orderly packing of the micelles during solvent evaporation. The molar ratio of phosphoric acid and tetraethyl orthosilicate is crucial to achieve the final mesostructure. The insertion of phosphorus species into the siloxane network is studied by (29) Si and (31) P MAS NMR spectra. The mesoporous phosphosilicate films exhibit steady cell adhesion properties and show great promise as excellent materials in bone-growth engineering applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, characterization, conformation and self-assembly behavior of polypeptide-based brush with oligo (ethylene glycol) side chains

NASA Astrophysics Data System (ADS)

Huang, Yugang; Luo, Weiang; Ye, Guodong

2015-02-01

A new polypeptide-based copolymer brush composed of poly (γ-propargyl-L-glutamate)-block-poly (propylene oxide)-block-poly (γ-propargyl-L-glutamate) backbone (PPLG-b-PPO-b-PPLG) and oligo (ethylene glycol) (PEG) side-chain was synthesized by combination of N-carboxyanhydride ring-opening polymerization and click chemistry. Nearly 100% grafting efficiency was achieved by copper-catalyzed azide-alkyne Huisgen 1,3-dipolar cycloaddition (CuAAc) reaction. The α-helical conformation adopted by the grafted polypeptide blocks in water was relatively stable and showed a reversible change in a heating-cooling circle from 5 to 70 °C. It displayed weak stability against elevated temperature but still reversible changes in the presence of 0.47 M NaCl. The brushes were amphiphilic and could self-assemble into thermo-sensitive micelles in water. Big micelles could break into small micelles upon heating due to the improved solubility.

Polymeric microcapsules assembled from a cationic/zwitterionic pair of responsive block copolymer micelles.

PubMed

Addison, Timothy; Cayre, Olivier J; Biggs, Simon; Armes, Steven P; York, David

2010-05-04

Using a layer-by-layer (LbL) approach, this work presents the preparation of hollow microcapsules with a membrane constructed entirely from a cationic/zwitterionic pair of pH-responsive block copolymer micelles. Our previous work with such systems highlighted that, in order to retain the responsive nature of the individual micelles contained within the multilayer membranes, it is important to optimize the conditions required for the selective dissolution of the sacrificial particulate templates. Consequently, here, calcium carbonate particles have been employed as colloidal templates as they can be easily dissolved in aqueous environments with the addition of chelating agents such as ethylenediaminetetraacetic acid (EDTA). Furthermore, the dissolution can be carried out in solutions buffered to a desirable pH so not to adversely affect the pH sensitive micelles forming the capsule membranes. First, we have deposited alternating layers of anionic poly[2-(dimethylamino)ethyl methacrylate-block-poly(2-(diethylamino)ethyl methacrylate)] (PDMA-PDEA) and cationic poly(2-(diethylamino)ethyl)methacrylate-block-poly(methacrylic acid) (PDEA-PMAA) copolymer micelles onto calcium carbonate colloidal templates. After deposition of five micelle bilayers, addition of dilute EDTA solution resulted in dissolution of the calcium carbonate and formation of hollow polymer capsules. The capsules were imaged using atomic force microscopy (AFM) and scanning electron microscopy (SEM), which shows that the micelle/micelle membrane is sufficiently robust to withstand dissolution of the supporting template. Quartz crystal microbalance studies were conducted and provide good evidence that the micelle multilayer structure is retained after EDTA treatment. In addition, a hydrophobic dye was incorporated into the micelle cores prior to adsorption. After dissolution of the particle template, the resulting hollow capsules retained a high concentration of dye, suggesting that the core/shell structure of the micelles remains intact. Finally, thermogravimetric analysis (TGA) of dried capsules confirmed complete removal of the sacrificial inorganic template. As far as we are aware, this is the first demonstration of LbL assembled capsules composed entirely from responsive block copolymer micelles. The results presented here when combined with our previous findings demonstrate that such systems have potential application in the encapsulation and triggered release of actives.

Curcumin-Loaded Blood-Stable Polymeric Micelles for Enhancing Therapeutic Effect on Erythroleukemia.

PubMed

Gong, Feirong; Chen, Dan; Teng, Xin; Ge, Junhua; Ning, Xianfeng; Shen, Ya-Ling; Li, Jian; Wang, Shanfeng

2017-08-07

Curcumin has high potential in suppressing many types of cancer and overcoming multidrug resistance in a multifaceted manner by targeting diverse molecular targets. However, the rather low systemic bioavailability resulted from its poor solubility in water and fast metabolism/excretion in vivo has hampered its applications in cancer therapy. To increase the aqueous solubility of curcumin while retaining the stability in blood circulation, here we report curcumin-loaded copolymer micelles with excellent in vitro and in vivo stability and antitumor efficacy. The two copolymers used for comparison were methoxy-poly(ethylene glycol)-block-poly(ε-caprolactone) (mPEG-PCL) and N-(tert-butoxycarbonyl)-l-phenylalanine end-capped mPEG-PCL (mPEG-PCL-Phe(Boc)). In vitro cytotoxicity evaluation against human pancreatic SW1990 cell line showed that the delivery of curcumin in mPEG-PCL-Phe(Boc) micelles to cancer cells was efficient and dosage-dependent. The pharmacokinetics in ICR mice indicated that intravenous (i.v.) administration of curcumin/mPEG-PCL-Phe(Boc) micelles could retain curcumin in plasma much better than curcumin/mPEG-PCL micelles. Biodistribution results in Sprague-Dawley rats also showed higher uptake and slower elimination of curcumin into liver, lung, kidney, and brain, and lower uptake into heart and spleen of mPEG-PCL-Phe(Boc) micelles, as compared with mPEG-PCL micelles. Further in vivo efficacy evaluation in multidrug-resistant human erythroleukemia K562/ADR xenograft model revealed that i.v. administration of curcumin-loaded mPEG-PCL-Phe(Boc) micelles significantly delayed tumor growth, which was attributed to the improved stability of curcumin in the bloodstream and increased systemic bioavailability. The mPEG-PCL-Phe(Boc) micellar system is promising in overcoming the key challenge of curcumin's to promote its applications in cancer therapy.

TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors

PubMed Central

Sethuraman, Vijay A; Bae, You Han

2007-01-01

A novel drug targeting system for acidic solid tumors has been developed based on ultra pH sensitive polymer and cell penetrating TAT. The delivery system consisted of two components: 1) A polymeric micelle that has a hydrophobic core made of Poly(L-lactic acid) (PLLA) and a hydrophilic shell consisting of Polyethylene Glycol (PEG) conjugated to TAT (TATmicelle), 2) An ultra pH sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and PEG (PSD-b-PEG). The anionic PSD is complexed with cationic TAT of the micelles to achieve the final carrier, which could systemically shield the micelles and expose them at slightly acidic tumor pH. TATmicelles had particle sizes between 20 to 45 nm and their critical micelle concentrations were 3.5 mg/L to 5.5 mg/L. The TATmicelles, upon mixing with pH sensitive PSD-b-PEG, showed slight increase in particle size between pH 8.0 and 6.8 (60–90 nm), indicating complexation. As the pH was decreased (pH 6.6 to 6.0) two populations were observed, one that of normal TAT micelles (45 nm) and the other of aggregated hydrophobic PSD-b-PEG. Zeta potential measurements showed similar trend substantiating the shielding/deshielding process. Flowcytometry and confocal microscopy showed significantly higher uptake of TAT micelles at pH 6.6 compared to pH 7.4 indicating shielding at normal pH and deshielding at tumor pH. The flowcytometry indicated that the TAT not only translocates into the cells but is also seen on the surface of the nucleus. These results strongly indicate that the above drug loaded micelles would be able to target any hydrophobic drug near the nucleus. PMID:17239466

Thermosensitive mPEG-b-PA-g-PNIPAM comb block copolymer micelles: effect of hydrophilic chain length and camptothecin release behavior.

PubMed

Yang, Xiao-Li; Luo, Yan-Ling; Xu, Feng; Chen, Ya-Shao

2014-02-01

Block copolymer micelles are extensively used as drug controlled release carriers, showing promising application prospects. The comb or brush copolymers are especially of great interest, whose densely-grafted side chains may be important for tuning the physicochemical properties and conformation in selective solvents, even in vitro drug release. The purpose of this work was to synthesize novel block copolymer combs via atom transfer radical polymerization, to evaluate its physicochemical features in solution, to improve drug release behavior and to enhance the bioavailablity, and to decrease cytotoxicity. The physicochemical properties of the copolymer micelles were examined by modulating the composition and the molecular weights of the building blocks. A dialysis method was used to load hydrophobic camptothecin (CPT), and the CPT release and stability were detected by UV-vis spectroscopy and high-performance liquid chromatography, and the cytotoxicity was evaluated by MTT assays. The copolymers could self-assemble into well-defined spherical core-shell micelle aggregates in aqueous solution, and showed thermo-induced micellization behavior, and the critical micelle concentration was 2.96-27.64 mg L(-1). The micelles were narrow-size-distribution, with hydrodynamic diameters about 128-193 nm, depending on the chain length of methoxy polyethylene glycol (mPEG) blocks and poly(N-isopropylacrylamide) (PNIPAM) graft chains or/and compositional ratios of mPEG to PNIPAM. The copolymer micelles could stably and effectively load CPT but avoid toxicity and side-effects, and exhibited thermo-dependent controlled and targeted drug release behavior. The copolymer micelles were safe, stable and effective, and could potentially be employed as CPT controlled release carriers.

Development of chitosan oleate ionic micelles loaded with silver sulfadiazine to be associated with platelet lysate for application in wound healing.

PubMed

Dellera, Eleonora; Bonferoni, Maria Cristina; Sandri, Giuseppina; Rossi, Silvia; Ferrari, Franca; Del Fante, Claudia; Perotti, Cesare; Grisoli, Pietro; Caramella, Carla

2014-11-01

In the treatment of chronic wounds, topical application of anti-infective drugs such as silver sulfadiazine (AgSD) is of primary importance to avoid infections and accelerate wound repair. AgSD is used in burns and chronic wounds for its wide antibacterial spectrum, but presents limitations due to poor solubility and cytotoxicity. In the present work polymeric micelles obtained by self-assembling of chitosan ionically modified by interaction with oleic acid were developed as carriers for AgSD to overcome the drawbacks of the drug. The AgSD loaded micelles were intended to be associated in wound healing with platelet lysate (PL), a hemoderivative rich in growth factors. Unloaded micelles demonstrated good compatibility with both fibroblasts and PL. The relevance of chitosan concentration and of the ratio between chitosan and oleic acid to the drug loading and the particle size of nanoparticles was studied. A marked increase (up to 100 times with respect to saturated solution) of AgSD concentration in micelle dispersion was obtained. Moreover, the encapsulation reduced the cytotoxic effect of the drug towards fibroblasts and the drug incompatibility with PDGF-AB (platelet derived growth factor), chosen as representative of platelet growth factors. Copyright © 2014. Published by Elsevier B.V.

Polymeric micelles encapsulating fisetin improve the therapeutic effect in colon cancer.

PubMed

Chen, Yishan; Wu, Qinjie; Song, Linjiang; He, Tao; Li, Yuchen; Li, Ling; Su, Weijun; Liu, Lei; Qian, Zhiyong; Gong, Changyang

2015-01-14

The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) was discovered to possess antitumor activity, revealing its potential value in future chemotherapy. However, its poor water solubility makes it difficult for intravenous administration. In this study, the monomethyl poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) copolymer was applied to prepare nanoassemblies of fisetin by a self-assembly procedure. The prepared fisetin micelles gained a mean particle size of 22 ± 3 nm, polydisperse index of 0.163 ± 0.032, drug loading of 9.88 ± 0.14%, and encapsulation efficiency of 98.53 ± 0.02%. Compared with free fisetin, fisetin micelles demonstrated a sustained and prolonged in vitro release behavior, as well as enhanced cytotoxicity, cellular uptake, and fisetin-induced apoptosis in CT26 cells. As for in vivo studies, fisetin micelles were more competent for suppressing tumor growth and prolonging survival time than free fisetin in the subcutaneous CT26 tumor model. Furthermore, histological analysis, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, immunohistochemical detection of Ki-67, and microvessel density detection were conducted, demonstrating that fisetin micelles gained increased tumor apoptosis induction, proliferation suppression, and antiangiogenesis activities. In conclusion, we have successfully produced a MPEG-PCL-based nanocarrier encapsulating fisetin with enhanced antitumor activity.

A folate modified pH sensitive targeted polymeric micelle alleviated systemic toxicity of doxorubicin (DOX) in multi-drug resistant tumor bearing mice.

PubMed

Li, Xinru; Yang, Xiucong; Lin, Zhiqiang; Wang, Dan; Mei, Dong; He, Bing; Wang, Xiaoyou; Wang, Xueqing; Zhang, Qiang; Gao, Wei

2015-08-30

The purpose of this work was to demonstrate the advantages of a folate modified pH sensitive micelle system (HPPF) on reducing the systemic toxicity of antitumor drug doxorubicin (DOX) as well as increasing the antitumor efficacy on multi-drug resistant tumor. The micelle HPPF was fabricated by PHIS-PEG and Fol-PEG-PLA using dialysis method. Multi-drug resistant human breast-cancer cell (MCF-7Adr) was used to test the therapeutic effect of DOX loaded HPPF micelles (HPPF/DOX). Nude mice bearing MCF-7Adr tumor was used to evaluate the systemic toxicity of HPPF/DOX. The micelle HPPF was successfully prepared with good size uniformity and pH sensitivity. The in vitro experiments showed that HPPF significantly increased the intracellular level and cytotoxicity of DOX. The in vivo experiments demonstrated that HPPF had largely reduced the mortality and body weight loss, improved the animal status and decreased damages on heart and lung tissues comparing to free DOX. The HPPF/DOX could significantly increase the antitumor efficacy of DOX and largely alleviate the systemic side effects induced by high dose DOX in the treatment of multi-drug resistant tumor. Copyright © 2015 Elsevier B.V. All rights reserved.

Tripartite polyionic complex (PIC) micelles as non-viral vectors for mesenchymal stem cell siRNA transfection.

PubMed

Raisin, Sophie; Morille, Marie; Bony, Claire; Noël, Danièle; Devoisselle, Jean-Marie; Belamie, Emmanuel

2017-08-22

In the context of regenerative medicine, the use of RNA interference mechanisms has already proven its efficiency in targeting specific gene expression with the aim of enhancing, accelerating or, more generally, directing stem cell differentiation. However, achievement of good transfection levels requires the use of a gene vector. For in vivo applications, synthetic vectors are an interesting option to avoid possible issues associated with viral vectors (safety, production costs, etc.). Herein, we report on the design of tripartite polyionic complex micelles as original non-viral polymeric vectors suited for mesenchymal stem cell transfection with siRNA. Three micelle formulations were designed to exhibit pH-triggered disassembly in an acidic pH range comparable to that of endosomes. One formulation was selected as the most promising with the highest siRNA loading capacity while clearly maintaining pH-triggered disassembly properties. A thorough investigation of the internalization pathway of micelles into cells with tagged siRNA was made before showing an efficient inhibition of Runx2 expression in primary bone marrow-derived stem cells. This work evidenced PIC micelles as promising synthetic vectors that allow efficient MSC transfection and control over their behavior, from the perspective of their clinical use.

Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery.

PubMed

Li, Juanjuan; Meng, Xuan; Deng, Jian; Lu, Di; Zhang, Xin; Chen, Yanrui; Zhu, Jundong; Fan, Aiping; Ding, Dan; Kong, Deling; Wang, Zheng; Zhao, Yanjun

2018-05-23

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT's antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.

Single and mixed poloxamine micelles as nanocarriers for solubilization and sustained release of ethoxzolamide for topical glaucoma therapy

PubMed Central

Ribeiro, Andreza; Sosnik, Alejandro; Chiappetta, Diego A.; Veiga, Francisco; Concheiro, Angel; Alvarez-Lorenzo, Carmen

2012-01-01

Polymeric micelles of single and mixed poloxamines (Tetronic) were evaluated regarding their ability to host the antiglaucoma agent ethoxzolamide (ETOX) for topical ocular application. Three highly hydrophilic varieties of poloxamine (T908, T1107 and T1307) and a medium hydrophilic variety (T904), possessing a similar number of propylene oxide units but different contents in ethylene oxide, were chosen for the study. The critical micellar concentration and the cloud point of mixed micelles in 0.9 per cent NaCl were slightly greater than the values predicted from the additive rule, suggesting that the co-micellization is hindered. Micellar size ranged between 17 and 120 nm and it was not altered after the loading of ETOX (2.7–11.5 mg drug g–1 poloxamine). Drug solubilization ability ranked in the order: T904 (50-fold increase in the apparent solubility) > T1107 ≅ T1307 > T908. Mixed micelles showed an intermediate capability to host ETOX but a greater physical stability, maintaining almost 100 per cent drug solubilized after 28 days. Furthermore, the different structural features of poloxamines and their combination in mixed micelles enabled the tuning of drug release profiles, sustaining the release in the 1–5 days range. These findings together with promising hen's egg test-chorioallantoic membrane biocompatibility tests make poloxamine micelles promising nanocarriers for carbonic anhydrase inhibitors in the treatment of glaucoma. PMID:22491977

High fluorescent water soluble CdTe quantum dots—a promising system for light harvesting applications

NASA Astrophysics Data System (ADS)

de Sa, Arsenio; Moura, Isabel; Abreu, Ana S.; Oliveira, Manuel; Ferreira, Miguel F.; Machado, Ana V.

2017-05-01

The entrapment of quantum dots (QDs) in the inner part of micelles formed by surfactant polymers is a powerful methodology to prepare stable and photoluminescent core nanoparticles with enhanced optical properties. These features are crucial for the application of QDs in the design of hybrid assemblies for light harvesting applications, where energy transfer processes are required. The present work was focused on the synthesis of a surfactant homopolymer, poly (acrylic acid) (PAA) macroRAFT, to be used as a stabilizer of hydrophobic cadmium telluride (CdTe) QDs in aqueous solution. PAA macroRAFT was synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization in a single chemical reaction. Its micelles were used to entangle and entrap hydrophobic CdTe QDs, with different molar ratio of polymer and QDs. The morphology and optical properties of the entrapped QDs were determined. The results showed that PAA macroRAFT is able to form micelles with a critical micelle concentration of 2.08 mg/mL. It was also noticed that the molar ratio of polymer and QDs have high influence on the QDs' morphology and their optical properties. The QDs' photoluminescence quantum yield was enhanced approximately 23% upon their entrapment in PAA macroRAFT micelles, using 60 equivalents of polymer. Moreover, while in solution, QDs are well-dispersed, having a 3.5 nm diameter, upon being entrapped in the micelles, tend to form clusters with a size around 100 nm.

Delivery of curcumin by directed self-assembled micelles enhances therapeutic treatment of non-small-cell lung cancer

PubMed Central

Zhu, Wen-Ting; Liu, Sheng-Yao; Wu, Lei; Xu, Hua-Li; Wang, Jun; Ni, Guo-Xin; Zeng, Qing-Bing

2017-01-01

Background It has been widely reported that curcumin (CUR) exhibits anticancer activity and triggers the apoptosis of human A549 non-small-cell lung cancer (NSCLC) cells. However, its application is limited owing to its poor solubility and bioavailability. Therefore, there is an urgent need to develop a new CUR formulation with higher water solubility and better biocompatibility for clinical application in the future. Materials and methods In this study, CUR-loaded methoxy polyethylene glycol–polylactide (CUR/mPEG–PLA) polymeric micelles were prepared by a thin-film hydration method. Their characteristics and antitumor effects were evaluated subsequently. Results The average size of CUR/mPEG–PLA micelles was 34.9±2.1 nm with its polydispersity index (PDI) in the range of 0.067–0.168. The encapsulation efficiency and drug loading were 90.2%±0.78% and 9.1%±0.07%, respectively. CUR was constantly released from the CUR/mPEG–PLA micelles, and its cellular uptake in A549 cells was significantly increased. It was also found that CUR/mPEG–PLA micelles inhibited A549 cell proliferation, increased the cell cytotoxicity, induced G2/M stage arrest and promoted cell apoptosis. Moreover, the CUR/mPEG–PLA micelles suppressed the migration and invasion of A549 cells more obviously than free CUR. Additionally, CUR/mPEG–PLA micelles inhibited human umbilical vein endothelial cells migration, invasion and corresponding tube formation, implying the antiangiogenesis ability. Its enhanced antitumor mechanism may be related to the reduced expression of vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, MMP-9 and Bcl-2 as well as the increased expression of Bax. Conclusion The mPEG–PLA copolymer micelles can serve as an efficient carrier for CUR. The CUR/mPEG–PLA micelles have promising clinical potential in treating NSCLC. PMID:28435247

Nrp-1 receptor targeting peptide-functionalized TPGS micellar nanosystems to deliver 10-hydroxycampothecin for enhanced cancer chemotherapy.

PubMed

Mozhi, Anbu; Ahmad, Israr; Kaleem, Qari Muhammad; Tuguntaev, Ruslan G; Eltahan, Ahmed Shaker; Wang, Chen; Yang, Rong; Li, Chan; Liang, Xing-Jie

2018-06-01

Mitochondria are considered the power house of cells where ATP is generated for cellular metabolism, and they also act as a crucial regulator of the intrinsic apoptosis pathway. During ATP synthesis, reactive oxygen species (ROS) are produced as secondary products. Overproduction of ROS can promote mitochondrial DNA mutation, dysfunction and depolarization of the mitochondrial membrane, ultimately resulting in cell death. Therefore, the destruction of mitochondria would be an effective therapeutic approach to kill malignant tumors. Herein, we formulated a PEGylated α-TOS polymeric micellar system loaded with 10-hydroxycamptothecin (HCPT) drug to inhibit the nuclear topoisomerase I enzyme and disrupt the mitochondrial membrane to induce apoptosis. In addition, tumor-penetrating CRGDK peptide-functionalized TPGS 2k specifically bound to the Nrp-1 receptor to facilitate higher cell uptake of polymeric micelles by tumor cells. Experimental studies confirmed that HCPT-loaded and peptide-functionalized TPGS 2k -TOS micelles (HLPFTTM) showed an enhanced anti-cancer effect in A549 cancer cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Mechano-responsive hydrogels crosslinked by reactive block copolymer micelles

NASA Astrophysics Data System (ADS)

Xiao, Longxi

Hydrogels are crosslinked polymeric networks that can swell in water without dissolution. Owing to their structural similarity to the native extracelluar matrices, hydrogels have been widely used in biomedical applications. Synthetic hydrogels have been designed to respond to various stimuli, but mechanical signals have not incorporated into hydrogel matrices. Because most tissues in the body are subjected to various types of mechanical forces, and cells within these tissues have sophisticated mechano-transduction machinery, this thesis is focused on developing hydrogel materials with built-in mechano-sensing mechanisms for use as tissue engineering scaffolds or drug release devices. Self-assembled block copolymer micelles (BCMs) with reactive handles were employed as the nanoscopic crosslinkers for the construction of covalently crosslinked networks. BCMs were assembled from amphiphilic diblock copolymers of poly(n-butyl acrylate) and poly(acrylic acid) partially modified with acrylate. Radical polymerization of acrylamide in the presence of micellar crosslinkers gave rise to elastomeric hydrogels whose mechanical properties can be tuned by varying the BCM composition and concentration. TEM imaging revealed that the covalently integrated BCMs underwent strain-dependent reversible deformation. A model hydrophobic drug, pyrene, loaded into the core of BCMs prior to the hydrogel formation, was dynamically released in response to externally applied mechanical forces, through force-induced reversible micelle deformation and the penetration of water molecules into the micelle core. The mechano-responsive hydrogel has been studied for tissue repair and regeneration purposes. Glycidyl methacrylate (GMA)-modified hyaluronic acid (HA) was photochemically crosslinked in the presence of dexamethasone (DEX)-loaded crosslinkable BCMs. The resultant HA gels (HAxBCM) contain covalently integrated micellar compartments with DEX being sequestered in the hydrophobic core. Compared to the traditional HA gels prepared by radical crosslinking of HAGMA, HAxBCM gels exhibited improved drug loading and release capacity. Moreover, compressive forces exerted on the gels were transmitted to the crosslinked BCMs, resulting in a force-modulated DEX release on demand. Micelle mobility in the crosslinked networks was analyzed by fluorescence correlation spectroscopy using nile red loaded BCMs. The anti-inflammatory activities of DEX-releasing HAxBCM gels were evaluated via the in vitro culture of lipopolysaccharide-activated macrophages.

Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin.

PubMed

Chen, Ling-Chun; Chen, Yin-Chen; Su, Chia-Yu; Wong, Wan-Ping; Sheu, Ming-Thau; Ho, Hsiu-O

2016-11-16

Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders.

Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin

PubMed Central

Chen, Ling-Chun; Chen, Yin-Chen; Su, Chia-Yu; Wong, Wan-Ping; Sheu, Ming-Thau; Ho, Hsiu-O

2016-01-01

Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders. PMID:27848996

Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin

NASA Astrophysics Data System (ADS)

Chen, Ling-Chun; Chen, Yin-Chen; Su, Chia-Yu; Wong, Wan-Ping; Sheu, Ming-Thau; Ho, Hsiu-O.

2016-11-01

Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders.

Curcumin-Loaded TPGS/F127/P123 Mixed Polymeric Micelles for Cervical Cancer Therapy: Formulation, Characterization, and InVitro and InVivo Evaluation.

PubMed

Wang, Jiao; Liu, Qiang; Yang, Linnan; Xia, Xiaofei; Zhu, Rongrong; Chen, Shengguang; Wang, Mei; Cheng, Liming; Wu, Xianzheng; Wang, Shilong

2017-12-01

Cervical cancer is the fourth most common cancer in women worldwide, and existing treatments cause severe side effects and great burdens. Thus, the development of safe, inexpensive therapeutic agents is necessary. Curcumin (Cur), a well-known natural product, exerts promising anti-cancer activities against various cancer types. However, its therapeutic efficacy is severely restrained due to rapid degradation, poor aqueous solubility, and low bioavailability. The objective of this study was to investigate the therapeutic potential of novel curcumin-loaded TPGS/F127/P123 mixed polymeric micelles (Cur@NPT100) for cervical cancer treatment. The Cur@NPT100 exhibited an average size of approximately 19 nm, a zeta potential of around -4 mV, a drug loading of 8.18 ± 0.36%, and an encapsulation efficiency of 79.38 ± 4.65%. Unlike free Cur, Cur@NPT100 are readily dispersed in aqueous medium, showing enhanced stability and a sustained release profile over a 6-day period. In vitro cell culture experiments revealed that TPGS/F127/P123 mixed polymeric micelles (NPT100) based nanocarriers substantially promoted the selective cellular uptake of Cur into HeLa cells rather than by non-cancerous NIH3T3 cells, inducing higher cytotoxicity and greater apoptosis and significantly increasing the percentage of cells arrested at the G2/M phase of the cell cycle. Additionally, the Cur@NPT100 facilitated more Cur accumulation in the mitochondria and decreased the mitochondrial membrane potential. In addition, western blot assays demonstrated that Cur@NPT100 were more potent than free Cur at activating the mitochondria-mediated apoptosis pathway. In vivo results further confirmed that Cur@NPT100 exhibited a much higher antitumor efficacy than free Cur and had excellent biocompatibility. In conclusion, Cur@NPT100 might be an effective therapeutic agent for cervical cancer.

Structure-directing star-shaped block copolymers: supramolecular vesicles for the delivery of anticancer drugs.

PubMed

Yang, Chuan; Liu, Shao Qiong; Venkataraman, Shrinivas; Gao, Shu Jun; Ke, Xiyu; Chia, Xin Tian; Hedrick, James L; Yang, Yi Yan

2015-06-28

Amphiphilic polycarbonate/PEG copolymer with a star-like architecture was designed to facilitate a unique supramolecular transformation of micelles to vesicles in aqueous solution for the efficient delivery of anticancer drugs. The star-shaped amphipilic block copolymer was synthesized by initiating the ring-opening polymerization of trimethylene carbonate (TMC) from methyl cholate through a combination of metal-free organo-catalytic living ring-opening polymerization and post-polymerization chain-end derivatization strategies. Subsequently, the self-assembly of the star-like polymer in aqueous solution into nanosized vesicles for anti-cancer drug delivery was studied. DOX was physically encapsulated into vesicles by dialysis and drug loading level was significant (22.5% in weight) for DOX. Importantly, DOX-loaded nanoparticles self-assembled from the star-like copolymer exhibited greater kinetic stability and higher DOX loading capacity than micelles prepared from cholesterol-initiated diblock analogue. The advantageous disparity is believed to be due to the transformation of micelles (diblock copolymer) to vesicles (star-like block copolymer) that possess greater core space for drug loading as well as the ability of such supramolecular structures to encapsulate DOX. DOX-loaded vesicles effectively inhibited the proliferation of 4T1, MDA-MB-231 and BT-474 cells, with IC50 values of 10, 1.5 and 1.0mg/L, respectively. DOX-loaded vesicles injected into 4T1 tumor-bearing mice exhibited enhanced accumulation in tumor tissue due to the enhanced permeation and retention (EPR) effect. Importantly, DOX-loaded vesicles demonstrated greater tumor growth inhibition than free DOX without causing significant body weight loss or cardiotoxicity. The unique ability of the star-like copolymer emanating from the methyl cholate core provided the requisite modification in the block copolymer interfacial curvature to generate vesicles of high loading capacity for DOX with significant kinetic stability that have potential for use as an anti-cancer drug delivery carrier for cancer therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

Magnetic nanoparticle-conjugated polymeric micelles for combined hyperthermia and chemotherapy

NASA Astrophysics Data System (ADS)

Kim, Hyun-Chul; Kim, Eunjoo; Jeong, Sang Won; Ha, Tae-Lin; Park, Sang-Im; Lee, Se Guen; Lee, Sung Jun; Lee, Seung Woo

2015-10-01

Magnetic nanoparticle-conjugated polymeric micelles (MNP-PMs) consisting of poly(ethylene glycol)-poly(lactide) (PEG-PLA) and iron oxide nanoparticles were prepared and used as nanocarriers for combined hyperthermia and chemotherapy. Doxorubicin (DOX) was encapsulated in MNP-PMs, and an alternating magnetic field (AMF) resulted in an increase to temperature within a suitable range for inducing hyperthermia and a higher rate of drug release than observed without AMF. In vitro cytotoxicity and hyperthermia experiments were carried out using human lung adenocarcinoma A549 cells. When MNP-PMs encapsulated with an anticancer drug were used to treat A549 cells in combination with hyperthermia under AMF, 78% of the cells were killed by the double effects of heat and the drug, and the combination was more effective than either chemotherapy or hyperthermia treatment alone. Therefore, MNP-PMs encapsulated with an anticancer drug show potential for combined chemotherapy and hyperthermia.Magnetic nanoparticle-conjugated polymeric micelles (MNP-PMs) consisting of poly(ethylene glycol)-poly(lactide) (PEG-PLA) and iron oxide nanoparticles were prepared and used as nanocarriers for combined hyperthermia and chemotherapy. Doxorubicin (DOX) was encapsulated in MNP-PMs, and an alternating magnetic field (AMF) resulted in an increase to temperature within a suitable range for inducing hyperthermia and a higher rate of drug release than observed without AMF. In vitro cytotoxicity and hyperthermia experiments were carried out using human lung adenocarcinoma A549 cells. When MNP-PMs encapsulated with an anticancer drug were used to treat A549 cells in combination with hyperthermia under AMF, 78% of the cells were killed by the double effects of heat and the drug, and the combination was more effective than either chemotherapy or hyperthermia treatment alone. Therefore, MNP-PMs encapsulated with an anticancer drug show potential for combined chemotherapy and hyperthermia. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr04130a

Michael Addition Polymerization of Trifunctional Amine and Acrylic Monomer: A Versatile Platform for Development of Biomaterials.

PubMed

Cheng, Weiren; Wu, Decheng; Liu, Ye

2016-10-10

Michael addition polymerizations of amines and acrylic monomers are versatile approaches to biomaterials for various applications. A combinatorial library of poly(β-amino ester)s and diverse poly(amido amine)s from diamines and diacrylates or bis(acrylamide)s have been reported, respectively. Furthermore, novel linear and hyperbranched polymers from Michael addition polymerizations of trifunctional amines and acrylic monomers significantly enrich this category of biomaterials. In this Review, we focus on the biomaterials from Michael addition polymerizations of trifunctional amines and acrylic monomers. First we discuss how the polymerization mechanisms, which are determined by the reactivity sequence of the three types of amines of trifunctional amines, i.e., secondary (2°) amines (original), primary (1°) amines, and 2° amines (formed), are affected by the chemistry of monomers, reaction temperature, and solvent. Then we update how to design and synthesize linear and hyperbranched polymers based on the understanding of polymerization mechanisms. Linear polymers containing 2° amines in the backbones can be obtained from polymerizations of diacrylates or bis(acrylamide)s with equimolar trifunctional amine, and several approaches, e.g., 2A 2 +BB'B″, A 3 +2BB'B', A 2 +BB'B″, to hyperbranched polymers are developed. Further through molecular design of monomers, conjugation of functional species to 2° amines in the backbones of linear polymers and the abundant terminal groups of hyperbranched polymers, the amphiphilicity of polymers can be adjusted, and additional stimuli, e.g., thermal, redox, reactive oxidation species (ROS), and light, responses can be integrated with the intrinsic pH response. Finally we discuss the applications of the polymers for gene/drug delivery and bioimaging through exploring their self-assemblies in various motifs, e.g., micelles, polyplexes particles/nanorings and hydrogels. Redox-responsive hyperbranched polymers can display 300 times higher in vitro gene transfection efficiency and provide a higher in vivo siRNA efficacy than PEI. Also redox-responsive micelle carriers can improve the efficacy of anticancer drug and the bioimaging contrast. Further molecular design and optimization of this category of polymers together with in vivo studies should provide safe and efficient biomaterials for clinical applications.

Nanotechnology-based treatment for chemotherapy-resistant breast cancer

NASA Astrophysics Data System (ADS)

Abouzeid, Abraham H.; Patel, Niravkumar R.; Rachman, Ilya M.; Senn, Sean; Torchilin, Vladimir P.

2014-08-01

Background: Treatment of metastatic cancer remains a formidable clinical challenge. Better therapeutic options with improved tissue penetration and tumor cell uptake are urgently needed. Targeted nanotherapy, for improved delivery, and combinatory drug administration aimed at inhibiting chemo-resistance may be the solution. Purpose: The study was performed to evaluate the therapeutic efficacy of polymeric PEG-PE micelles, co-loaded with curcumin (CUR) and doxorubicin (DOX), and targeted with anti-GLUT1 antibody (GLUT1) against MDA-MB-231 human breast adenocarcinoma cells both in vitro and in vivo. Methods: MDA-MB-231 DOX-resistant cells were treated with non-targeted and GLUT1-targeted CUR and DOX micelles as a single agent or in combination. Tumor cells were also inoculated in female nude mice. Established tumors were treated with the micellar formulations at a dose of 6 mg/kg CUR and 1 mg/kg DOX every 2 d for a total of 7 injections. Results: CUR+DOX-loaded micelles decorated with GLUT1 had a robust killing effect even at low doses of DOX in vitro. At the doses chosen, non-targeted CUR and CUR+DOX micelles did not exhibit significant tumor inhibition versus control. However, GLUT1-CUR and GLUT1-CUR+DOX micelles showed a significant tumor inhibition effect with an improvement in survival. Conclusion: We showed a dramatic improvement in efficacy between the non-targeted and GLUT1-targeted formulations both in vitro and in vivo. Also, importantly, the addition of CUR to the micelle, has restored sensitivity to DOX, with resultant tumor growth inhibition. Hence, we confirmed that GLUT1-CUR+DOX micelles are effective in vitro and in vivo and deserve further investigation.

Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-Lapachone delivery.

PubMed

Zhou, Yinjian; Dong, Ying; Huang, Gang; Wang, Yiguang; Huang, Xiaonan; Zhang, Fayun; Boothman, David A; Gao, Jinming; Liang, Wei

2016-12-14

β-Lapachone (β-lap), a novel anticancer agent, is bioactivated by NADP(H):quinone oxidoreductase 1 (NQO1), an enzyme over-expressed in numerous tumors, including lung, pancreas, breast, and prostate cancers. Fast renal clearance and methemaglobinemia / hemolytic side-effects from the clinical formulation (β-lap-hydroxyl propyl-β-cyclodextrin complex) hindered its clinical translation. Here, we investigated a dual model pH responsive polymers for β-lap delivery. Three pH-sensitive linkages, including acylhydrazone, ketal and imine bonds for β-lap prodrug syntheses result in an aryl imine linkage the most optimal linkage. The conversion to β-lap was 2.8%, 4.5% and 100% at pH 7.4, 6.5 and 5.0 in 8 h, respectively. β-lap aryl imine prodrug conjugated ultra pH-sensitive (UPS) polymer reached high β-lap loading density (8.3%) and exhibited dual-stages responsiveness to pH variation. In pHs under pH t , at stage I, micelle immediately dissociation and subsequently entering stage II, micelles start quickly release β-lap. In vitro release study showed that the micelles constantly release β-lap (14.9 ± 0.1%) at pHs above pH t in 72 h, whereas boosted release of β-lap (79.4 ± 1.2%) at pH 5.0. Micelle intracellular distribution predominantly in the lysosome organelle guaranteed their pH responsive dissociation and subsequently β-lap controlled release. The M-P micelles retained NQO1-dependent cytotoxicity in A549 lung cancer cells, similar to free drug in both efficacy and mechanism of cell death. The lysosome-oriented dual-stage ultra pH responsive β-lap prodrug micelles potentially offer an alternative nanotherapeutic strategy for lung, as well as other NQO1+ cancer therapies.

pH-Responsive Triblock Copolymeric Micelles Decorated with a Cell-Penetrating Peptide Provide Efficient Doxorubicin Delivery

NASA Astrophysics Data System (ADS)

Ng, Khen Eng; Amin, Mohd Cairul Iqbal Mohd; Katas, Haliza; Amjad, Muhammad Wahab; Butt, Adeel Masood; Kesharwani, Prashant; Iyer, Arun K.

2016-12-01

This study developed novel triblock pH-responsive polymeric micelles (PMs) using cholic acid-polyethyleneimine-poly- l-arginine (CA-PEI-pArg) copolymers. PEI provided pH sensitivity, while the hydrophilic cell-penetrating pArg peptide promoted cellular PM internalization. The copolymers self-assembled into PMs in aqueous solution at above the critical micelle concentration (2.98 × 10-7 M) and encapsulated doxorubicin in the core region, with a 34.2% ( w/ w) entrapment efficiency. PMs showed pH-dependent swelling, increasing in size by almost sevenfold from pH 7.4 to 5.0. Doxorubicin release was pH-dependent, with about 65% released at pH 5.0, and 32% at pH 7.4. Cellular uptake, assessed by confocal microscopy and flow cytometry, was enhanced by using doxorubicin-loaded CA-PEI-pArg PMs, as compared to free doxorubicin and DOX-loaded CA-PEI PMs. Moreover, 24-h incubation of these PMs with a human breast cancer cell line produced greater cytotoxicity than free doxorubicin. These results indicate that pH-responsive CA-PEI-pArg micelles could provide a versatile delivery system for targeted cancer therapy using hydrophobic drugs.

Synthesis and evaluation of poly(styrene-co-maleic acid) micellar nanocarriers for the delivery of tanespimycin

PubMed Central

Larson, Nate; Greish, Khaled; Bauer, Hillevi; Maeda, Hiroshi; Ghandehari, Hamidreza

2011-01-01

Polymeric micelles carrying the heat shock protein 90 inhibitor tanespimycin (17-N-Allylamino-17-demethoxygeldanamycin) were synthesized using poly(styrene-co-maleic acid) (SMA) copolymers and evaluated in vitro and in vivo. SMA-tanespimycin micelles were prepared with a loading efficiency of 93%. The micelles incorporated 25.6% tanespimycin by weight, exhibited a mean diameter of 74 ± 7 nm by dynamic light scattering and a zeta potential of -35 ± 3 mV. Tanespimycin was released from the micelles in a controlled manner in vitro, with 62% released in 24 hours from a pH 7.4 buffer containing bovine serum albumin. The micellar drug delivery systems for tanespimycin showed potent activity against DU145 human prostate cancer cells, with an IC50 of 230 nM. They further exhibited potent anti-cancer activity in vivo in nu/nu mice bearing subcutaneous DU145 human prostate cancer tumor xenografts, with significantly higher anticancer efficacy as measured by tumor regression when compared to free tanespimycin at an equivalent single dose of 10 mg/kg. These data suggest further investigation of SMA-tanespimycin as a promising agent in the treatment of prostate cancer. PMID:21856392

Polysaccharide-Modified Synthetic Polymeric Biomaterials

PubMed Central

Baldwin, Aaron D.; Kiick, Kristi L.

2010-01-01

This review presents an overview of polysaccharide-conjugated synthetic polymers and their use in tissue-engineered scaffolds and drug-delivery applications. This topic will be divided into four categories: (1) polymeric materials modified with non-mammalian polysaccharides such as alginate, chitin, and dextran; (2) polymers modified with mammalian polysaccharides such as hyaluronan, chondroitin sulfate, and heparin; (3) multi-polysaccharide-derivatized polymer conjugate systems; and (4) polymers containing polysaccharide-mimetic molecules. Each section will discuss relevant conjugation techniques, analysis, and the impact of these materials as micelles, particles, or hydrogels used in in-vitro and in-vivo biomaterial applications. PMID:20091875

GRP78 enabled micelle-based glioma targeted drug delivery.

PubMed

Ran, Danni; Mao, Jiani; Shen, Qing; Xie, Cao; Zhan, Changyou; Wang, Ruifeng; Lu, Weiyue

2017-06-10

GRP78, a specific cancer cell-surface marker, is implicated in cancer cells proliferation, apoptosis resistance, metastasis and drug resistance. l-VAP (SNTRVAP) is a tumor homing peptide exhibiting high binding affinity in vitro to GRP78 protein overexpressed on glioma, glioma stem cells, vasculogenic mimicry and neovasculature. Even though short peptides are often non-immunogenic and demonstrate high affinity to tumor cells, their targeting efficacy is always undermined by rapid blood clearance and enzymatic degradation. In the present study, two d peptides RI-VAP (retro inverso isomer of l-VAP) and d-VAP (retro isomer of l-VAP) were developed by structure-guided peptide design and retro-inverso isomerization technique for glioma targeting. RI-VAP and d-VAP were predicted to bind their receptor GRP78 protein with similar binding affinity, which was experimentally confirmed. The results of in vivo imaging demonstrated that RI-VAP and d-VAP had remarkably advantage over l-VAP for tumor accumulation. In addition, RI-VAP and d-VAP modified paclitaxel-loaded polymeric micelle had better anti-tumor efficacy in comparison to taxol, paclitaxel-loaded plain micelles and l-VAP modified micelles. Overall, the VAP modified micelles suggested in the present study could effectively achieve glioma-targeted drug delivery, validating the potential of the stable VAP peptides in improving the therapeutic efficacy of paclitaxel for glioma. Copyright © 2017 Elsevier B.V. All rights reserved.

Electrostatic interactions between polyglutamic acid and polylysine yields stable polyion complex micelles for deoxypodophyllotoxin delivery

PubMed Central

Tang, Lidan; Sun, Runing; Shi, Di; Webster, Thomas J; Tu, Jiasheng; Sun, Chunmeng

2017-01-01

To achieve enhanced physical stability of poly(ethylene glycol)-poly(d,l-lactide) polymeric micelles (PEG-PDLLA PMs), a mixture of methoxy PEG-PDLLA-polyglutamate (mPEG-PDLLA-PLG) and mPEG-PDLLA-poly(l-lysine) (mPEG-PDLLA-PLL) copolymers was applied to self-assembled stable micelles with polyion-stabilized cores. Prior to micelle preparation, the synthetic copolymers were characterized by 1H-nuclear magnetic resonance (NMR) and infrared spectroscopy (IR), and their molecular weights were calculated by 1H-NMR and gel permeation chromatography (GPC). Dialysis was used to prepare PMs with deoxypodophyllotoxin (DPT). Transmission electron microscopy (TEM) images showed that DPT polyion complex micelles (DPT-PCMs) were spherical, with uniform distribution and particle sizes of 36.3±0.8 nm. In addition, compared with nonpeptide-modified DPT-PMs, the stability of DPT-PCMs was significantly improved under various temperatures. In the meantime, the pH sensitivity induced by charged peptides allowed them to have a stronger antitumor effect and a pH-triggered release profile. As a result, the dynamic characteristic of DPT-PCM was retained, and high biocompatibility of DPT-PCM was observed in an in vivo study. These results indicated that the interaction of anionic and cationic charged polyionic segments could be an effective strategy to control drug release and to improve the stability of polymer-based nanocarriers. PMID:29133981

Electrostatic interactions between polyglutamic acid and polylysine yields stable polyion complex micelles for deoxypodophyllotoxin delivery.

PubMed

Wang, Yutong; Huang, Liping; Shen, Yan; Tang, Lidan; Sun, Runing; Shi, Di; Webster, Thomas J; Tu, Jiasheng; Sun, Chunmeng

2017-01-01

To achieve enhanced physical stability of poly(ethylene glycol)-poly(d,l-lactide) polymeric micelles (PEG-PDLLA PMs), a mixture of methoxy PEG-PDLLA-polyglutamate (mPEG-PDLLA-PLG) and mPEG-PDLLA-poly(l-lysine) (mPEG-PDLLA-PLL) copolymers was applied to self-assembled stable micelles with polyion-stabilized cores. Prior to micelle preparation, the synthetic copolymers were characterized by 1 H-nuclear magnetic resonance (NMR) and infrared spectroscopy (IR), and their molecular weights were calculated by 1 H-NMR and gel permeation chromatography (GPC). Dialysis was used to prepare PMs with deoxypodophyllotoxin (DPT). Transmission electron microscopy (TEM) images showed that DPT polyion complex micelles (DPT-PCMs) were spherical, with uniform distribution and particle sizes of 36.3±0.8 nm. In addition, compared with nonpeptide-modified DPT-PMs, the stability of DPT-PCMs was significantly improved under various temperatures. In the meantime, the pH sensitivity induced by charged peptides allowed them to have a stronger antitumor effect and a pH-triggered release profile. As a result, the dynamic characteristic of DPT-PCM was retained, and high biocompatibility of DPT-PCM was observed in an in vivo study. These results indicated that the interaction of anionic and cationic charged polyionic segments could be an effective strategy to control drug release and to improve the stability of polymer-based nanocarriers.

Polymeric mixed micelles loaded mitoxantrone for overcoming multidrug resistance in breast cancer via photodynamic therapy

PubMed Central

Zhao, Yiqiao; Yu, Hua; Zhou, Haiyu; Chen, Meiwan

2017-01-01

Mitoxantrone (MIT) is an anticancer agent with photosensitive properties that is commonly used in various cancers. Multidrug resistance (MDR) effect has been an obstacle to using MIT for cancer therapy. Photochemical internalization, on account of photodynamic therapy, has been applied to improve the therapeutic effect of cancers with MDR effect. In this study, an MIT-poly(ε-caprolactone)-pluronic F68-poly(ε-caprolactone)/poly(d,l-lactide-co-glycolide)–poly(ethylene glycol)–poly(d,l-lactide-co-glycolide) (MIT-PFP/PPP) mixed micelles system was applied to reverse the effect of MDR in MCF-7/ADR cells via photochemical reaction when exposed to near-infrared light. MIT-PFP/PPP mixed micelles showed effective interaction with near-infrared light at the wavelength of 660 nm and exerted great cytotoxicity in MCF-7/ADR cells with irradiation. Furthermore, MIT-PFP/PPP mixed micelles could improve reactive oxygen species (ROS) levels, decrease P-glycoprotein activity, and increase the cellular uptake of drugs with improved intracellular drug concentrations, which induced cell apoptosis in MCF-7/ADR cells under irradiation, despite MDR effect, as indicated by the increased level of cleaved poly ADP-ribose polymerase. These findings suggested that MIT-PFP/PPP mixed micelles may become a promising strategy to effectively reverse the MDR effect via photodynamic therapy in breast cancer. PMID:28919756

The effects of non-ionic polymeric surfactants on the cleaning of biofouled hydrogel materials.

PubMed

Guan, Allan; Li, Zhenyu; Phillips, K Scott

2015-01-01

Block co-polymer surfactants have been used for cleaning hydrogel medical devices that contact the body (e.g., contact lenses) because of their biocompatibility. This work examined the relationship between concentration and detergency of two non-ionic polymeric surfactants (Pluronic F127 and Triton X-100) for cleaning protein soil, with anionic surfactants (sodium dodecyl sulfate and sodium laureth sulfate) as positive controls. Surface plasmon resonance was used to quantify removal of simulated tear soil from self-assembled monolayer surfaces, and a microplate format was used to study the removal of fluorescently labeled soil proteins from contact lenses. While detergency increased as a function of concentration for anionic surfactants, it decreased with concentration for the two polymeric surfactants. The fact that the protein detergency of some non-ionic polymeric surfactants did not increase with concentration above the critical micelle concentration could have implications for optimizing the tradeoff between detergency and biocompatibility.

Polymeric nanoparticles: potent vectors for vaccine delivery targeting cancer and infectious diseases.

PubMed

Bolhassani, Azam; Javanzad, Shabnam; Saleh, Tayebeh; Hashemi, Mehrdad; Aghasadeghi, Mohammad Reza; Sadat, Seyed Mehdi

2014-01-01

Nanocarriers with various compositions and biological properties have been extensively applied for in vitro/in vivo drug and gene delivery. The family of nanocarriers includes polymeric nanoparticles, lipid-based carriers (liposomes/micelles), dendrimers, carbon nanotubes, and gold nanoparticles (nanoshells/nanocages). Among different delivery systems, polymeric carriers have several properties such as: easy to synthesize, inexpensive, biocompatible, biodegradable, non-immunogenic, non-toxic, and water soluble. In addition, cationic polymers seem to produce more stable complexes led to a more protection during cellular trafficking than cationic lipids. Nanoparticles often show significant adjuvant effects in vaccine delivery since they may be easily taken up by antigen presenting cells (APCs). Natural polymers such as polysaccharides and synthetic polymers have demonstrated great potential to form vaccine nanoparticles. The development of new adjuvants or delivery systems for DNA and protein immunization is an expanding research field. This review describes polymeric carriers especially PLGA, chitosan, and PEI as vaccine delivery systems.

Polymeric nanoparticles

PubMed Central

Bolhassani, Azam; Javanzad, Shabnam; Saleh, Tayebeh; Hashemi, Mehrdad; Aghasadeghi, Mohammad Reza; Sadat, Seyed Mehdi

2014-01-01

Nanocarriers with various compositions and biological properties have been extensively applied for in vitro/in vivo drug and gene delivery. The family of nanocarriers includes polymeric nanoparticles, lipid-based carriers (liposomes/micelles), dendrimers, carbon nanotubes, and gold nanoparticles (nanoshells/nanocages). Among different delivery systems, polymeric carriers have several properties such as: easy to synthesize, inexpensive, biocompatible, biodegradable, non-immunogenic, non-toxic, and water soluble. In addition, cationic polymers seem to produce more stable complexes led to a more protection during cellular trafficking than cationic lipids. Nanoparticles often show significant adjuvant effects in vaccine delivery since they may be easily taken up by antigen presenting cells (APCs). Natural polymers such as polysaccharides and synthetic polymers have demonstrated great potential to form vaccine nanoparticles. The development of new adjuvants or delivery systems for DNA and protein immunization is an expanding research field. This review describes polymeric carriers especially PLGA, chitosan, and PEI as vaccine delivery systems. PMID:24128651

Core–Shell Structure and Aggregation Number of Micelles Composed of Amphiphilic Block Copolymers and Amphiphilic Heterografted Polymer Brushes Determined by Small-Angle X-ray Scattering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szymusiak, Magdalena; Kalkowski, Joseph; Luo, Hanying

2017-08-31

A large group of functional nanomaterials employed in biomedical applications, including targeted drug delivery, relies on amphiphilic polymers to encapsulate therapeutic payloads via self-assembly processes. Knowledge of the micelle structures will provide critical insights into design of polymeric drug delivery systems. Core–shell micelles composed of linear diblock copolymers poly(ethylene glycol)-b-poly(caprolactone) (PEG-b-PCL), poly(ethylene oxide)-b-poly(lactic acid) (PEG-b-PLA), as well as a heterografted brush consisting of a poly(glycidyl methacrylate) backbone with PEG and PLA branches (PGMA-g-PEG/PLA) were characterized by dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) measurements to gain structural information regarding the particle morphology, core–shell size, and aggregation number. Themore » structural information at this quasi-equilibrium state can also be used as a reference when studying the kinetics of polymer micellization.« less

Core–Shell Structure and Aggregation Number of Micelles Composed of Amphiphilic Block Copolymers and Amphiphilic Heterografted Polymer Brushes Determined by Small-Angle X-ray Scattering

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szymusiak, Magdalena; Kalkowski, Joseph; Luo, Hanying

2017-08-16

A large group of functional nanomaterials employed in biomedical applications, including targeted drug delivery, relies on amphiphilic polymers to encapsulate therapeutic payloads via self-assembly processes. Knowledge of the micelle structures will provide critical insights into design of polymeric drug delivery systems. Core–shell micelles composed of linear diblock copolymers poly(ethylene glycol)-b-poly(caprolactone) (PEG-b-PCL), poly(ethylene oxide)-b-poly(lactic acid) (PEG-b-PLA), as well as a heterografted brush consisting of a poly(glycidyl methacrylate) backbone with PEG and PLA branches (PGMA-g-PEG/PLA) were characterized by dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) measurements to gain structural information regarding the particle morphology, core–shell size, and aggregation number. Themore » structural information at this quasi-equilibrium state can also be used as a reference when studying the kinetics of polymer micellization.« less

Preparation of biocompatible copolymeric micelles as a carrier of atorvastatin and rosuvastatin for potential anticancer activity study.

PubMed

Hamidreza Kheiri, Manjili; Alimohammadi, Niusha; Danafar, Hossein

2018-05-18

Statins are widely used for the treatment of hypercholesterolemia. However, their inhibitory action on HMG-CoA reductase also results in the depletion of intermediate biosynthetic products, which importantly contribute to cell proliferation. The aim of the present study was to compare the effects of the individual commercially available statins on investigational breast cancer. Thus, in this study, biodegradable polymeric micelles as carrier of statins were prepared using biodegradable copolymers (PCL-PEG-PCL). These nanoparticles were prepared with two statins (atorvastatin and rosuvastatin) and drug loading, release, kinetic release, and anti-cancer activity of these drugs were studied. The triblock copolymer PCL-PEG-PCL was synthesized by a ring opening polymerization of e-caprolactone in the presence of PEG as the initiator and Sn(oct) 2 as the catalyst. The synthesized copolymers and nanoparticles were characterized by FTIR, HNMR, GPC, DLS, and AFM analyses. The drug loading and release of drugs were studied by UV-Vis. Additionally, MTT assays on HFF-2 cell lines were performed for determination of biocompatibility of micelles. Finally, the anticancer activity of micelles was studied on MCF-7 breast cancer cell lines. The results showed that the average diameter of nanoparticles was less than 45 nm. The loading capacity of atorvastatin and rosuvastatin was 20.0 ± 1.01% and 13.21 ± 1.18%, respectively, and encapsulation efficiency of atorvastatin and rosuvastatin was 88.19 ± 1.11% and 69.32 ± 0.23%, respectively. The results showed strong and dose-dependent inhibition of cell (MCF-7line) growth by the nanoparticles compared with statins. The result of cell viability assay on the MCF-7 cell line verified that the bare nanoparticles showed little inherent cytotoxicity whereas the statins-loaded nanoparticles were cytotoxic.

Unimolecular Micelles of Amphiphilic Cyclodextrin-Core Star-Like Copolymers with Covalent pH-Responsive Linkage of Anticancer Prodrugs.

PubMed

Jia, Tao; Huang, Shuo; Yang, Cangjie; Wang, Mingfeng

2017-08-07

Multifunctional stable and stimuli-responsive drug delivery systems are important for efficient cancer treatment due to their advantages such as enhanced cancer-targeting efficiency, improved pharmacokinetics, minimized drug leaching, and reduced undesirable side effects. Here we report a robust and pH-responsive anticancer drug delivery system based on unimolecular micelles of star-like amphiphilic copolymers. The polymers (denoted as CPOFs) were facilely synthesized via one-step atom transfer radical polymerization of functionalizable benzoaldehyde and hydrophilic poly[(oligo ethylene glycol) methyl ether methacrylate] as comonomers from the core of heptakis [2,3,6-tri-o-(2-bromo-2-methyl propionyl]-β-cyclodextrin as the initiator. Doxorubicin (DOX) as an anticancer drug was covalently linked to the benzoaldehyde groups of CPOFs through pH-sensitive Schiff-base bonds. The DOX-conjugated polymers, denoted as CPOF-DOX, formed robust unimolecular micelles with an average diameter of 18 nm in aqueous media. More importantly, these unimolecular micelles showed higher drug loading capacity and more controllable drug release characteristics, compared to our previous unimolecular micelles of β-cyclodextrin-poly(lactic acid)-b-poly[(oligo ethylene glycol) methyl ether methacrylates] that physically encapsulated DOX via hydrophobic interaction. Moreover, the CPOF-DOX unimolecular micelles could be internalized by human cervical cancer HeLa cells in a stepwise way and showed less cytotoxicity compared to carrier-free DOX. We foresee that CPOF-DOX would provide a promising robust and controllable anticancer drug delivery system for future animal study and clinical trials for cancer treatment.

Polymeric contrast agents for medical imaging.

PubMed

Torchilin, V P

2000-09-01

Synthetic polymers and co-polymers are described, to be used as carriers of reporter groups for gamma-, magnetic resonance (MR), and computed tomography (CT) imaging. Those compounds include polychelating and amphiphilic polymers and serve as key components of various contrast agents. Single terminus-activated polychelating polymers were synthesized using poly-L-lysine (PLL) as a main chain and chelating moieties (such as diethylene triamine pentaacetic acid or DTPA) as side groups. These polymers were used for the modification of diagnostic monoclonal antibodies to increase their load with reporter metal atoms. As a result, better images within shorter time intervals were obtained in animal experiments. The application of liposomes and micelles as carriers for diagnostic imaging agents in experimental and clinical medicine is considered. The load of liposomes and micelles with contrast agents for gamma- and MR imaging (MRI) was sharply increased by using polychelating polymers additionally modified on one end with a hydrophobic phospholipid residue to give amphiphilic polymers. Such polymers easily incorporate the liposome membrane or micelle core and provide better loading of liposomes and micelles with reporter metals and, consequently, better and faster imaging of various physiological compartments, such as lymphatic and vascular systems. A block-copolymer of methoxy-poly(ethylene glycol) (MPEG) and iodine-substituted PLL was synthesized to prepare long-circulating contrast agent for CT imaging of the blood pool. In the aqueous solution, this copolymer forms stable and heavily loaded with iodine (up to 30% of iodine by weight) micelles. These micelle were successfully used for CT visualization of the vascular network in experimental animals. General trends in developing contrast polymers are discussed.

Periodic organosilica hollow nanospheres as anode materials for lithium ion rechargeable batteries

NASA Astrophysics Data System (ADS)

Sasidharan, Manickam; Nakashima, Kenichi; Gunawardhana, Nanda; Yokoi, Toshiyuki; Ito, Masanori; Inoue, Masamichi; Yusa, Shin-Ichi; Yoshio, Masaki; Tatsumi, Takashi

2011-11-01

Polymeric micelles with core-shell-corona architecture have been found to be the efficient colloidal templates for synthesis of periodic organosilica hollow nanospheres over a broad pH range from acidic to alkaline media. In alkaline medium, poly (styrene-b-[3-(methacryloylamino)propyl] trimethylammonium chloride-b-ethylene oxide) (PS-PMAPTAC-PEO) micelles yield benzene-silica hollow nanospheres with molecular scale periodicity of benzene groups in the shell domain of hollow particles. Whereas, an acidic medium (pH 4) produces diverse hollow particles with benzene, ethylene, and a mixture of ethylene and dipropyldisulfide bridging functionalities using poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-PVP-PEO) micelles. These hollow particles were thoroughly characterized by powder X-ray diffraction (XRD), dynamic light scattering (DLS), thermogravimetric analysis (TG/DTA), Fourier transformation infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), magic angle spinning-nuclear magnetic resonance (29Si MAS NMR and 13CP-MAS NMR), Raman spectroscopy, and nitrogen adsorption/desorption analyses. The benzene-silica hollow nanospheres with molecular scale periodicity in the shell domain exhibit higher cycling performance of up to 300 cycles in lithium ion rechargeable batteries compared with micron-sized dense benzene-silica particles.Polymeric micelles with core-shell-corona architecture have been found to be the efficient colloidal templates for synthesis of periodic organosilica hollow nanospheres over a broad pH range from acidic to alkaline media. In alkaline medium, poly (styrene-b-[3-(methacryloylamino)propyl] trimethylammonium chloride-b-ethylene oxide) (PS-PMAPTAC-PEO) micelles yield benzene-silica hollow nanospheres with molecular scale periodicity of benzene groups in the shell domain of hollow particles. Whereas, an acidic medium (pH 4) produces diverse hollow particles with benzene, ethylene, and a mixture of ethylene and dipropyldisulfide bridging functionalities using poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-PVP-PEO) micelles. These hollow particles were thoroughly characterized by powder X-ray diffraction (XRD), dynamic light scattering (DLS), thermogravimetric analysis (TG/DTA), Fourier transformation infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), magic angle spinning-nuclear magnetic resonance (29Si MAS NMR and 13CP-MAS NMR), Raman spectroscopy, and nitrogen adsorption/desorption analyses. The benzene-silica hollow nanospheres with molecular scale periodicity in the shell domain exhibit higher cycling performance of up to 300 cycles in lithium ion rechargeable batteries compared with micron-sized dense benzene-silica particles. Electronic supplementary information (ESI) available: FTIR, Raman spectral data, additional TEM pictures, N2 adsorption and physical characteristics of hollow particles data, and cycling performance of dense silica particles. See DOI: 10.1039/c1nr10804b

Block copolymer micelles with acid-labile ortho ester side-chains: Synthesis, characterization, and enhanced drug delivery to human glioma cells.

PubMed

Tang, Rupei; Ji, Weihang; Panus, David; Palumbo, R Noelle; Wang, Chun

2011-04-10

A new type of block copolymer micelles for pH-triggered delivery of poorly water-soluble anticancer drugs has been synthesized and characterized. The micelles were formed by the self-assembly of an amphiphilic diblock copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a hydrophobic polymethacrylate block (PEYM) bearing acid-labile ortho ester side-chains. The diblock copolymer was synthesized by atom transfer radical polymerization (ATRP) from a PEG macro-initiator to obtain well-defined polymer chain-length. The PEG-b-PEYM micelles assumed a stable core-shell structure in aqueous buffer at physiological pH with a low critical micelle concentration as determined by proton NMR and pyrene fluorescence spectroscopy. The hydrolysis of the ortho ester side-chain at physiological pH was minimal yet much accelerated at mildly acidic pHs. Doxorubicin (Dox) was successfully loaded into the micelles at pH 7.4 and was released at a much higher rate in response to slight acidification to pH 5. Interestingly, the release of Dox at pH 5 followed apparently a biphasic profile, consisting of an initial fast phase of several hours followed by a sustained release period of several days. Dox loaded in the micelles was rapidly taken up by human glioma (T98G) cells in vitro, accumulating in the endolysosome and subsequently in the nucleus in a few hours, in contrast to the very low uptake of free drug at the same dose. The dose-dependent cytotoxicity of the Dox-loaded micelles was determined by the MTT assay and compared with that of the free Dox. While the empty micelles themselves were not toxic, the IC(50) values of the Dox-loaded micelles were approximately ten-times (by 24h) and three-times (by 48h) lower than the free drug. The much enhanced potency in killing the multi-drug-resistant human glioma cells by Dox loaded in the micelles could be attributed to high intracellular drug concentration and the subsequent pH-triggered drug release. These results establish the PEG-b-PEYM block copolymer with acid-labile ortho ester side-chains as a novel and effective pH-responsive nano-carrier for enhancing the delivery of drugs to cancer cells. Copyright © 2010 Elsevier B.V. All rights reserved.

Reverse micelle synthesis of nanoscale metal containing catalysts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Darab, J.G.; Fulton, J.L.; Linehan, J.C.

1993-03-01

The need for morphological control during the synthesis of catalyst precursor powders is generally accepted to be important. In the liquefaction of coal, for example, iron-bearing catalyst precursor particles containing individual crystallites with diameters in the 1-100 nanometer range are believed to achieve good dispersion through out the coal-solvent slurry during liquefaction 2 runs and to undergo chemical transformations to catalytically active iron sulfide phases. The production of the nanoscale powders described here employs the confining spherical microdomains comprising the aqueous phase of a modified reverse micelle (MRM) microemulsion system as nanoscale reaction vessels in which polymerization, electrochemical reduction andmore » precipitation of solvated salts can occur. The goal is to take advantage of the confining nature of micelles to kinetically hinder transformation processes which readily occur in bulk aqueous solution in order to control the morphology and phase of the resulting powder. We have prepared a variety of metal, alloy, and metal- and mixed metal-oxide nanoscale powders from appropriate MRM systems. Examples of nanoscale powders produced include Co, Mo-Co, Ni{sub 3}Fe, Ni, and various oxides and oxyhydroxides of iron. Here, we discuss the preparation and characterization of nickel metal (with a nickel oxide surface layer) and iron oxyhydroxide MRM nanoscale powders. We have used extended x-ray absorption fine structure (EXAFS) spectroscopy to study the chemical polymerization process in situ, x-ray diffraction (XRD), scanning and transmission electron microcroscopies (SEM and TEM), elemental analysis and structural modelling to characterize the nanoscale powders produced. The catalytic activity of these powders is currently being studied.« less

The Impact of Polymeric Nanoencapsulation on the Bioavailability of Lutein

NASA Astrophysics Data System (ADS)

Kamil, Alison

Lutein, a fat-soluble xanthophyll, contributes partially to the health benefits from consuming plant foods. Like all dietary carotenoids, lutein has a low bioavailability. In addition to increasing the intake of lutein-rich foods to enhance lutein status, delivery of lutein in polymeric nanoparticles (NP) presents a novel approach to enhancing lutein bioavailability. The overall research objective of this project was to investigate, in rats, the impact of nanoencapsulation using poly(lactic-co-glycolic acid) (PLGA) on the pharmacokinetics of lutein. We also used an in vitro cell culture approach utilizing human epithelial colorectal adenocarcinoma (Caco-2) cells grown in both conventional (CONV) and permeable support (PS) systems to investigate the impact of PLGA-NP on the absorption of lutein in intestinal cells. In chapter one, we compared the efficacy of lutein absorption in vitro using Caco-2 cells grown in both CONV and PS systems. We further examined the role of the micelle, the physiological vehicle for lutein within the small intestine, on its intestinal absorption in vitro compared to an organic solvent, ethanol, which is safe and consumed by humans. The finding from this study demonstrated that the CONV system displayed a larger efficacy of lutein uptake by Caco-2 cells. Further, in the PS system, micelle components appeared to facilitate more effective intestinal secretion of lutein. These findings suggest that lutein uptake by Caco-2 cells is subject to the influence of culturing system (CONV vs. PS) and delivery vehicle (ethanol vs. micelle). Chapter two examined the impact of PLGA-NP in rats on lutein pharmacokinetics in plasma and distribution in selected tissues as compared to free lutein. We also investigated the effect of nanoencapsulation on the absorption of lutein in intestinal cells compared to a more physiological vehicle, the micelle, using the PS method. In addition, we explored the need of additional micelles for the ultimate absorption of lutein loaded in a water soluble NP. The findings of the rat study indicated that, compared to free lutein, PLGA-NP improved the pharmacokinetics (Cmax and AUC) of lutein in the plasma of rats and in general promoted lutein accumulation in mesenteric adipose tissue and spleen but not liver. Yet, compared to micellized lutein, although NP improved the maximal concentration of lutein in the plasma of rats as well as in selected tissues it decreased the cell uptake and secretion of lutein in Caco-2 cells. The negative effect of the NP on cell uptake and secretion was partially remedied by the addition of micelle components. These findings suggest that the delivery of lutein within polymeric NP appears to be a promising approach to improving the bioavailability of lutein in rats. The inconsistent results between the rat and cell culture models warrant further investigations to determine which approach better predicts responses in humans. Further, bile salts and phospholipids, which are necessary to stimulate synthesis and secretion of chylomicrons, appear to facilitate more effective intestinal secretion of PLGA-NP lutein. In summary, with Caco-2 cells cultured in the PS system reliably grown to display phenotypes and functions of enterocytes in the small intestine, this in vitro platform enables the generation of information that is closer to the physiology of the absorptive enterocytes. However, although the CONV system has the physiological attributes of colonic tissue, it appeared to display a greater efficacy of lutein uptake by Caco-2 cells which can provide a rapid preliminary tool for methodology development for nutrient absorption studies. Further, the delivery of lutein in polymeric NP appears to be a promising approach to improve the bioavailability of lutein in vivo but raises issues with regard to the comparability and the predictive value of in vitro models to in vivo responses.

pH protective Y1 receptor ligand functionalized antiphagocytosis BPLP-WPU micelles for enhanced tumor imaging and therapy with prolonged survival time.

PubMed

Jiang, Zhenqi; Tian, Yuchen; Shan, Dingying; Wang, Yinjie; Gerhard, Ethan; Xia, Jianbi; Huang, Rong; He, Yan; Li, Aiguo; Tang, Jianchao; Ruan, Huimin; Li, Yong; Li, Juan; Yang, Jian; Wu, Aiguo

2018-07-01

Nanoparticle-based tumor therapies are extensively studied; however, few are capable of improving patient survival time due to premature drug leakage, off target effects, and poor tissue penetration. Previously, we successfully synthesized a novel family of Y 1 receptor (Y 1 R) ligand modified, photoluminescent BPLP nanobubbles and nanoparticles for targeted breast cancer ultrasound imaging; however, increased accumulation could also be observed in the liver, kidney, and spleen, suggesting significant interaction of the particles with macrophages in vivo. Herein, for the first time, we imparted antiphagocytosis capability to Y 1 R ligand functionalized BPLP-WPU polymeric micelles through the incorporation of a CD47 human glycoprotein based self-peptide. Application of self-peptide modified, DOX loaded micelles in vivo resulted in a 100% survival rate and complete tumor necrosis over 100 days of treatment. In vivo imaging of SPION loaded, self-peptide modified micelles revealed effective targeting to the tumor site while analysis of iron content demonstrated reduced particle accumulation in the liver and kidney, demonstrating reduced macrophage interaction, as well as a 2-fold increase of particles in the tumor. As these results demonstrate, Y 1 R ligand, self-peptide modified BPLP-WPU micelles are capable of target specific cancer treatment and imaging, making them ideal candidates to improve survival rate and tumor reduction clinically. Copyright © 2018 Elsevier Ltd. All rights reserved.

In vitro characterization of pH-sensitive azithromycin-loaded methoxy poly (ethylene glycol)-block-poly (aspartic acid-graft-imidazole) micelles.

PubMed

Teng, Fangfang; Deng, Peizong; Song, Zhimei; Zhou, Feilong; Feng, Runliang; Liu, Na

2017-06-15

In order to improve azithromycin's antibacterial activity in acidic medium, monomethoxy poly (ethylene glycol)-block-poly (aspartic acid-graft-imidazole) copolymer was synthesized through allylation, free radical addition, ring-opening polymerization and amidation reactions with methoxy poly (ethylene glycol) as raw material. Drug loading capacity and encapsulation efficiency of azithromycin-loaded micelles prepared via thin film hydration method were 11.58±0.86% and 96.06±1.93%, respectively. The drug-loaded micelles showed pH-dependent property in the respects of particle size, zeta potential at the range of pH 5.5-7.8. It could control drug in vitro release and demonstrate higher release rate at pH 6.0 than that at pH 7.4. In vitro antibacterial experiment indicated that the activity of azithromycin-loaded micelles against S. aureus was superior to free azithromycin in medium at both pH 6.0 and pH 7.4. Using fluorescein as substitute with pH-dependent fluorescence decrease property, laser confocal fluorescence microscopy analysis confirmed that cellular uptake of micelles was improved due to protonation of copolymer's imidazole groups at pH 6.0. The enhanced cellular uptake and release of drug caused its activity enhancement in acidic medium when compared with free drug. The micellar drug delivery system should be potential application in the field of bacterial infection treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

One-step synthesis and self-assembly behavior of thermo-responsive star-shaped β-cyclodextrin-(P(MEO2MA- co-PEGMA))21 copolymers

NASA Astrophysics Data System (ADS)

Wei, Lulu; Lu, Beibei; Li, Lei; Wu, Jianning; Liu, Zhiyong; Guo, Xuhong

2017-09-01

A novel β-cyclodextrin-poly(2-(2-methoxyethoxy)ethyl methacrylate)- co-poly(ethylene glycol) methacrylate (abbreviated as: β-CD-(P(MEO2MA- co-PEGMA))21) was prepared by using the one-step strategy, and then the star-shaped copolymers were used in the atom transfer radical polymerization (ATRP). The structure of star-shaped β-CD-(P(MEO2MA- co-PEGMA))21 copolymers were studied by FTIR, 1H NMR and gel permeation chromatography (GPC). The star-shaped copolymers could self-assembled into micelles in aqueous solution owing to the outer amphiphilic β-CD as a core and the hydrophilic P(MEO2MA- co-PEGMA) segments as a shell. These thermo-responsive starshaped copolymers micelles exhibited lower critical solution temperature (LCST) in water, which could be finely tuned by changing the feed ratio of MEO2MA to PEGMA. The LCST of star-shaped β-CD-(P(MEO2MA- co-PEGMA))21 copolymer micelles were increased from 35°C to 58°C with the increasing content of PEGMA. The results were investigated by DLS and TEM. When the temperature was higher than corresponding LCSTs, the micelles started to associate and form spherical nanoparticles. Therefore, β-CD-(P(MEO2MA- co-PEGMA))21 star-shaped copolymer micelles could be potentially applied in nano-carrier, nano-reactor, smart materials and biomedical fields.

Extraction protocol and liquid chromatography/tandem mass spectrometry method for determining micelle-entrapped paclitaxel at the cellular and subcellular levels: Application to a cellular uptake and distribution study.

PubMed

Zheng, Nan; Lian, Bin; Du, Wenwen; Xu, Guobing; Ji, Jiafu

2018-01-01

Paclitaxel-loaded polymeric micelles (PTX-PM) are commonly used as tumor-targeted nanocarriers and display outstanding antitumor features in clinic, but its accumulation and distribution in vitro are lack of investigation. It is probably due to the complex micellar system and its low concentration at the cellular or subcellular levels. In this study, we developed an improved extraction method, which was a combination of mechanical disruption and liquid-liquid extraction (LLE), to extract the total PTX from micelles in the cell lysate and subcellular compartments. An ultra-performance liquid chromatography tandem mass spectroscopy (UPLC-MS/MS) method was optimized to detect the low concentration of PTX at cellular and subcellular levels simultaneously, using docetaxel as internal standard (IS). The method was proved to release PTX totally from micelles (≥95.93%) with a consistent and reproducible extraction recovery (≥75.04%). Good linearity was obtained at concentrations ranging from 0.2 to 20ng/mL. The relative error (RE%) for accuracy varied from 0.68 to 7.56%, and the intra- and inter-precision (relative standard deviation, RSD%) was less than 8.64% and 13.14%, respectively. This method was fully validated and successfully applied to the cellular uptake and distribution study of PTX-loaded PLGA-PEG micelles in human breast cancer cells (MCF-7). Copyright © 2017 Elsevier B.V. All rights reserved.

Polyaniline particles: Material properties when synthesized with aqueous nonionic micelles and environmental stability

NASA Astrophysics Data System (ADS)

Hobaica, Stephen Charles

Polyaniline is a member of the class of electrically conducting polymers, which have possible commercial applications as anticorrosive or static charge removal coatings. Aqueous-based polyaniline coatings are preferred over organic solvent or strong acid based coatings because the water used in these coatings does not pollute the environment. The overall goal of this dissertation was to further the development of useful water-based polyaniline coatings by studying new methods of synthesizing polyaniline particles for water-based coatings, to investigate the material properties of these particles such as molecular weight, electrical conductivity, particle size distribution, and stability of polyaniline in air and water. One method of polymerizing polyaniline for aqueous-based coatings uses micelles, which are composed of a cluster of amphiphile surfactants. Micelles can change the local environment by aligning and absorbing the monomer, and may yield polymers with improved material properties and reaction rates. Nonionic micelles have not been extensively investigated. Therefore the first specific goal of this work was to use an aqueous nonionic micelle solution of nonylphenoxypoly(ethyleneoxy) ethanol surfactant (NP-30 surfactant) to comprehensively investigate a one step chemical polymerization of polyaniline conducted at -3°C, in 1.25 M HCl, with ammonium peroxydisulfate oxidizer. The results show that increasing surfactant concentrations caused a decrease in molecular weight, electrical conductivity and sharper particle size distribution of the polymer. The second specific objective of this dissertation was to determine the effect of water and air on polyaniline. The results showed no degradation of molecular weight, a decrease in chloride and hydrogen composition, and decrease in electrical conductivity for polyaniline immersed in water for extended periods. A chloride ion diffusion coefficient of 2.5 to 74 x 10-9 cm2/hour was measured. The aging of polyaniline powders in a desiccator for 5 years showed no effect on the molecular structure as indicated by the FTIR spectrum. The third specific goal of the research was to measure the real and imaginary refractive index of polyaniline saturated with 1.25 M HCl, which was found to be 1.345 to 1.355 and 0.025 to 0.027, respectively. This information is crucial to measuring the distribution of polyaniline colloids by light scattering.

Polymeric micellar nanoplatforms for Fenton reaction as a new class of antibacterial agents.

PubMed

Park, Seong-Cheol; Kim, Nam-Hong; Yang, Wonseok; Nah, Jae-Woon; Jang, Mi-Kyeong; Lee, Dongwon

2016-01-10

Reactive oxygen species (ROS) produced by host phagocytes exert antibacterial action against a variety of pathogens and ROS-induced oxidative stress is the governing mechanism for the antibacterial activity of major bactericidal antibiotics. In particular, hydroxyl radical is a strong and nonselective oxidant which can damage biomolecules such as DNA, proteins and lipids. Ferrous ion is known to convert mild oxidant hydrogen peroxide (H2O2) into highly reactive and toxic hydroxyl radicals, referred to as Fenton reaction. Herein, we report a new class of antibacterial agents based on Fenton reaction-performing nanostructures, composed of H2O2-generating polymer (PCAE) and iron-containing ferrocene. Amphiphilic PCAE was designed to incorporate H2O2-generating cinnamaldehyde through acid-cleavable linkages and self-assemble to form thermodynamically stable micelles which could encapsulate ferrocene in their hydrophobic core. All the experiments in vitro display that ferrocene-loaded PCAE micelles produce hydroxyl radicals to kill Escherichia coli and Pseudomonas aeruginosa through membrane damages. Intraperitoneally injected ferrocene-loaded PCAE micelles significantly reduced the lung damages and therefore increased the survival rate of mice infected with drug resistant P. aeruginosa. Given their potent antibacterial activity, ferrocene-loaded PCAE micelles hold great potential as a new class of ROS-manipulating antibacterial agents. Copyright © 2015 Elsevier B.V. All rights reserved.

Phase separation in solution of worm-like micelles: a dilute ? spin-vector model

NASA Astrophysics Data System (ADS)

Panizza, Pascal; Cristobal, Galder; Curély, Jacques

1998-12-01

We show how the dilute 0953-8984/10/50/006/img2 spin vector model introduced originally by Wheeler and co-workers for describing the polymerization phenomenon in solutions of liquid sulphur and of living polymers may be conveniently adapted for studying phase separation in systems containing long flexible micelles. We draw an isomorphism between the coupling constant appearing in the exchange Hamiltonian and the surfactant energies in the micellar problem. We solve this problem within the mean-field approximation and compare the main results we have obtained with respect to polymer theory and previous theories of phase separation in micellar solutions. We show that the attractive interaction term 0953-8984/10/50/006/img3 between monomers renormalizes the aggregation energy and subsequently the corresponding size distribution. Under these conditions, we observe that the general aspect of the phase diagram in the 0953-8984/10/50/006/img4 plane (where 0953-8984/10/50/006/img5 is the surfactant concentration) is different from previous results. The spinodal line shows a re-entrant behaviour and, at low concentrations, we point out the possibility of specific nucleation phenomena related to the existence of a metastable transition line between a region composed of spherical micelles and another one corresponding to a dilute solution of long flexible micelles.

Molecular Dynamics Simulations of Adsorption of Poly(acrylic acid) and Poly(methacrylic acid) on Dodecyltrimethylammonium Chloride Micelle in Water: Effect of Charge Density.

PubMed

Sulatha, Muralidharan S; Natarajan, Upendra

2015-09-24

We have investigated the interaction of dodecyltrimethylammonium chloride (DoTA) micelle with weak polyelectrolytes, poly(acrylic acid) and poly(methacrylic acid). Anionic as well as un-ionized forms of the polyelectrolytes were studied. Polyelectrolyte-surfactant complexes were formed within 5-11 ns of the simulation time and were found to be stable. Association is driven purely by electrostatic interactions for anionic chains whereas dispersion interactions also play a dominant role in the case of un-ionized chains. Surfactant headgroup nitrogen atoms are in close contact with the carboxylic oxygens of the polyelectrolyte chain at a distance of 0.35 nm. In the complexes, the polyelectrolyte chains are adsorbed on to the hydrophilic micellar surface and do not penetrate into the hydrophobic core of the micelle. Polyacrylate chain shows higher affinity for complex formation with DoTA as compared to polymethacrylate chain. Anionic polyelectrolyte chains show higher interaction strength as compared to corresponding un-ionized chains. Anionic chains act as polymeric counterion in the complexes, resulting in the displacement of counterions (Na(+) and Cl(-)) into the bulk solution. Anionic chains show distinct shrinkage upon adsorption onto the micelle. Detailed information about the microscopic structure and binding characteristics of these complexes is in agreement with available experimental literature.

In situ diselenide-crosslinked polymeric micelles for ROS-mediated anticancer drug delivery.

PubMed

Deepagan, V G; Kwon, Seunglee; You, Dong Gil; Nguyen, Van Quy; Um, Wooram; Ko, Hyewon; Lee, Hansang; Jo, Dong-Gyu; Kang, Young Mo; Park, Jae Hyung

2016-10-01

Stimuli-responsive micelles have emerged as the drug carrier for cancer therapy since they can exclusively release the drug via their structural changes in response to the specific stimuli of the target site. Herein, we developed the in situ diselenide-crosslinked micelles (DCMs), which are responsive to the abnormal ROS levels of tumoral region, as anticancer drug carriers. The DCMs were spontaneously derived from selenol-bearing triblock copolymers consisting of polyethylene glycol (PEG) and polypeptide derivatives. During micelle formation, doxorubicine (DOX) was effectively encapsulated in the hydrophobic core, and diselenide crosslinks were formed in the shell. The DCMs maintained their structural integrity, at least for 6 days in physiological conditions, even in the presence of destabilizing agents. However, ROS-rich conditions triggered rapid release of DOX from the DOX-encapsulating DCMs (DOX-DCMs) because the hydrophobic diselenide bond was cleaved into hydrophilic selenic acid derivatives. Interestingly, after their systemic administration into the tumor-bearing mice, DOX-DCMs delivered significantly more drug to tumors (1.69-fold and 3.73-fold higher amount compared with their non-crosslinked counterparts and free drug, respectively) and effectively suppressed tumor growth. Overall, our data indicate that DCMs have great potential as drug carriers for anticancer therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gd-DTPA-loaded polymer-metal complex micelles with high relaxivity for MR cancer imaging.

PubMed

Mi, Peng; Cabral, Horacio; Kokuryo, Daisuke; Rafi, Mohammad; Terada, Yasuko; Aoki, Ichio; Saga, Tsuneo; Takehiko, Ishii; Nishiyama, Nobuhiro; Kataoka, Kazunori

2013-01-01

Nanodevices for magnetic resonance imaging of cancer were self-assembled to core-shell micellar structures by metal complex formation of K(2)PtCl(6) with diethylenetriaminepentaacetic acid gadolinium (III) dihydrogen (Gd-DTPA), a T(1)-contrast agent, and poly(ethylene glycol)-b-poly{N-[N'-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-b-PAsp(DET)) copolymer in aqueous solution. Gd-DTPA-loaded polymeric micelles (Gd-DTPA/m) showed a hydrodynamic diameter of 45 nm and a core size of 22 nm. Confining Gd-DTPA inside the core of the micelles increased the relaxivity of Gd-DTPA more than 13 times (48 mM(-1) s(-1)). In physiological conditions Gd-DTPA/m sustainedly released Gd-DTPA, while the Pt(IV) complexes remain bound to the polymer. Gd-DTPA/m extended the circulation time in plasma and augmented the tumor accumulation of Gd-DTPA leading to successful contrast enhancement of solid tumors. μ-Synchrotron radiation-X-ray fluorescence results confirmed that Gd-DTPA was delivered to the tumor site by the micelles. Our study provides a facile strategy for incorporating contrast agents, dyes and bioactive molecules into nanodevices for developing safe and efficient drug carriers for clinical application. Copyright © 2012 Elsevier Ltd. All rights reserved.

Mixed micelles for encapsulation of doxorubicin with enhanced in vitro cytotoxicity on breast and ovarian cancer cell lines versus Doxil®.

PubMed

Cagel, Maximiliano; Bernabeu, Ezequiel; Gonzalez, Lorena; Lagomarsino, Eduardo; Zubillaga, Marcela; Moretton, Marcela A; Chiappetta, Diego A

2017-11-01

Doxorubicin (DOX) is used as a "first-line" antineoplastic drug in ovarian and metastatic breast cancer. However, serious side effects, such as cardiotoxicity have been reported after DOX intravenous administration. Hence, we investigated different micelle-former biomaterials, as Soluplus ® , Pluronic F127, Tetronic T1107 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) to develop a potential mixed micellar nanocarrier for DOX delivery. Since DOX hydrochloride is a poor candidate to be encapsulated inside the hydrophobic core of the mixed micelles, we assayed a hydrophobic complex between DOX and sodium deoxycholate (NaDC) as an excellent candidate to be encapsulated within polymeric micelles. The combination of T1107:TPGS (1:3, weight ratio) demonstrated the best physicochemical properties together with a high DL capacity (6.43% w/v). Particularly, DOX in vitro release was higher at acidic tumour microenvironment pH value (5.5) than at physiological counterpart (7.4). The hydrodynamic diameter of the DOX/NaDC-loaded mixed micellar system was 10.7nm (PDI=0.239). The in vitro cytotoxicity of the mixed micellar formulation resulted significantly (p<0.05) higher than Doxil ® against ovarian (SKOV-3) and triple-negative breast cancer cells (MDA-MB- 231). Further, the in vitro cellular uptake assays demonstrated a significant increment (p<0.05) of the DOX intracellular content for the mixed micelles versus Doxil ® for both, SKOV-3 (at 2, 4 and 6h of incubation) and MDA-MB-231 (at 4h of incubation) cells. These findings suggest that T1107:TPGS (1:3) mixed micelles could be employed as a potential nanotechnological platform for drug delivery of DOX. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Engineering Folate-Targeting Diselenide-containing Triblock Copolymer as a Redox-Responsive Shell-sheddable Micelle for Antitumor Therapy In Vivo.

PubMed

Behroozi, Farnaz; Abdkhodaie, Mohammad-Jafar; Sadeghi Abandansari, Hamid; Satarian, Leila; Molazem, Mohammad; Al-Jamal, Khuloud T; Baharvand, Hossein

2018-06-18

The oxidation-reduction (redox)-responsive micelle system is based on a diselenide-containing triblock copolymer, poly(ε-caprolactone)-bis(diselenide-methoxy poly(ethylene glycol)/poly(ethylene glycol)-folate) [PCL-(SeSe-mPEG/PEG-FA) 2 ]. This has helped in the development of tumor-targeted delivery for hydrophobic anticancer drugs. The diselenide bond, as a redox-sensitive linkage, was designed in such a manner that it is located at the hydrophilic-hydrophobic hinge to allow complete collapse of the micelle and thus efficient drug release in redox environments. The amphiphilic block copolymers self-assembled into micelles at concentrations higher than the critical micelle concentration (CMC) in an aqueous environment. Dynamic light scattering (DLS) and transmission electron microscopy (TEM) analyses showed that the micelles were spherical with an average diameter of 120 nm. The insoluble anticancer drug paclitaxel (PTX) was loaded into micelles, and its triggered release behavior under different redox conditions was verified. Folate-targeting micelles showed an enhanced uptake in 4T1 breast cancer cells and in vitro cytotoxicity by flow cytometry and (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay, respectively. Delayed tumor growth was confirmed in the subcutaneously implanted 4T1 breast cancer in mice after intraperitoneal injection. The proposed redox-responsive copolymer offers a new type of biomaterial for drug delivery into cancer cells in vivo. On-demand drug actuation is highly desired. Redox-responsive polymeric DDSs have been shown to be able to respond and release their cargo in a selective manner when encountering a significant change in the potential difference, such as that present between cancerous and healthy tissues. This study offers an added advantage to the field of redox-responsive polymers by reporting a new type of shell-sheddable micelle based on an amphiphilic triblock co-polymer, containing diselenide as a redox-sensitive linkage. The linkage was smartly located at the hydrophilic-hydrophilic bridge in the co-polymer offering complete collapse of the micelle when exposed to the right trigger. The system was able to delay tumor growth and reduce toxicity in a breast cancer tumor model following intraperitoneal injection in mice. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Homopolymer Micelles in Heterogeneous Solvent Mixtures

PubMed Central

Basu, Subhadeep; Vutukuri, Dharma Rao

2008-01-01

Amphiphilic homopolymers containing a hydrophilic and a hydrophobic functionality in each monomer unit have been shown to form polar or apolar containers depending on the solvent environment. When presented with a mixture of solvents, these polymeric containers are capable of releasing certain guest molecules. The fundamental mechanism behind these properties is investigated and the utility of these assemblies in separations has been demonstrated with an example. PMID:16316219

Synthesis of Polylactide-Based Core-Shell Interface Cross-Linked Micelles for Anticancer Drug Delivery.

PubMed

Chen, Chih-Kuang; Lin, Wei-Jen; Hsia, Yu; Lo, Leu-Wei

2017-03-01

Well-defined poly(ethylene glycol)-b-allyl functional polylactide-b-polylactides (PEG-APLA-PLAs) are synthesized through sequential ring-opening polymerization. PEG-APLA-PLAs that have amphiphilic properties and reactive allyl side chains on their intermediate blocks are successfully transferred to core-shell interface cross-linked micelles (ICMs) by micellization and UV-initiated irradiation. ICMs have demonstrated enhanced colloidal stability in physiological-mimicking media. Hydrophobic molecules such as Nile Red or doxorubicin (Dox) are readily loaded into ICMs; the resulting drug-ICM formulations possess slow and sustained drug release profiles under physiological-mimicking conditions. ICMs exhibit negligible cytotoxicity in human uterine sarcoma cancer cells by using biodegradable aliphatic polyester as the hydrophobic segments. Relative to free Dox, Dox-loaded ICMs show a reduced cytotoxicity due to the late intracellular release of Dox from ICMs. Overall, ICMs represent a new type of biodegradable cross-linked micelle and can be employed as a promising platform for delivering a broad variety of hydrophobic drugs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Structure of a Unimolecular Dendritic Reverse Micelle in Dense CO2 Via Small Angle Scattering

NASA Astrophysics Data System (ADS)

Lin, J. S.

1997-03-01

Dilute solutions in dense CO2 (5Kpsi and 25 degC) of a unimolecular reverse micelle were studied via small angle x ray scattering (SAXS). The unimolecular micelle was based on a fourth generation poly(propylene imine) dendrimer, functionalized with perfluoropolyether acid fluoride chains. A value of 26 added chains per dendrimer was obtained from other characterization techniques, and this number of chains was fixed in the fitting of the SAXS data to an f-arm star model. The molecular weight ( 33.5K g mol-1) agreed well with estimates from other techniques. The observed negative second virial coefficient, A2 = -1.2 x 10-4 cm^3 g-2 mol, correlates with prior observations, as does the observed radius of gyration, Rg = 32ÅSponsors: Div. of Mat. Sci., Basic Energy Sc., USDOE, contract DE-AC05-96OR22464, Oak Ridge Nat. Lab., managed by Lockheed Martin Energy Research Corp.; The Royal Commission for the Exhibition of 1851; National Science Foundation; Consortium for the Sythesis and Processing of Polymeric Materials in Carbon Dioxide.

Codelivery of dual drugs from polymeric micelles for simultaneous targeting of both cancer cells and cancer stem cells.

PubMed

Krishnamurthy, Sangeetha; Ng, Victor W L; Gao, Shujun; Tan, Min-Han; Hedrick, James L; Yang, Yi Yan

2015-01-01

Phenformin-loaded micelles (Phen M) were used in combination with gemcitabine-loaded micelles (Gem M) to study their combined effect against H460 human lung cancer cells and cancer stem cells (CSCs) in vitro and in vivo. Gem M and Phen M were prepared via self-assembly of a mixture of a diblock copolymer of PEG and urea-functionalized polycarbonate (PEG-PUC) and a diblock copolymer of PEG and acid-functionalized polycarbonate (PEG-PAC) through hydrogen bonding and ionic interactions. Gem M and Phen M were characterized and tested for efficacy both in vitro and in vivo against cancer cells and CSCs. The combination of Gem M/Phen M exhibited higher cytotoxicity against CSCs and non-CSCs than Gem M and Phen M alone, and showed significant cell cycle growth arrest in vitro. The combination therapy had superior tumor suppression and apoptosis in vivo without inducing toxicity to liver and kidney. The combination of Gem M and Phen M may be potentially used in lung cancer therapy.

Reverse micelle synthesis of nanoscale metal containing catalysts. [Nickel metal (with a nickel oxide surface layer) and iron oxyhydroxide nanoscale powders

DOE Office of Scientific and Technical Information (OSTI.GOV)

Darab, J.G.; Fulton, J.L.; Linehan, J.C.

1993-03-01

The need for morphological control during the synthesis of catalyst precursor powders is generally accepted to be important. In the liquefaction of coal, for example, iron-bearing catalyst precursor particles containing individual crystallites with diameters in the 1-100 nanometer range are believed to achieve good dispersion through out the coal-solvent slurry during liquefaction 2 runs and to undergo chemical transformations to catalytically active iron sulfide phases. The production of the nanoscale powders described here employs the confining spherical microdomains comprising the aqueous phase of a modified reverse micelle (MRM) microemulsion system as nanoscale reaction vessels in which polymerization, electrochemical reduction andmore » precipitation of solvated salts can occur. The goal is to take advantage of the confining nature of micelles to kinetically hinder transformation processes which readily occur in bulk aqueous solution in order to control the morphology and phase of the resulting powder. We have prepared a variety of metal, alloy, and metal- and mixed metal-oxide nanoscale powders from appropriate MRM systems. Examples of nanoscale powders produced include Co, Mo-Co, Ni[sub 3]Fe, Ni, and various oxides and oxyhydroxides of iron. Here, we discuss the preparation and characterization of nickel metal (with a nickel oxide surface layer) and iron oxyhydroxide MRM nanoscale powders. We have used extended x-ray absorption fine structure (EXAFS) spectroscopy to study the chemical polymerization process in situ, x-ray diffraction (XRD), scanning and transmission electron microcroscopies (SEM and TEM), elemental analysis and structural modelling to characterize the nanoscale powders produced. The catalytic activity of these powders is currently being studied.« less

A Smart Magnetically Active Nanovehicle for on-Demand Targeted Drug Delivery: Where van der Waals Force Balances the Magnetic Interaction.

PubMed

Panja, Sudipta; Maji, Somnath; Maiti, Tapas K; Chattopadhyay, Santanu

2015-11-04

The magnetic field is a promising external stimulus for controlled and targeted delivery of therapeutic agents. Here, we focused on the preparation of a novel magnetically active polymeric micelle (MAPM) for magnetically targeted controlled drug delivery. To accomplish this, a number of superparamagnetic as well as biocompatible hybrid micelles were prepared by grafting four armed pentaerythretol poly(ε-caprolactone) (PE-PCL) onto the surface of Fe3O4 magnetic nanoparticles (MNPs) of two different ranges of size (∼5 nm and ∼15 nm). PE-PCL (four-armed) was synthesized by ring-opening polymerization, and it has been subsequently grafted onto the surface of modified MNP through urethane (-NHCO-) linkage. Polymer-immobilized MNP (5 and 15 nm) showed peculiar dispersion behavior. One displayed uniform dispersion of MNP (5 nm), while the other (15 nm) revealed associated structure. This type of size dependent contradictory dispersion behavior was realized by taking the van der Waals force as well as magnetic dipole-dipole force into consideration. The uniformly dispersed polymer immobilized MNP (5 nm) was used for the preparation of MAPM. The hydrodynamic size and bulk morphology of MAPM were studied by dynamic light scattering and high-resolution transmission electron microscopy. The anticancer drug (DOX) was encapsulated into the MAPM. The magnetic field triggers cell uptake of MAPM micelles preferentially toward targeted cells compare to untargeted ones. The cell viabilities of MAMP, DOX-encapsulated MAPM, and free DOX were studied against HeLa cell by MTT assay. In vitro release profile displayed about 51.5% release of DOX from MAPM (just after 1 h) under the influence of high frequency alternating magnetic field (HFAMF; prepared in-house device). The DOX release rate has also been tailored by on-demand application of HFAMF.

Nanoformulation of poly(ethylene glycol) polymerized organic insect repellent by PIT emulsification method and its application for Japanese encephalitis vector control.

PubMed

Balaji, A P B; Mishra, Prabhakar; Suresh Kumar, R S; Mukherjee, Amitava; Chandrasekaran, Natarajan

2015-04-01

The utilization of increased dosage of insect repellents to overcome mosquito resistance has raised environmental concerns globally. In accord to this, we have formulated an efficacious, water-dispersive, nanometric formulation of a poor water-soluble insect repellent, diethylphenylacetamide (DEPA) by poly(ethylene glycol) (PEG) polymerization followed by PIT emulsification method. The critical micelle concentration of PEG in the spontaneously emulsified conventional DEPA droplets was determined, based on the droplets physical stability. Subjecting them to PIT emulsification yielded monodispersed polymeric nanomicelles of DEPA (Nano DEPA) with hydrodynamic mean diameter of 153.74 nm. The high-resolution scanning and transmission electron microscopic studies revealed the characteristic core-shell structure of micelle. The comparative efficacy of Bulk DEPA and Nano DEPA was evaluated by larvicidal and WHO cone bioassay against the Japanese encephalitis vector Culex tritaeniorhynchus. The median lethal concentrations (48 h) for 3rd instars C. tritaeniorhynchus larvae were found to be 0.416 mg/L for Bulk DEPA and 0.052 mg/L for Nano DEPA, respectively. The median knockdown concentrations (60 min) for the two to three-day-old, sucrose-fed, female adult mosquitoes were 5.372% (v/v) and 3.471% (v/v) for Bulk and Nano DEPA, respectively. Further investigation by histopathological and biochemical studies propound that Nano DEPA exerted better bioefficacy as comparative to its bulk form even at minimal exposure concentrations. Hence, Nano DEPA will serve as an effective alternate in controlling the vector expansion with reduced dosage. Copyright © 2015 Elsevier B.V. All rights reserved.

Responsive Boronic Acid-Decorated (Co)polymers: From Glucose Sensors to Autonomous Drug Delivery.

PubMed

Vancoillie, Gertjan; Hoogenboom, Richard

2016-10-19

Boronic acid-containing (co)polymers have fascinated researchers for decades, garnering attention for their unique responsiveness toward 1,2- and 1,3-diols, including saccharides and nucleotides. The applications of materials that exert this property are manifold including sensing, but also self-regulated drug delivery systems through responsive membranes or micelles. In this review, some of the main applications of boronic acid containing (co)polymers are discussed focusing on the role of the boronic acid group in the response mechanism. We hope that this summary, which highlights the importance and potential of boronic acid-decorated polymeric materials, will inspire further research within this interesting field of responsive polymers and polymeric materials.

Responsive Boronic Acid-Decorated (Co)polymers: From Glucose Sensors to Autonomous Drug Delivery

PubMed Central

Vancoillie, Gertjan; Hoogenboom, Richard

2016-01-01

Boronic acid-containing (co)polymers have fascinated researchers for decades, garnering attention for their unique responsiveness toward 1,2- and 1,3-diols, including saccharides and nucleotides. The applications of materials that exert this property are manifold including sensing, but also self-regulated drug delivery systems through responsive membranes or micelles. In this review, some of the main applications of boronic acid containing (co)polymers are discussed focusing on the role of the boronic acid group in the response mechanism. We hope that this summary, which highlights the importance and potential of boronic acid-decorated polymeric materials, will inspire further research within this interesting field of responsive polymers and polymeric materials. PMID:27775572

Synthesis and self-assembly of amphiphilic polymeric microparticles.

PubMed

Dendukuri, Dhananjay; Hatton, T Alan; Doyle, Patrick S

2007-04-10

We report the synthesis and self-assembly of amphiphilic, nonspherical, polymeric microparticles. Wedge-shaped particles bearing segregated hydrophilic and hydrophobic sections were synthesized in a microfludic channel by polymerizing across laminar coflowing streams of hydrophilic and hydrophobic polymers using continuous flow lithography (CFL). Particle monodispersity was characterized by measuring both the size of the particles formed and the extent of amphiphilicity. The coefficient of variation (COV) was found to be less than 2.5% in all measured dimensions. Particle structure was further characterized by measuring the curvature of the interface between the sections and the extent of cross-linking using FTIR spectroscopy. The amphiphilic particles were allowed to self-assemble in water or at water-oil interfaces. In water, the geometry of the particles enabled the formation of micelle-like structures, while in emulsions, the particles migrated to the oil-water interface and oriented themselves to minimize their surface energy.

Neutral Polymer Micelle Carriers with pH-Responsive, Endosome-Releasing Activity Modulate Antigen Trafficking to Enhance CD8 T-Cell Responses

PubMed Central

Keller, Salka; Wilson, John T; Patilea, Gabriela I; Kern, Hanna B; Convertine, Anthony J; Stayton, Patrick S

2014-01-01

Synthetic subunit vaccines need to induce CD8+ cytotoxic T-cell (CTL) responses for effective vaccination against intracellular pathogens. Most subunit vaccines primarily generate humoral immune responses, with a weaker than desired CD8+ cytotoxic T-cell response. Here, a neutral, pH-responsive polymer micelle carrier that alters intracellular antigen trafficking was shown to enhance CD8+ T-cell responses with a correlated increase in cytosolic delivery and a decrease in exocytosis. Polymer diblock carriers consisted of a N-(2-hydroxypropyl) methacrylamide corona block with pendant pyridyl disulfide groups for reversible conjugation of thiolated ovalbumin, and a tercopolymer ampholytic core-forming block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The diblock copolymers self-assembled into 25–30 nm diameter micellar nanoparticles. Conjugation of ovalbumin to the micelles significantly enhanced antigen cross-presentation in vitro relative to free ovalbumin, an unconjugated physical mixture of ovalbumin and polymer, and a non pH-responsive micelle-ovalbumin control. Mechanistic studies in a murine dendritic cell line (DC2.4) demonstrated micelle-mediated enhancements in intracellular antigen retention and cytosolic antigen accumulation. Approximately 90% of initially internalized ovalbumin-conjugated micelles were retained in cells after 1.5 h, compared to only ~40% for controls. Furthermore, cells dosed with conjugates displayed 67-fold higher cytosolic antigen levels relative to soluble ovalbumin 4 h post uptake. Subcutaneous immunization of mice with ovalbumin-polymer conjugates significantly enhanced antigen-specific CD8+ T cell responses (0.4 % IFN-γ+ of CD8+) compared to immunization with soluble protein, ovalbumin and polymer mixture, and the control micelle without endosome-releasing activity. Additionally, pH-responsive carrier facilitated antigen delivery to antigen presenting cells in the draining lymph nodes. As early as 90 min post injection ova-micelle conjugates were associated with 28% and 55% of dendritic cells and macrophages, respectively. After 24 h, conjugates preferentially associated with dendritic cells, affording 30-, 3-, and 3-fold enhancements in uptake relative to free protein, physical mixture, and the non pH-responsive conjugate controls, respectively. These results demonstrate the potential of pH-responsive polymeric micelles for use in vaccine applications that rely on CD8+ T cell activation. PMID:24698946

Neutral polymer micelle carriers with pH-responsive, endosome-releasing activity modulate antigen trafficking to enhance CD8(+) T cell responses.

PubMed

Keller, Salka; Wilson, John T; Patilea, Gabriela I; Kern, Hanna B; Convertine, Anthony J; Stayton, Patrick S

2014-10-10

Synthetic subunit vaccines need to induce CD8(+) cytotoxic T cell (CTL) responses for effective vaccination against intracellular pathogens. Most subunit vaccines primarily generate humoral immune responses, with a weaker than desired CD8(+) cytotoxic T cell response. Here, a neutral, pH-responsive polymer micelle carrier that alters intracellular antigen trafficking was shown to enhance CD8(+) T cell responses with a correlated increase in cytosolic delivery and a decrease in exocytosis. Polymer diblock carriers consisted of a N-(2-hydroxypropyl) methacrylamide corona block with pendent pyridyl disulfide groups for reversible conjugation of thiolated ovalbumin, and a tercopolymer ampholytic core-forming block composed of propylacrylic acid (PAA), dimethylaminoethyl methacrylate (DMAEMA), and butyl methacrylate (BMA). The diblock copolymers self-assembled into 25-30nm diameter micellar nanoparticles. Conjugation of ovalbumin to the micelles significantly enhanced antigen cross-presentation in vitro relative to free ovalbumin, an unconjugated physical mixture of ovalbumin and polymer, and a non-pH-responsive micelle-ovalbumin control. Mechanistic studies in a murine dendritic cell line (DC 2.4) demonstrated micelle-mediated enhancements in intracellular antigen retention and cytosolic antigen accumulation. Approximately 90% of initially internalized ovalbumin-conjugated micelles were retained in cells after 1.5h, compared to only ~40% for controls. Furthermore, cells dosed with conjugates displayed 67-fold higher cytosolic antigen levels relative to soluble ovalbumin 4h post uptake. Subcutaneous immunization of mice with ovalbumin-polymer conjugates significantly enhanced antigen-specific CD8(+) T cell responses (0.4% IFN-γ(+) of CD8(+)) compared to immunization with soluble protein, ovalbumin and polymer mixture, and the control micelle without endosome-releasing activity. Additionally, pH-responsive carrier facilitated antigen delivery to antigen presenting cells in the draining lymph nodes. As early as 90min post injection, ova-micelle conjugates were associated with 28% and 55% of dendritic cells and macrophages, respectively. After 24h, conjugates preferentially associated with dendritic cells, affording 30-, 3-, and 3-fold enhancements in uptake relative to free protein, physical mixture, and the non-pH-responsive conjugate controls, respectively. These results demonstrate the potential of pH-responsive polymeric micelles for use in vaccine applications that rely on CD8(+) T cell activation. Copyright © 2014 Elsevier B.V. All rights reserved.

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38.

PubMed

Bala, Vaskor; Rao, Shasha; Boyd, Ben J; Prestidge, Clive A

2013-11-28

SN38 (7-ethyl-10-hydroxy camptothecin) is a prominent and efficacious anticancer agent. It is poorly soluble in both water and pharmaceutically approved solvents; therefore, the direct formulation of SN38 in solution form is limited. Currently, the water soluble prodrug of SN38, irinotecan (CPT-11), is formulated as a low pH solution and is approved for chemotherapy. However, CPT-11, along with most other water-soluble prodrugs shows unpredictable inter-patient conversion to SN38 in vivo, instability in the physiological environment and variable dose-related toxicities. More recently, macromolecular prodrugs (i.e. EZN-2208, IMMU-130) and nanomedicine formulations (i.e. nanoemulsions, polymeric micelles, lipid nanocapsule/nanoparticle, and liposomes) of SN38 have been investigated for improved delivery to cancer cells and tissues. Specifically, these carriers can take advantage of the EPR effect to direct drug preferentially to tumour tissues, thereby substantially improving efficacy and minimising side effects. Furthermore, oral delivery has been shown to be possible in preclinical results using nanomedicine formulations (i.e. dendrimers, lipid nanocapsules, polymeric micelles). This review summarizes the recent advances for the delivery of SN38 with a focus on macromolecular prodrugs and nanomedicines. © 2013 Elsevier B.V. All rights reserved.

Co-delivery of doxorubicin and AS1411 aptamer by poly(ethylene glycol)-poly( β-amino esters) polymeric micelles for targeted cancer therapy

NASA Astrophysics Data System (ADS)

Zhang, Ran; Wang, Shi-Bin; Wu, Wen-Guo; Kankala, Ranjith Kumar; Chen, Ai-Zheng; Liu, Yuan-Gang; Fan, Jing-Qian

2017-06-01

Recently, targeted drug delivery systems (TDDS) have offered a great potential and benefits towards the anti-tumor drug delivery. In this work, we designed the TDDS using a biocompatible poly(ethylene glycol)-poly( β-amino esters) amphiphilic block copolymer (PEG-PAEs) synthesized by Michael addition polymerization for combinatorial therapy. Further, the chemotherapeutic agents' doxorubicin (DOX) and AS1411 DNA aptamer (Apt) are encapsulated in the PEG-PAEs NPs (PDANs) for co-delivery therapeutics. PDANs have shown the monodisperse spherical shape, smooth surface with a net positive charge (average diameter—183.1 ± 27.2 nm, zeta potential—31.2 ± 6.3 mV), and good colloidal stability (critical micelle concentration of PEG-PAEs is about 6.3 μg/mL). The pH-sensitive PAEs endowed PDANs both pH-triggered drug release characteristics and enhanced endo/lysosomal escape ability, thus improving the localization and cytotoxicity of DOX. AS1411 Apt conjugated PDANs precisely targeted nucleolin and their uptake correlates to a significant activity enhancement only in tumor cells (MCF-7) but not in normal cells (MCF-10A). Thus, PDANs can be a very promising targeted drug delivery platform for effective breast cancer therapy.

Polymer therapeutics: Top 10 selling pharmaceuticals - what next?

PubMed

Duncan, Ruth

2014-09-28

At the time of the first issue of the Journal of Controlled Release (JCR), polymeric drugs, polymer-drug and protein conjugates and block copolymer micelles carrying bound drugs, i.e. polymer therapeutics, were still regarded as scientific curiosities with little or no prospect of generating practical to use medicines. How this perception has changed. Many major Pharma now have R&D programmes in this area and in 2013 two polymer therapeutics, Copaxone and Neulasta, are featured in the Top 10 US pharmaceutical sales list. Although there are a growing number of marketed products (e.g. PEGylated proteins, a PEG-aptamer and oral polymeric sequestrants), and the first follow-on (generic products) are emerging, the first polymer-drug conjugates and block copolymer micelle products (as covalent conjugates) have yet to enter routine clinical use. Industrial familiarity and recent advances in the underpinning scientific disciplines will no doubt accelerate the transfer of polymer therapeutics into clinically useful medicines and imaging agents. This short personal perspective reflects on the current status of polymer therapeutics and the future opportunities to improve their successful translation. It adds to recent and historical reviews that comprehensively document the evolution of the field since JCR was born. Copyright © 2014 Elsevier B.V. All rights reserved.

In situ electrochemical polymerization of a nanorod-PANI-Graphene composite in a reverse micelle electrolyte and its application in a supercapacitor.

PubMed

Hu, Liwen; Tu, Jiguo; Jiao, Shuqiang; Hou, Jungang; Zhu, Hongmin; Fray, Derek J

2012-12-05

Highly porous nanorod-PANI-Graphene composite films were prepared by in situ electrochemical polymerization onto an ITO substrate in a reverse micelle electrolyte. The morphology and microstructure of the composite films were analyzed by using a field emission scanning electron microscope. It was observed that the films were highly porous and the nanorod PANI films were inserted by graphene nanosheets. This indicated that a good conductive network between PANI nanorods and graphene sheets was formed. Further electrochemical tests involved cyclic voltammetry (CV), galvanostatic charge-discharge (GCD) and electrochemical impedance spectroscopy (EIS) in 1 mol L(-1) HClO(4) solution. The results showed that the composite film had a favorable capacitance with a high electron transfer rate and low resistance. The highest specific capacitance that could be achieved was as high as 878.57 F g(-1) with the charge loading of 500 mC at a current density of 1 A g(-1). The GCD at different charge loadings showed good cycle stability with a low fading rate of specific capacitance after 1000 cycles. The results demonstrated that the nanorod-PANI-Graphene composite was proved to be of great potential as an electrode material for supercapacitors.

Novel thermosensitive polymeric micelles for docetaxel delivery.

PubMed

Yang, Mi; Ding, Yitao; Zhang, Leyang; Qian, Xiaoping; Jiang, Xiqun; Liu, Baorui

2007-06-15

Targeted delivery of antitumor drugs triggered by hyperthermia has significant advantages in clinical applications, since it is easy to implement and side effects are reduced. To release drugs site-specifically upon local heating often requires the drugs to be loaded into a thermosensitive polymer matrix with a low critical solution temperature (LCST) between 37 and 42 degrees C. However, the LCSTs of most thermosensitive materials were below 37 degrees C, which limits their application in clinic because they would precipitate once injected into human body and lost thermal targeting function. Herein, we prepared a novel thermosensitive copolymer (poly(N-isopropylacrylamide-co-acrylamide)-b-poly (DL-lactide)) that exhibits no obvious physical change up to 41 degrees C when heated. Docetaxel loaded micelles made of such thermosensitive polymer were prepared by dialysis method and the maximum loading content was found to be up to 27%. The physical properties, such as structure, morphology, and size distribution of the micelles with and without docetaxel were investigated by NMR, X-ray diffraction, dynamic light scattering, atomic force microscopy, etc. The efficacy of this drug delivery system was also evaluated by examining the proliferation inhibiting activity against different cell lines in vitro. After hyperthermia, the cytotoxicity of docetaxel-loaded micelles increased prominently. Our results demonstrated that this copolymer could be an ideal candidate for thermal targeted antitumor drug delivery. (c) 2007 Wiley Periodicals, Inc.

Carbon nanotubes as templates for polymerized lipid assemblies

NASA Astrophysics Data System (ADS)

Thauvin, Cédric; Rickling, Stéphane; Schultz, Patrick; Célia, Hervé; Meunier, Stéphane; Mioskowski, Charles

2008-12-01

Amphiphilic molecules-molecules that have both hydrophobic and hydrophilic properties-can self-assemble in water to form diverse structures such as micelles, vesicles and tubes, and these nanostructures can be used for delivering drugs, stabilizing membrane proteins or as nanoreactors. We have previously shown that lipids can self-organize on the surface of single-walled carbon nanotubes into regular ring-shaped assemblies. Here we show that these lipid assemblies can be polymerized and isolated from the nanotube template by application of an electric field. We also demonstrate that these assemblies are monodispersed, water-soluble, and can dissolve various hydrophobic rylene dyes, fullerenes and membrane proteins. The stability of these constructs and their diverse applications will be useful in the fields of cosmetics, medicine and material sciences.

Polymeric micelles as a diagnostic tool for image-guided drug delivery and radiotherapy of HER2 overexpressing breast cancer

NASA Astrophysics Data System (ADS)

Hoang, Nu Bryan

Block copolymer micelles have emerged as a viable formulation strategy with several drugs relying on this technology in clinical evaluation. To date, information on the tumor penetration and intratumoral distribution of block copolymer micelles (BCM) has been quite limited. Thus, there is impetus to develop a radiolabeled formulation that can be used to gain invaluable insight into the intratumoral distribution of the BCMs. This information could then be used to direct formulation strategies as a means to optimize treatment outcomes. This thesis describes the synthesis and characterization of a targeted block copolymer micelle system based on poly(ethylene glycol)-block -poly(epsilon-caprolactone) labeled with the radionuclide Indium-111 (111In). The incorporation of the imageable component, 111In permits pursuit of image-guided drug delivery for real-time monitoring of tumor localization and intratumoral distribution. Intracellular trafficking of drugs and therapies such as Auger electron emitting radionuclides to perinuclear and nuclear regions of cells is critical to realizing their full therapeutic potential. HER2 specific antibodies (trastuzumab fab fragments) and nuclear localization signal peptides were conjugated to the surface of the BCMs to direct uptake in HER2 expressing cells and subsequent localization in the cell nucleus. Cell uptake was HER2 density dependent, confirming receptor-mediated internalization of the BCMs. Importantly, conjugation of NLS resulted in a significant increase in nuclear uptake of the radionuclide 111In. Successful nuclear targeting was shown to improve the antiproliferative effect of the Auger electrons. In addition, a significant radiation enhancement effect was observed by concurrent delivery of low-dose MTX and 111In in all breast cancer cell lines evaluated. Imaging enabled the accurate quantification of the specific tumor uptake of the micelles and visualization of their degree of tumor penetration in relation to microvessel density. Ultimately, the 111In-micelles could be used for such diverse applications as detection of malignancies, molecular characterization of tumors, improved therapy guidance and targeted anti-cancer treatment.

Biodistribution of biodegradable polymeric nano-carriers loaded with busulphan and designed for multimodal imaging.

PubMed

Asem, Heba; Zhao, Ying; Ye, Fei; Barrefelt, Åsa; Abedi-Valugerdi, Manuchehr; El-Sayed, Ramy; El-Serafi, Ibrahim; Abu-Salah, Khalid M; Hamm, Jörg; Muhammed, Mamoun; Hassan, Moustapha

2016-12-19

Multifunctional nanocarriers for controlled drug delivery, imaging of disease development and follow-up of treatment efficacy are promising novel tools for disease diagnosis and treatment. In the current investigation, we present a multifunctional theranostic nanocarrier system for anticancer drug delivery and molecular imaging. Superparamagnetic iron oxide nanoparticles (SPIONs) as an MRI contrast agent and busulphan as a model for lipophilic antineoplastic drugs were encapsulated into poly (ethylene glycol)-co-poly (caprolactone) (PEG-PCL) micelles via the emulsion-evaporation method, and PEG-PCL was labelled with VivoTag 680XL fluorochrome for in vivo fluorescence imaging. Busulphan entrapment efficiency was 83% while the drug release showed a sustained pattern over 10 h. SPION loaded-PEG-PCL micelles showed contrast enhancement in T 2 *-weighted MRI with high r 2 * relaxivity. In vitro cellular uptake of PEG-PCL micelles labeled with fluorescein in J774A cells was found to be time-dependent. The maximum uptake was observed after 24 h of incubation. The biodistribution of PEG-PCL micelles functionalized with VivoTag 680XL was investigated in Balb/c mice over 48 h using in vivo fluorescence imaging. The results of real-time live imaging were then confirmed by ex vivo organ imaging and histological examination. Generally, PEG-PCL micelles were highly distributed into the lungs during the first 4 h post intravenous administration, then redistributed and accumulated in liver and spleen until 48 h post administration. No pathological impairment was found in the major organs studied. Thus, with loaded contrast agent and conjugated fluorochrome, PEG-PCL micelles as biodegradable and biocompatible nanocarriers are efficient multimodal imaging agents, offering high drug loading capacity, and sustained drug release. These might offer high treatment efficacy and real-time tracking of the drug delivery system in vivo, which is crucial for designing of an efficient drug delivery system.

Periodic organosilica hollow nanospheres as anode materials for lithium ion rechargeable batteries.

PubMed

Sasidharan, Manickam; Nakashima, Kenichi; Gunawardhana, Nanda; Yokoi, Toshiyuki; Ito, Masanori; Inoue, Masamichi; Yusa, Shin-ichi; Yoshio, Masaki; Tatsumi, Takashi

2011-11-01

Polymeric micelles with core-shell-corona architecture have been found to be the efficient colloidal templates for synthesis of periodic organosilica hollow nanospheres over a broad pH range from acidic to alkaline media. In alkaline medium, poly (styrene-b-[3-(methacryloylamino)propyl] trimethylammonium chloride-b-ethylene oxide) (PS-PMAPTAC-PEO) micelles yield benzene-silica hollow nanospheres with molecular scale periodicity of benzene groups in the shell domain of hollow particles. Whereas, an acidic medium (pH 4) produces diverse hollow particles with benzene, ethylene, and a mixture of ethylene and dipropyldisulfide bridging functionalities using poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-PVP-PEO) micelles. These hollow particles were thoroughly characterized by powder X-ray diffraction (XRD), dynamic light scattering (DLS), thermogravimetric analysis (TG/DTA), Fourier transformation infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), magic angle spinning-nuclear magnetic resonance ((29)Si MAS NMR and (13)CP-MAS NMR), Raman spectroscopy, and nitrogen adsorption/desorption analyses. The benzene-silica hollow nanospheres with molecular scale periodicity in the shell domain exhibit higher cycling performance of up to 300 cycles in lithium ion rechargeable batteries compared with micron-sized dense benzene-silica particles.

Thermosensitive behavior of poly(ethylene glycol)-based block copolymer (PEG-b-PADMO) controlled via self-assembled microstructure.

PubMed

Cui, Qianling; Wu, Feipeng; Wang, Erjian

2011-05-19

Stimuli-responsive, well-defined diblock copolymers (PEG-b-PADMO) comprising poly(ethylene glycol) (PEG, DP (degree of polymerization)=45) as the hydrophilic and temperature-sensitive part and poly(N-acryloyl-2,2-dimethyl-1,3-oxazolidine) (PADMO, DP=18-47) as the hydrophobic and acid-labile part self-assembled in water into spherical micelles with high aggregation number. The micellar structures and thermally induced phase transitions of the copolymers were investigated with (1)H NMR spectroscopy, light scattering, microscopy, turbidimetry, and fluorescence techniques. Thermoresponsive phase transitions of the copolymers in water were controlled via formation of core-shell-type micelles with densely compact PEG corona. Their lower critical solution temperatures (LCSTs) were modulated within the range 40-72 °C by varying PADMO block length. This unusually low LCST was attributed to the densely packed PEG structure in the polymer micelles, which resulted in strong n-clustering attractive interactions and insufficient hydration of PEG chains in the shell and greatly enhanced the thermosensitivity. The LCST behavior can also be modulated by partial acid hydrolysis of PADMO segments through the resulting change of hydrophobicity. © 2011 American Chemical Society

pH-Responsive biodegradable polymeric micelles with anchors to interface magnetic nanoparticles for MR imaging in detection of cerebral ischemic area

NASA Astrophysics Data System (ADS)

Yang, Hong Yu; Jang, Moon-Sun; Gao, Guang Hui; Lee, Jung Hee; Lee, Doo Sung

2016-06-01

A novel type of pH-responsive biodegradable copolymer was developed based on methyloxy-poly(ethylene glycol)-block-poly[dopamine-2-(dibutylamino) ethylamine-l-glutamate] (mPEG-b-P(DPA-DE)LG) and applied to act as an intelligent nanocarrier system for magnetic resonance imaging (MRI). The mPEG-b-P(DPA-DE)LG copolymer was synthesized by a typical ring opening polymerization of N-carboxyanhydrides (NCAs-ROP) using mPEG-NH2 as a macroinitiator, and two types of amine-terminated dopamine groups and pH-sensitive ligands were grafted onto a side chain by a sequential aminolysis reaction. This design greatly benefits from the addition of the dopamine groups to facilitate self-assembly, as these groups can act as high-affinity anchors for iron oxide nanoparticles, thereby increasing long-term stability at physiological pH. The mPEG moiety in the copolymers helped the nanoparticles to remain well-dispersed in an aqueous solution, and pH-responsive groups could control the release of hydrophobic Fe3O4 nanoparticles in an acidic environment. The particle size of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles was measured by dynamic light scattering (DLS) and cryo-TEM. The superparamagnetic properties of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles were confirmed by a superconducting quantum interference device (SQUID). T2-weighted magnetic resonance imaging (MRI) of Fe3O4-loaded mPEG-b-P(DPA-DE)LG phantoms exhibited enhanced negative contrast with an r2 relaxivity of approximately 106.7 mM-1 s-1. To assess the ability of the Fe3O4-loaded mPEG-P(DE-DPA)LG micelles to act as MRI probes, we utilized a cerebral ischemia disease rat model with acidic tissue. We found that a gradual change in contrast in the cerebral ischemic area could be visualized by MRI after 1 h, and maximal signal loss was detected after 24 h post-injection. These results demonstrated that the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles can act as pH-triggered MRI probes for diagnostic imaging of acidic pathological tissues.A novel type of pH-responsive biodegradable copolymer was developed based on methyloxy-poly(ethylene glycol)-block-poly[dopamine-2-(dibutylamino) ethylamine-l-glutamate] (mPEG-b-P(DPA-DE)LG) and applied to act as an intelligent nanocarrier system for magnetic resonance imaging (MRI). The mPEG-b-P(DPA-DE)LG copolymer was synthesized by a typical ring opening polymerization of N-carboxyanhydrides (NCAs-ROP) using mPEG-NH2 as a macroinitiator, and two types of amine-terminated dopamine groups and pH-sensitive ligands were grafted onto a side chain by a sequential aminolysis reaction. This design greatly benefits from the addition of the dopamine groups to facilitate self-assembly, as these groups can act as high-affinity anchors for iron oxide nanoparticles, thereby increasing long-term stability at physiological pH. The mPEG moiety in the copolymers helped the nanoparticles to remain well-dispersed in an aqueous solution, and pH-responsive groups could control the release of hydrophobic Fe3O4 nanoparticles in an acidic environment. The particle size of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles was measured by dynamic light scattering (DLS) and cryo-TEM. The superparamagnetic properties of the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles were confirmed by a superconducting quantum interference device (SQUID). T2-weighted magnetic resonance imaging (MRI) of Fe3O4-loaded mPEG-b-P(DPA-DE)LG phantoms exhibited enhanced negative contrast with an r2 relaxivity of approximately 106.7 mM-1 s-1. To assess the ability of the Fe3O4-loaded mPEG-P(DE-DPA)LG micelles to act as MRI probes, we utilized a cerebral ischemia disease rat model with acidic tissue. We found that a gradual change in contrast in the cerebral ischemic area could be visualized by MRI after 1 h, and maximal signal loss was detected after 24 h post-injection. These results demonstrated that the Fe3O4-loaded mPEG-b-P(DPA-DE)LG micelles can act as pH-triggered MRI probes for diagnostic imaging of acidic pathological tissues. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06542a

Micellar emulsions composed of mPEG-PCL/MCT as novel nanocarriers for systemic delivery of genistein: a comparative study with micelles

PubMed Central

Zhang, Tianpeng; Wang, Huan; Ye, Yanghuan; Zhang, Xingwang; Wu, Baojian

2015-01-01

Polymeric micelles receive considerable attention as drug delivery vehicles, depending on the versatility in drug solubilization and targeting therapy. However, their use invariably suffers with poor stability both in in vitro and in vivo conditions. Here, we aimed to develop a novel nanocarrier (micellar emulsions, MEs) for a systemic delivery of genistein (Gen), a poorly soluble anticancer agent. Gen-loaded MEs (Gen-MEs) were prepared from methoxy poly(ethylene glycol)-block-(ε-caprolactone) and medium-chain triglycerides (MCT) by solvent-diffusion technique. Nanocarriers were characterized by dynamic light scattering, transmission electron microscopy, and in vitro release. The resulting Gen-MEs were approximately 46 nm in particle size with a narrow distribution. Gen-MEs produced a different in vitro release profile from the counterpart of Gen-ME. The incorporation of MCT significantly enhanced the stability of nanoparticles against dilution with simulated body fluid. Pharmacokinetic study revealed that MEs could notably extend the mean retention time of Gen, 1.57- and 7.38-fold as long as that of micelles and solution formulation, respectively, following intravenous injection. Furthermore, MEs markedly increased the elimination half-life (t1/2β) of Gen, which was 2.63-fold larger than that of Gen solution. Interestingly, Gen distribution in the liver and kidney for MEs group was significantly low relative to the micelle group in the first 2 hours, indicating less perfusion in such two tissues, which well accorded with the elongated mean retention time. Our findings suggested that MEs may be promising carriers as an alternative of micelles to systemically deliver poorly soluble drugs. PMID:26491290

Design and Evaluation of Multi-functional Nanocarriers for Selective Delivery of Coenzyme Q10 to Mitochondria

PubMed Central

Sharma, Anjali; Soliman, Ghareb M.; Al-Hajaj, Noura; Sharma, Rishi; Maysinger, Dusica; Kakkar, Ashok

2016-01-01

Impairments of mitochondrial functions have been associated with failure of cellular functions in different tissues leading to various pathologies. We report here a mitochondria–targeted nanodelivery system for coenzyme Q10 (CoQ10) which can reach mitochondria, and deliver CoQ10 in adequate quantities. Multifunctional nanocarriers based on ABC miktoarm polymers (A= PEG, B = polycaprolactone (PCL) and C = triphenylphosphonium bromide (TPPBr)) were synthesized using a combination of click chemistry with ring opening polymerization, self-assembled into nano-sized micelles, and were employed for CoQ10-loading. Drug loading capacity (60 weight%), micelle size (25–60 nm) and stability were determined using a variety of techniques. The micelles had a small critical association concentration, and were colloidally stable in solution for more than 3 months. The extraordinarily high CoQ10 loading capacity in the micelles is attributed to good compatibility between CoQ10 and PCL, as indicated by low Flory-Huggins interaction parameter. Confocal microscopy studies of fluorescently labeled polymer analog together with the mitochondria-specific vital dye label, indicated that the carrier did indeed reach mitochondria. The high CoQ10 loading efficiency allowed testing of micelles within a broad concentration range, and provided evidence for CoQ10 effectiveness in two different experimental paradigms: oxidative stress and inflammation. Combined results from chemical, analytical and biological experiments suggest that the new miktoarm-based carrier provides a suitable means of CoQ10 delivery to mitochondria without loss of drug effectiveness. The versatility of the click chemistry used to prepare this new mitochondria-targeting nanocarrier offers a widely applicable, simple and easily reproducible procedure to deliver drugs to mitochondria or other intracellular organelles. PMID:22148549

β-Lapachone and Paclitaxel Combination Micelles with Improved Drug Encapsulation and Therapeutic Synergy as Novel Nanotherapeutics for NQO1-Targeted Cancer Therapy.

PubMed

Zhang, Ling; Chen, Zhen; Yang, Kuan; Liu, Chun; Gao, Jinming; Qian, Feng

2015-11-02

β-Lapachone (LPC) is a novel cytotoxic agent that is bioactivated by NADP(H): quinone oxidoreductase 1 (NQO1), an enzyme elevated in a variety of tumors, such as non-small cell lung cancer (NSCLC), pancreatic cancer, liver cancer, and breast cancer. Despite its unique mechanism of action, its clinical evaluation has been largely hindered by low water solubility, short blood half-life, and narrow therapeutic window. Although encapsulation into poly(ethylene glycol)-b-poly(D,L-lactic acid) (PEG-PLA) micelles could modestly improve its solubility and prolong its half-life, the extremely fast intrinsic crystallization tendency of LPC prevents drug loading higher than ∼2 wt %. The physical stability of the LPC-loaded micelles is also far from satisfactory for further development. In this study, we demonstrate that paclitaxel (PTX), a front-line drug for many cancers, can provide two functions when coencapsulated together with LPC in the PEG-PLA micelles; first, as a strong crystallization inhibitor for LPC, thus to significantly increase the LPC encapsulation efficiency in the micelle from 11.7 ± 2.4% to 100.7 ± 2.2%. The total drug loading efficiency of both PTX and LPC in the combination polymeric micelle reached 100.3 ± 3.0%, and the drug loading density reached 33.2 ± 1.0%. Second, the combination of LPC/PTX demonstrates strong synergistic cytotoxicity effect against the NQO1 overexpressing cancer cells, including A549 NSCLC cells, and several pancreatic cancer cells (combination index <1). In vitro drug release study showed that LPC was released faster than PTX either in phosphate-buffered saline (PH = 7.4) or in 1 M sodium salicylate, which agrees with the desired dosing sequence of the two drugs to exert synergistic pharmacologic effect at different cell checkpoints. The PEG-PLA micelles coloaded with LPC and PTX offer a novel nanotherapeutic, with high drug loading, sufficient physical stability, and biological synergy to increase drug delivery efficiency and optimize the therapeutic window for NOQ1-targeted therapy of cancer.

Convection-enhanced delivery of a synthetic retinoid Am80, loaded into polymeric micelles, prolongs the survival of rats bearing intracranial glioblastoma xenografts.

PubMed

Yokosawa, Michiko; Sonoda, Yukihiko; Sugiyama, Shin-ichiro; Saito, Ryuta; Yamashita, Yoji; Nishihara, Masamichi; Satoh, Taku; Kumabe, Toshihiro; Yokoyama, Masayuki; Tominaga, Teiji

2010-08-01

Prognosis for the patients with glioblastoma, the most common malignant brain tumor, remains dismal. A major barrier to progress in treatment of glioblastoma is the relative inaccessibility of tumors to chemotherapeutic agents. Convection-enhanced delivery (CED) is a direct intracranial drug infusion technique to deliver chemotherapeutic agents to the central nervous system, circumventing the blood-brain barrier and reducing systemic side effects. CED can provide wider distribution of infused agents compared to simple diffusion. We have reported that CED of a polymeric micelle carrier system could yield a clinically relevant distribution of encapsulated agents in the rat brain. Our aim was to evaluate the efficacy of CED of polymeric micellar Am80, a synthetic agonist with high affinity to nuclear retinoic acid receptor, in a rat model of glioblastoma xenografts. We also used systemic administration of temozolomide, a DNA-alkylating agent, which has been established as the standard of care for newly diagnosed malignant glioma. U87MG human glioma cells were injected into the cerebral hemisphere of nude rats. Rats bearing U87MG xenografts were treated with CED of micellar Am80 (2.4 mg/m(2)) on day 7 after tumor implantation. Temozolomide (200 mg/m(2)/day) was intraperitoneally administered daily for 5 days, starting on day 7 after tumor implantation. CED of micellar Am80 provided significantly longer survival than the control. The combination of CED of micellar Am80 and systemic administration of temozolomide provided significantly longer survival than single treatment. In conclusion, temozolomide combined with CED of micellar Am80 may be a promising method for the treatment of malignant gliomas.

Diethylenetriaminepentaacetic acid-gadolinium (DTPA-Gd)-conjugated polysuccinimide derivatives as magnetic resonance imaging contrast agents.

PubMed

Lee, Ha Young; Jee, Hye Won; Seo, Sung Mi; Kwak, Byung Kook; Khang, Gilson; Cho, Sun Hang

2006-01-01

Biocompatible polysuccinimide (PSI) derivatives conjugated with diethylenetriaminepentaacetic acid gadolinium (DTPA-Gd) were prepared as magnetic resonance imaging (MRI) contrast agents. In this study, we synthesized PSI derivatives incorporating methoxy-poly(ethylene glycol) (mPEG) as hydrophilic ligand, hexadecylamine as hydrophobic ligand, and DTPA-Gd as contrast agent. PSI was synthesized by the polycondensation polymerization of aspartic acid. All the synthesized materials were characterized by proton nuclear magnetic resonance (1H NMR). Critical micellization concentrations were determined using fluorescent probes (pyrene). Micelle size and shape were measured by electro-photometer light scattering (ELS) and atomic force microscopy (AFM). The formed micelle size ranged from 100 to 300 nm. The T1-weighted MR images of the phantom prepared with PSI-mPEG-C16-(DTPA-Gd) were obtained in a 3.0 T clinical MR imager, and the conjugates showed a great potential as MRI contrast agents.

Preparation of pH-sensitive zwitterionic nano micelles and drug controlled release for enhancing cellular uptake.

PubMed

Wu, Luyan; Ni, Caihua; Zhang, Liping; Shi, Gang

2016-01-01

Zwitterionic copolymers have exhibited high resistance to nonspecific protein adsorption and have wide applications in drug delivery systems. Herein, a pH-responsive poly(Lysine-alt-N,N'-bis(acryloyl) diaminohexane) was synthesized through the Michael addition polymerization between N, N'-bis(acryloyl) diaminohexane and lysine. Subsequently, nano micelles (NMs) were formed by self-assembly of the copolymer in an aqueous solution. The NMs showed a slightly negative charge in blood environment, but a positively charged surface in extracellular pH of tumor. This feature could be used to enhance permeability and retention effect, and reinforce tumor cell uptake. Vitro release studies revealed that the release of DOX from the DOX-loaded NMs was evidently faster at pH 5.0 than at pH 7.4. MTT assays revealed that NMs were nontoxic. Thus, these smart NMs were feasible candidates and could be potentially used in cancer chemotherapy.

Switchable pH-responsive polymeric membranes prepared via block copolymer micelle assembly.

PubMed

Nunes, Suzana P; Behzad, Ali Reza; Hooghan, Bobby; Sougrat, Rachid; Karunakaran, Madhavan; Pradeep, Neelakanda; Vainio, Ulla; Peinemann, Klaus-Viktor

2011-05-24

A process is described to manufacture monodisperse asymmetric pH-responsive nanochannels with very high densities (pore density >2 × 10(14) pores per m(2)), reproducible in m(2) scale. Cylindric pores with diameters in the sub-10 nm range and lengths in the 400 nm range were formed by self-assembly of metal-block copolymer complexes and nonsolvent-induced phase separation. The film morphology was tailored by taking into account the stability constants for a series of metal-polymer complexes and confirmed by AFM. The distribution of metal-copolymer micelles was imaged by transmission electron microscopy tomography. The pH response of the polymer nanochannels is the strongest reported with synthetic pores in the nm range (reversible flux increase of more than 2 orders of magnitude when switching the pH from 2 to 8) and could be demonstrated by cryo-field emission scanning electron microscopy, SAXS, and ultra/nanofiltration experiments.

Chitosan-palmitic acid based polymeric micelles as promising carrier for circumventing pharmacokinetic and drug delivery concerns of tamoxifen.

PubMed

Thotakura, Nagarani; Dadarwal, Mukesh; Kumar, Rajendra; Singh, Bhupinder; Sharma, Gajanand; Kumar, Pramod; Katare, Om Prakash; Raza, Kaisar

2017-09-01

Being a BCS class II drug and a good substrate for microsomal enzymes, tamoxifen (TAM) offers a scope for research owing to poor aqueous solubility and compromised bioavailability. The present study designs a novel copolymer derived from palmitic acid and chitosan, and evaluate the derived TAM-loaded micelles for various delivery attributes. The nanometric micellar carriers not only substantially loaded the drug, but also controlled the rate of release of TAM. The designed nanocarrier significantly enhanced the cytotoxicity of TAM on MCF-7 cancer cells. The developed system was designed for intravenous route and was observed to be substantially haemo-compatible with an enhancement of approx. 5 times in AUC vis-a-vis plain drug. The findings employing new polymer-based carrier are promising in nature for the better delivery of similar drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Preparation, co-assembling and interfacial crosslinking of photocurable and folate-conjugated amphiphilic block copolymers for controlled and targeted drug delivery: smart armored nanocarriers.

PubMed

Khoee, Sepideh; Kavand, Alireza

2014-02-12

Novel pH-sensitive, biodegradable and biocompatible copolymers based on polycaprolactone-poly(ethylene glycol) (PCL/PEG) were synthesized and further modified with folic acid and/or acryloyl chloride. The mixed polymeric micelles were formed by self-assembling of folated-copolymer and non-folated-copolymer with different compositions via nanoprecipitation method. The solubilization of quercetin as anti-cancer drug by the mixed micelle with the optimized composition (folated/non-folated 20/80) was more efficient than those made of each one alone. Nanogels with different crosslinking density were produced in the presence of ethylene glycol dimethacrylate (EGDMA) as the crosslinker via a photochemical method. Interfacial crosslinking of acrylated groups were utilized to produce a core-shell spherical nanoparticle to evaluate their in-vitro drug release and degradation rate. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

pH-induced vesicle-to-micelle transition in amphiphilic diblock copolymer: investigation by energy transfer between in situ formed polymer embedded gold nanoparticles and fluorescent dye.

PubMed

Maiti, Chiranjit; Banerjee, Rakesh; Maiti, Saikat; Dhara, Dibakar

2015-01-01

The ability to regulate the formation of nanostructures through self-assembly of amphiphilic block copolymers is of immense significance in the field of biology and medicine. In this work, a new block copolymer synthesized by using reversible addition-fragmentation chain transfer (RAFT) polymerization technique from poly(ethylene glycol) monomethyl ether acrylate (PEGMA) and Boc-l-tryptophan acryloyloxyethyl ester (Boc-l-trp-HEA) was found to spontaneously form pH-responsive water-soluble nanostructures after removal of the Boc group. While polymer vesicles or polymerosomes were formed at physiological pH, the micelles were formed at acidic pH (< 5.2), and this facilitated a pH-induced reversible vesicle-to-micelle transition. Formation of these nanostructures was confirmed by different characterization techniques, viz. transmission electron microscopy, dynamic light scattering, and steady-state fluorescence measurements. Further, these vesicles were successfully utilized to reduce HAuCl4 and stabilize the resulting gold nanoparticles (AuNPs). These AuNPs, confined within the hydrophobic shell of the vesicles, could participate in energy transfer process with fluorescent dye molecules encapsulated in the core of the vesicles, thus forming a nanometal surface energy transfer (NSET) pair. Subsequently, following the efficiency of energy transfer between this pair, it was possible to monitor the process of transition from vesicles to micelles. Thus, in this work, we have successfully demonstrated that NSET can be used to follow the transition between nanostructures formed by amphiphilic block copolymers.

In vitro and in vivo protein release and anti-ischemia/reperfusion injury properties of bone morphogenetic protein-2-loaded glycyrrhetinic acid-poly(ethylene glycol)-b-poly(l-lysine) nanoparticles

PubMed Central

Shan, Fang; Liu, YuJuan; Jiang, Haiying; Tong, Fei

2017-01-01

Here, we describe a bone morphogenetic protein-2 (BMP-2) nanocarrier based on glycyrrhetinic acid (GA)-poly(ethylene glycol) (PEG)-b-poly(l-lysine) (PLL). A protein nanocarrier was synthesized, characterized and evaluated as a BMP-2 delivery system. The designed nanocarrier was synthesized based on the ring-opening polymerization of amino acid N-carboxyanhydride. The final product was measured with 1H nuclear magnetic resonance. GA-PEG-b-PLL nanocarrier could combine with BMP-2 through electrostatic interaction to form polyion complex (PIC) micelles. BMP-2 could be rapidly and efficiently encapsulated through the GA-PEG-b-PLL nanocarrier under physiological conditions, exhibiting efficient encapsulation and sustained release. In addition, the GA-PEG-b-PLL-mediated BMP-2 delivery system could target the liver against hepatic diseases as it has GA-binding receptors. The anti-hepatic ischemia/reperfusion injury (anti-HI/RI) effect of BMP-2/GA-PEG-b-PLL PIC micelles was investigated in rats using free BMP-2 and BMP-2/PEG-b-PLL PIC micelles as controls, and the results showed that BMP-2/GA-PEG-b-PLL PIC micelles indicated significantly enhanced anti-HI/RI property compared to BMP-2 and BMP-2/PEG-b-PLL. All results suggested that GA-PEG-b-PLL could be used as a potential BMP-2 nanocarrier. PMID:29089759

Thermoresponsive AuNPs Stabilized by Pillararene-Containing Polymers.

PubMed

Liao, Xiaojuan; Guo, Lei; Chang, Junxia; Liu, Sha; Xie, Meiran; Chen, Guosong

2015-08-01

Pillararene-containing thermoresponsive polymers are synthesized via reversible addition-fragmentation chain transfer polymerization using pillararene derivatives as the effective chain transfer agents for the first time. These polymers can self-assemble into micelles and form vesicles after guest molecules are added. Furthermore, such functional polymers can be further applied to prepare hybrid gold nanoparticles, which integrate the thermoresponsivity of polymers and molecular recognition of pillararenes. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Physical characterization and in vivo pharmacokinetic study of self-assembling amphotericin B-loaded lecithin-based mixed polymeric micelles.

PubMed

Chen, Ying-Chen; Su, Chia-Yu; Jhan, Hua-Jun; Ho, Hsiu-O; Sheu, Ming-Thau

2015-01-01

To alleviate the inherent problems of amphotericin B (AmB), such as poor water solubility and nephrotoxicity, a novel self-assembling mixed polymeric micelle delivery system based on lecithin and combined with amphiphilic polymers, Pluronic(®), Kolliphor(®), d-alpha tocopheryl polyethylene glycol succinate, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(poly(ethylene glycol)-2000 (DSPE-PEG2K) was developed. An optimal formulation (Ambicelles) composed of AmB:lecithin:DSPE-PEG2K in a 1:1:10 weight ratio was obtained. The particle size, polydispersion index, drug encapsulation efficiency, and drug loading were 187.20±10.55 nm, 0.51±0.017, 90.14%, and 7.51%, respectively, and the solubility was increased from 0.001 to 5 mg/mL. Compared with that of Fungizone(®), the bioavailability of Ambicelles administered intravenously and orally increased 2.18- and 1.50-fold, respectively. Regarding the in vitro cytotoxicity, Ambicelles had a higher cell viability than free AmB solution or Fungizone(®) did. With pretreatment of 50 μg/mL ethanolic extract of Taiwanofungus camphoratus followed by AmB to HT29 colon cancer cells, the 50% inhibitory concentration of AmB solution was 12 μg/mL, whereas that of Ambicelles was 1 μg/mL, indicating that Ambicelles exerted a greater synergistic anticancer effect.

Physical characterization and in vivo pharmacokinetic study of self-assembling amphotericin B-loaded lecithin-based mixed polymeric micelles

PubMed Central

Chen, Ying-Chen; Su, Chia-Yu; Jhan, Hua-Jun; Ho, Hsiu-O; Sheu, Ming-Thau

2015-01-01

To alleviate the inherent problems of amphotericin B (AmB), such as poor water solubility and nephrotoxicity, a novel self-assembling mixed polymeric micelle delivery system based on lecithin and combined with amphiphilic polymers, Pluronic®, Kolliphor®, d-alpha tocopheryl polyethylene glycol succinate, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(poly(ethylene glycol)-2000 (DSPE-PEG2K) was developed. An optimal formulation (Ambicelles) composed of AmB:lecithin:DSPE-PEG2K in a 1:1:10 weight ratio was obtained. The particle size, polydispersion index, drug encapsulation efficiency, and drug loading were 187.20±10.55 nm, 0.51±0.017, 90.14%, and 7.51%, respectively, and the solubility was increased from 0.001 to 5 mg/mL. Compared with that of Fungizone®, the bioavailability of Ambicelles administered intravenously and orally increased 2.18- and 1.50-fold, respectively. Regarding the in vitro cytotoxicity, Ambicelles had a higher cell viability than free AmB solution or Fungizone® did. With pretreatment of 50 μg/mL ethanolic extract of Taiwanofungus camphoratus followed by AmB to HT29 colon cancer cells, the 50% inhibitory concentration of AmB solution was 12 μg/mL, whereas that of Ambicelles was 1 μg/mL, indicating that Ambicelles exerted a greater synergistic anticancer effect. PMID:26664117

Effect of pH and temperature upon self-assembling process between poly(aspartic acid) and Pluronic F127.

PubMed

Nita, Loredana E; Chiriac, Aurica P; Bercea, Maria

2014-07-01

The present investigation was made in order to evaluate the capability of self-assembling of the two water soluble polymers, respectively, poly(aspartic acid) and Pluronic F127 into well interpenetrated mixture, and to evidence the connection effects intervened during polymer complex formation to exhibit good stability once formed, as well to understand and correlate the binding strength and the interval between better association domains. The effect of pH and temperature on the interpolymeric complex formation between poly(aspartic acid) and Pluronic F127 was studied by combining rheology with light scattering technique. The solution mixtures between poly(aspartic acid) and Pluronic F127 are Newtonian fluids for all ratios among them. Depending on the polymeric mixture composition and experimental temperature, positive or negative deviations of the experimental values from the additive dependence appear. An interesting behavior was registered around 1/1 wt. ratio between the two polymers, when the hydrodynamic diameter of the interpenetrated polymeric particles decreased suddenly. This allows us to conclude the formation of core-shell micelle structure with poly(aspartic acid) core and Pluronic F127 as shell, performed through strong interactions between polymers. This behavior was sustained by the increase of absolute value of zeta potential owing to the decrease of functional groups number at the surface of micelles. Copyright © 2014 Elsevier B.V. All rights reserved.

Chiral micellar electrokinetic chromatography (CMEKC)-atmospheric pressure photoionization of benzoin derivatives using mixed molecular micelles

PubMed Central

He, Jun; Shamsi, Shahab A.

2012-01-01

In the present work we report, for the first time, the successful on-line coupling of chiral micellar electrokinetic chromatography (CMEKC) to atmospheric pressure photo-ionization mass spectrometry (APPI-MS). Four structurally similar neutral test solutes (e.g., benzoin derivatives) were successfully ionized by APPI-MS. The mass spectra in the positive ion mode showed that the protonated molecular ions of benzoins are not the most abundant fragment ions. Simultaneous enantioseparation by CMEKC and on-line APPI-MS detection of four photoinitiators: hydrobenzoin (HBNZ), benzoin (BNZ), benzoin methyl ether (BME), benzoin ethyl ether (BEE), were achieved using an optimized molar ratio of mixed molecular micelle of two polymeric chiral surfactants (polysodium N-undecenoxy carbonyl-L-leucinate and polysodium N-undecenoyl-L,L-leucylvalinate). The CMEKC conditions, such as voltage, chiral polymeric surfactant concentration, buffer pH, and BGE concentration, were optimized using a multivariate central composite design (CCD). The sheath liquid composition (involving % v/v methanol, dopant concentration, electrolyte additive concentration, and flow rate) and spray chamber parameters (drying gas flow rate, drying gas temperature, and vaporizer temperature) were also optimized with CCD. Models built based on the CCD results and response surface method was used to analyze the interactions between factors and their effects on the responses. The final overall optimum conditions for CMEKC-APPI-MS were also predicted and found in agreement with the experimentally optimized parameters. PMID:21500208

Polymer Nanocarriers to Enhance the Efficiency of Platinum-Based Chemotherapeutics

NASA Astrophysics Data System (ADS)

Callari, Manuela

The aim of this Thesis was to design and prepare polymer nanocarriers capable of encapsulating, carrying and delivering platinum-based chemotherapeutics. Polymer nanocarrier have been widely studied and employed as platinum drug delivery systems with the primary scope to overcome limitations presented by platinum-based chemotherapeutics. The conjugation of platinum onto polymers, however, presents some challenges, and, although there has been great progress in the field of drug delivery in the past years, to date only three polymer nanocarriers for platinum drugs have found their way to the clinic. In this Thesis, hydrophilic block copolymers were synthesised via reversible addition fragmentation chain transfer (RAFT) polymerisation or N-carboxyanhydride ring-opening polymerization (NCA-ROP). Upon attachment of a hydrophobic platinum drug the block copolymer becomes amphiphilic and can self-assemble in aqueous media into nanoparticles of different morphology depending on the block copolymer features. Spherical micelles consisting of a poly(methacrylic acid) core which conjugates and encapsulates the platinum chemotherapeutic and a hydrophilic shell made of sugar blocks were prepared and their biological activities compared in vitro. Among the sugars considered here, fructose based micelles showed promising results in terms of their targeting ability towards breast cancer cells. Consequently, fructose-shelled micelles were selected to explore the effect of different loading quantities of platinum drug. It was discovered that the amount of platinum in the core of the micelle highly influences the internal morphology of the micelle which, in turn, affects the micelle-cell interactions. Micelles with low dual drug loading had better cellular uptake and higher toxicity than the micelles with high drug loading, despite having the same fructose-based outer shell. Interestingly, this aspect had been neglected by literature so far, and is important to explore. Micelles made of a fructose shell were then compared to micelles with a non-targeting hydrophilic shell made of poly(ethylene glycol) methyl ether methacrylate (PEGMEMA). The aim was to compare the process of cellular uptake and the mechanism of platinum release inside the cell. For this scope, a fluorescent platinum drug was synthesised as a probing tool. Finally, a polymer vesicle based on PEG and poly(glutamic acid) was designed to co-deliver a platinum drug and the cancer inhibitor, paclitaxel, simultaneously. The two drugs have a synergistic effect when used in combination or co-delivered by the vesicles. Moreover, a viability study using multicellular tumour spheroids (MCTS) showed a significant decrease in cell proliferation when the MCTS were treated with single drug, a combination of free drugs and dual-drug loaded vesicles compared with untreated MCTS. An improvement is observed in the case of the dual-drug vesicles.

Nanotherapies for treating prostate cancer

NASA Astrophysics Data System (ADS)

Danquah, Michael

Current prostate cancer treatment remains ineffective primarily due to ineffectual therapeutic strategies and numerous tumor-associated physiological barriers which hinder efficacy of anticancer agents. Therefore, the focus of this study was to investigate a new combination therapy approach for treating prostate cancer and develop polymeric nanocarriers to facilitate anticancer drug and nucleic acid delivery. It was hypothesized that simultaneously targeting androgen-androgen receptor (AR) and X-linked inhibitor of apoptosis protein (XIAP) signaling pathways would be effective in treating prostate cancer. The effect of bicalutamide (antiandrogen) and embelin (XIAP inhibitor) on the growth of prostate cancer cells in vitro and in vivo was first examined. Embelin induced caspase 3 and 9 activation in LNCaP and C4-2 cells by decreasing XIAP expression and was more potent than bicalutamide in killing prostate tumor cells irrespective of their androgen status. Using a combination of MTT assay and isobologram analyses, combination of bicalutamide and embelin was observed to be cell line and schedule dependent. Since bicalutamide and embelin are extremely hydrophobic, polymeric micelles were fabricated using polyethylene glycol-b-polylactic acid (PEG-b-PLA) copolymer to improve drug solubility. Micellar formulations were found to result in at least 60-fold increase in the aqueous solubility of bicalutamide and embelin. Tumor growth was also effectively regressed upon treatment with bicalutamide, but the extent of tumor regression was significantly higher when bicalutamide was formulated in micelles. To further improve bicalutamide aqueous solubility, a series of novel biodegradable copolymers for the systematic micellar delivery of bicalutamide was designed and synthesized. Flory-Huggins interaction parameter (χFH) was used to assess compatibility between bicalutamide and poly (L-lactide) or poly (carbonate-co-lactide) polymer pairs. Polyethylene glycol-b-poly (carbonate-co-lactide) [PEG-b-P(CB-co-LA)] copolymers were synthesized and characterized by NMR and gel permeation chromatography. Micelles formulated using these copolymers had average diameter of 100 nm and distinct spherical shape. Drug loading studies revealed that adding the carbonate monomer could increase bicalutamide loading. Among the series, drug loading of micelles formulated with PEG-b-P(CB-co-LA) copolymer containing 20 mol% carbonate was about four-fold higher than PEG-b-PLLA and aqueous solubility of bicalutamide increased from 5 to 4000 μg/mL. CMC values for PEG-b-P(CB-co-LA) copolymers was up to 10-fold lower than those of PEG-b-PLLA. Bicalutamide-loaded PEG-b-P(CB-co-LA) micelles showed significant inhibition of LNCaP cell growth in a dose dependent manner which was similar to the methanol solution of free drug. Bicalutamide tends to act as an agonist rather than an antagonist after prolonged treatment. Hence, a second generation antiandrogen ((S)-N-(4-cyano-3-(trifluoromethyl) phenyl)-3-((4-cyanophenyl)(methyl)amino)-2-hydroxy-2-methylpropanamide) (CBDIV17)) was synthesized and its effect in combination with XIAP inhibitors for treating advanced prostate cancer was determined. CBDIV17 was more potent than bicalutamide and inhibited proliferation of C4-2 and LNCaP cells. CBDIV17-induced apoptosis more effectively compared to bicalutamide and significantly inhibited DNA replication. Combination of CBDIV17 and embelin resulted in supra-additive antiproliferative and apoptotic effects. Embelin downregulated AR expression and decreased androgen-mediated AR phosphorylation at Ser81. These hydrophobic drugs were solubilized using micelles prepared using polyethylene glycol-b-poly (carbonate-co-lactide) (PEG-b-p(CB-co-PLA)) copolymer. Combination therapy inhibited prostate tumor growth more effectively compared to control or monotherapy in vivo. The findings reported in this work demonstrate the potential benefit of combination therapy targeting AR and XIAP pathways for treating prostate cancer using polymeric nanocarriers. Systematic chemical tailoring of polymers for improving drug loading as well as efforts made to improve micelle stability through crosslinking also generated insights which can be applied to other drugs and cancer types. Results reported in this study therefore offer a new way of addressing the time old problem of treating cancer. (Abstract shortened by UMI.).

Nanonization strategies for poorly water-soluble drugs.

PubMed

Chen, Huabing; Khemtong, Chalermchai; Yang, Xiangliang; Chang, Xueling; Gao, Jinming

2011-04-01

Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor(®) EL). In this review, several major nanonization techniques that seek to overcome these limitations for drug solubilization are presented. Strategies including drug nanocrystals, nanoemulsions and polymeric micelles are reviewed. Finally, perspectives on existing challenges and future opportunities are highlighted. Published by Elsevier Ltd.

Lipid-absorbing Polymers

NASA Technical Reports Server (NTRS)

Marsh, H. E., Jr.; Wallace, C. J.

1973-01-01

The removal of bile acids and cholesterol by polymeric absorption is discussed in terms of micelle-polymer interaction. The results obtained with a polymer composed of 75 parts PEO and 25 parts PB plus curing ingredients show an absorption of 305 to 309%, based on original polymer weight. Particle size effects on absorption rate are analyzed. It is concluded that crosslinked polyethylene oxide polymers will absorb water, crosslinked polybutadiene polymers will absorb lipids; neither polymer will absorb appreciable amounts of lipids from micellar solutions of lipids in water.

Drug-Loaded Nanoemulsions/Microbubbles for Combined Tumor Imaging and Therapy

NASA Astrophysics Data System (ADS)

Rapoport, Natalya; Gao, Zhonggao; Kennedy, Ann

2007-05-01

A new class of multifunctional nanoparticles that combine properties of polymeric drug carriers, ultrasound imaging contrast agents, and enhancers of ultrasound-mediated intracellular drug delivery was developed. At room temperature, the developed systems comprise perfluorocarbon nanodroplets stabilized by the walls made of biodegradable block copolymers. The nanodroplets convert into microbubbles upon heating to physiological temperatures. The phase state of the systems and nanodroplet size may be controlled by the copolymer/perfluorocarbon volume ratio. Three areas observed in phase diagrams correspond to micelles; micelle/microbubble coexistence; and nano/microbubble coexistence. These systems manifest a relatively high drug loading capacity (about 15 % wt/wt). As indicated by biodistribution measurements and ultrasound imaging, the micelles and nanobubbles extravasate selectively into the tumor interstitia. Microbubble cavitate and collapse under the action of tumor-directed ultrasound, resulting in a dramatically enhanced intracellular drug uptake by the tumor cells. Upon intravenous injections, a long-lasting, strong and selective ultrasound contrast is observed in the tumor volume confirming nanobubble extravasation through the defected tumor microvasculature and suggesting their coalescence into larger, highly echogenic microbubbles in the tumor tissue. This effect is tumor-selective; no accumulation of echogenic microbubbles is observed in other organs. Tumor contrast increases in time confirming gradual accumulation of echogenic microbubbles in the tumor tissue, presumably via the enhanced penetration and retention (EPR) effect.

Facile Modification of Reverse Osmosis Membranes by Surfactant-Assisted Acrylate Grafting for Enhanced Selectivity.

PubMed

Baransi-Karkaby, Katie; Bass, Maria; Levchenko, Stanislav; Eitan, Shahar; Freger, Viatcheslav

2017-02-21

The top polyamide layer of composite reverse osmosis (RO) membranes has a fascinatingly complex structure, yet nanoscale nonuniformities inherently present in polyamide layer may reduce selectivity, e.g., for boron rejection. This study examines improving selectivity by in situ "caulking" such nonuniformities using concentration polarization-enhanced graft-polymerization with a surfactant added to the reactive solution. The surfactant appears to enhance both polarization (via monomer solubilization in surfactant micelles) and adherence of graft-polymer to the membrane surface, which facilitates grafting and reduces monomer consumption. The effect of surfactant was particularly notable for a hydrophobic monomer glycidyl methacrylate combined with a nonionic surfactant Triton X-100. With Triton added at an optimal level, close to critical micellization concentration (CMC), monomer gets solubilized and highly concentrated within micelles, which results in a significantly increased degree of grafting and uniformity of the coating compared to a procedure with no surfactant added. Notably, no improvement was obtained for an anionic surfactant SDS or the cationic surfactant DTAB, in which cases the high CMC of surfactant precludes high monomer concentration within micelles. The modification procedure was also up-scalable to membranes elements and resulted in elements with permeability comparable to commercial brackish water RO elements with superior boric acid rejection.

Mithramycin encapsulated in polymeric micelles by microfluidic technology as novel therapeutic protocol for beta-thalassemia

PubMed Central

Capretto, Lorenzo; Mazzitelli, Stefania; Brognara, Eleonora; Lampronti, Ilaria; Carugo, Dario; Hill, Martyn; Zhang, Xunli; Gambari, Roberto; Nastruzzi, Claudio

2012-01-01

This report shows that the DNA-binding drug, mithramycin, can be efficiently encapsulated in polymeric micelles (PM-MTH), based on Pluronic® block copolymers, by a new microfluidic approach. The effect of different production parameters has been investigated for their effect on PM-MTH characteristics. The compared analysis of PM-MTH produced by microfluidic and conventional bulk mixing procedures revealed that microfluidics provides a useful platform for the production of PM-MTH with improved controllability, reproducibility, smaller size, and polydispersity. Finally, an investigation of the effects of PM-MTH, produced by microfluidic and conventional bulk mixing procedures, on the erythroid differentiation of both human erythroleukemia and human erythroid precursor cells is reported. It is demonstrated that PM-MTH exhibited a slightly lower toxicity and more pronounced differentiative activity when compared to the free drug. In addition, PM-MTH were able to upregulate preferentially γ-globin messenger ribonucleic acid production and to increase fetal hemoglobin (HbF) accumulation, the percentage of HbF-containing cells, and their HbF content without stimulating α-globin gene expression, which is responsible for the clinical symptoms of β-thalassemia. These results represent an important first step toward a potential clinical application, since an increase in HbF could alleviate the symptoms underlying β-thalassemia and sickle cell anemia. In conclusion, this report suggests that PM-MTH produced by microfluidic approach warrants further evaluation as a potential therapeutic protocol for β-thalassemia. PMID:22287841

Dual-pH Sensitive Charge-reversal Nanocomplex for Tumor-targeted Drug Delivery with Enhanced Anticancer Activity.

PubMed

Zhou, Qing; Hou, Yilin; Zhang, Li; Wang, Jianlin; Qiao, Youbei; Guo, Songyan; Fan, Li; Yang, Tiehong; Zhu, Lin; Wu, Hong

2017-01-01

Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity.

Dual-pH Sensitive Charge-reversal Nanocomplex for Tumor-targeted Drug Delivery with Enhanced Anticancer Activity

PubMed Central

Zhou, Qing; Hou, Yilin; Zhang, Li; Wang, Jianlin; Qiao, Youbei; Guo, Songyan; Fan, Li; Yang, Tiehong; Zhu, Lin; Wu, Hong

2017-01-01

Poly(β-L-malic acid) (PMLA), a natural aliphatic polyester, has been proven to be a promising carrier for anti-cancer drugs. In spite of excellent bio-compatibility, the application of PMLA as the drug carrier for cancer therapy is limited by its low cellular uptake efficiency. The strong negative charge of PMLA impedes its uptake by cancer cells because of the electrostatic repulsion. In this study, a dual pH-sensitive charge-reversal PMLA-based nanocomplex (PMLA-PEI-DOX-TAT@PEG-DMMA) was developed for effective tumor-targeted drug delivery, enhanced cellular uptake, and intracellular drug release. The prepared nanocomplex showed a negative surface charge at the physiological pH, which could protect the nanocomplex from the attack of plasma proteins and recognition by the reticuloendothelial system, so as to prolong its circulation time. While at the tumor extracellular pH 6.8, the DMMA was hydrolyzed, leading to the charge reversal and exposure of the TAT on the polymeric micelles, thus enhancing the cellular internalization. Then, the polymeric micelles underwent dissociation and drug release in response to the acidic pH in the lyso/endosomal compartments of the tumor cell. Both in vitro and in vivo efficacy studies indicated that the nanocomplex significantly inhibited the tumor growth while the treatment showed negligible systemic toxicity, suggesting that the developed dual pH-sensitive PMLA-based nanocomplex would be a promising drug delivery system for tumor-targeted drug delivery with enhanced anticancer activity. PMID:28638469

Glycyrrhetinic acid-modified TPGS polymeric micelles for hepatocellular carcinoma-targeted therapy.

PubMed

Zhu, Xiumei; Tsend-Ayush, Altansukh; Yuan, Zhongyue; Wen, Jing; Cai, Jiaxin; Luo, Shifu; Yao, Jianxu; Bian, Junxing; Yin, Linfang; Zhou, Jianping; Yao, Jing

2017-08-30

In this study, glycyrrhetinic acid (GA)-modified D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymeric micelles (TGA PMs) were developed for the delivery of etoposide (ETO) to hepatoma cells. GA was incorporated as a ligand because of its high affinity to the hepatocytes, while TPGS functioned as a P-gp inhibitor to reverse multidrug resistance. ETO-loaded TGA PMs (ETO-TGA PMs) displayed a mean particle size of 133.6±1.2nm with a low poly-dispersity index (0.224±0.013) and negative zeta potential (-16.30mV). The drug loading and entrapment efficiency of ETO-TGA PMs were 10.4% and 79.8%, respectively. ETO-TGA PMs also exhibited faster drug release behavior at pH 5.8 and relatively stable drug release at pH 7.4. Confocal laser scanning microscope (CLSM) observations and in vivo imaging studies revealed that TGA PMs displayed higher cellular uptake and selective accumulation at the tumor site, indicating good tumor targetability. Furthermore, ETO-TGA PMs displayed significant cytotoxicity towards HepG2 cells and higher anti-tumor efficacy (75.96%), compared to the control group. This could be due to TGA-mediated targeted drug delivery to the hepatocytes as well as P-gp inhibition. These findings suggest that TGA PMs have the potential to be used as a targeted drug delivery system for hepatic cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Chiral micellar electrokinetic chromatography-atmospheric pressure photoionization of benzoin derivatives using mixed molecular micelles.

PubMed

He, Jun; Shamsi, Shahab A

2011-05-01

In the present work we report, for the first time, the successful on-line coupling of chiral MEKC (CMEKC) to atmospheric pressure photoionization MS (APPI-MS). Four structurally similar neutral test solutes (e.g. benzoin (BNZ) derivatives) were successfully ionized by APPI-MS. The mass spectra in the positive ion mode showed that the protonated molecular ions of BNZs are not the most abundant fragment ions. Simultaneous enantioseparation by CMEKC and on-line APPI-MS detection of four photoinitiators, hydrobenzoin, BNZ, benzoin methyl ether, benzoin ethyl ether, were achieved using an optimized molar ratio of mixed molecular micelle of two polymeric chiral surfactants (polysodium N-undecenoxy carbonyl-L-leucinate and polysodium N-undecenoyl-L,L-leucylvalinate). The CMEKC conditions, such as voltage, chiral polymeric surfactant concentration, buffer pH, and BGE concentration, were optimized using a multivariate central composite design (CCD). The sheath liquid composition (involving %v/v methanol, dopant concentration, electrolyte additive concentration, and flow rate) and spray chamber parameters (drying gas flow rate, drying gas temperature, and vaporizer temperature) were also optimized with CCD. Models built based on the CCD results and response surface method were used to analyze the interactions between factors and their effects on the responses. The final overall optimum conditions for CMEKC-APPI-MS were also predicted and found in agreement with the experimentally optimized parameters. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis and Characterization of Cleavable Core-Cross-Linked Micelles Based on Amphiphilic Block Copolypeptoids as Smart Drug Carriers.

PubMed

Li, Ang; Zhang, Donghui

2016-03-14

Amphiphilic block copolypeptoids consisting of a hydrophilic poly(N-ethyl glycine) segment and a hydrophobic poly[(N-propargyl glycine)-r-(N-decyl glycine)] random copolymer segment [PNEG-b-P(NPgG-r-NDG), EPgD] have been synthesized by sequential primary amine-initiated ring-opening polymerization (ROP) of the corresponding N-alkyl N-carboxyanhydride monomers. The block copolypeptoids form micelles in water and the micellar core can be cross-linked with a disulfide-containing diazide cross-linker by copper-mediated alkyne-azide cycloaddition (CuAAC) in aqueous solution. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis revealed the formation of spherical micelles with uniform size for both the core-cross-linked micelles (CCLMs) and non-cross-linked micelles (NCLMs) precursors for selective block copolypeptoid polymers. The CCLMs exhibited increased dimensional stability relative to the NCLMs in DMF, a nonselective solvent for the core and corona segments. Micellar dissociation of CCLMs can be induced upon addition of a reducing agent (e.g., dithiothreitol) in dilute aqueous solutions, as verified by a combination of fluorescence spectroscopy, size exclusion chromatography (SEC), and (1)H NMR spectroscopic measurement. Doxorubicin (DOX), an anticancer drug, can be loaded into the hydrophobic core of CCLMs with a maximal 23% drug loading capacity (DLC) and 37% drug loading efficiency (DLE). In vitro DOX release from the CCLMs can be triggered by DTT (10 mM), in contrast to significantly reduced DOX release in the absence of DTT, attesting to the reductively responsive characteristic of the CCLMs. While the CCLMs exhibited minimal cytotoxicity toward HepG2 cancer cells, DOX-loaded CCLMs inhibited the proliferation of the HepG2 cancer cells in a concentration and time dependent manner, suggesting the controlled release of DOX from the DOX-loaded CCLMS in the cellular environment.

NMR investigations of self-aggregation characteristics of SDS in a model assembled tri-block copolymer solution.

PubMed

Kumar, B V N Phani; Priyadharsini, S Umayal; Prameela, G K S; Mandal, Asit Baran

2011-08-01

The present work was undertaken with a view to understand the influence of a model non-ionic tri-block copolymer PEO-PPO-PEO (poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide)) with molecular weight 5800 i.e., P123 [(EO)(20)-(PO)(70)-(EO)(20)] on the self-aggregation characteristics of the anionic surfactant sodium dodecylsulfate (SDS) in aqueous solution (D(2)O) using NMR chemical shift, self-diffusion and nuclear spin-relaxation as suitable experimental probes. In addition, polymer diffusion has been monitored as a function of SDS concentration. The concentration-dependent chemical shift, diffusion data and relaxation data indicated the significant interaction of polymeric micelles with SDS monomers and micelles at lower and intermediate concentrations of SDS, whereas the weak interaction of the polymer with SDS micelles at higher concentrations of SDS. It has been observed that SDS starts aggregating on the polymer at a lower concentration i.e., critical aggregation concentration (cac=1.94 mM) compared to polymer-free situation, and the onset of secondary micelle concentration (C(2)=27.16 mM) points out the saturation of the 0.2 wt% polymer or free SDS monomers/micelles at higher concentrations of SDS. It has also been observed that the parameter cac is almost independent in the polymer concentrations of study. The TMS (tetramethylsilane) has been used as a solubilizate to measure the bound diffusion coefficient of SDS-polymer mixed system. The self-diffusion data were analyzed using two-site exchange model and the obtained information on aggregation dynamics was commensurate with that inferred from chemical shift and relaxation data. The information on slow motions of polymer-SDS system was also extracted using spin-spin and spin-lattice relaxation rate measurements. The relaxation data points out the disintegration of polymer network at higher concentrations of SDS. The present NMR investigations have been well corroborated by surface tension and conductivity measurements. Copyright © 2011 Elsevier Inc. All rights reserved.

Optimization of a Nanomedicine-based Pc 4-PDT Strategy for Targeted Treatment of EGFR-Overexpressing Cancers

PubMed Central

Master, Alyssa M.; Livingston, Megan; Oleinick, Nancy L.; Gupta, Anirban Sen

2012-01-01

The current clinical mainstays for cancer treatment, namely, surgical resection, chemotherapy and radiotherapy, can cause significant trauma, systemic toxicity, and functional/cosmetic debilitation of tissue, especially if repetitive treatment becomes necessary due to tumor recurrence. Hence there is significant clinical interest in alternate treatment strategies like photodynamic therapy (PDT) which can effectively and selectively eradicate tumors and can be safely repeated if needed. We have previously demonstrated that the second-generation photosensitizer Pc 4 can be formulated within polymeric micelles, and these micelles can be specifically targeted to EGFR-overexpressing cancer cells using GE11 peptide ligands, to enhance cell-specific Pc 4 delivery and internalization. In the current study, we report on the in vitro optimization of the EGFR-targeting, Pc 4 loading of the micellar nanoformulation, along with optimization of the corresponding photoirradiation conditions to maximize Pc 4 delivery, internalization and subsequent PDT-induced cytotoxicity in EGFR-overexpressing cells in vitro. In our studies, absorption and fluorescence spectroscopy were used to monitor the cell-specific uptake of the GE11-decorated Pc 4-loaded micelles and the cytotoxic singlet oxygen production from the micelle-encapsulated Pc 4, to determine the optimum ligand density and Pc 4 loading. It was found that the micelle formulations bearing 10 mole% of GE11-modified polymer component resulted in the highest cellular uptake in EGFR-overexpressing A431 cells within the shortest incubation periods. Also, the loading of ~50 μg Pc 4 per mg of polymer in these micellar formulations resulted in the highest levels of singlet oxygen production. When formulations bearing these optimized parameters were tested in vitro on A431 cells for PDT effect, a formulation dose containing 400 nM Pc 4 and photoirradiation duration of 400 seconds at a fluence of 200 mJ/cm2 yielded close to 100% cell death. PMID:22775587

Bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles as novel tumor targeting carriers

NASA Astrophysics Data System (ADS)

Ding, Hong; Yong, Ken-Tye; Roy, Indrajit; Hu, Rui; Wu, Fang; Zhao, Lingling; Law, Wing-Cheung; Zhao, Weiwei; Ji, Wei; Liu, Liwei; Bergey, Earl J.; Prasad, Paras N.

2011-04-01

In this study, we have developed a novel carrier, micelle-type bioconjugated PLGA-4-arm-PEG branched polymeric nanoparticles (NPs), for the detection and treatment of pancreatic cancer. These NPs contained 4-arm-PEG as corona, and PLGA as core, the particle surface was conjugated with cyclo(arginine-glycine-aspartate) (cRGD) as ligand for in vivo tumor targeting. The hydrodynamic size of the NPs was determined to be 150-180 nm and the critical micellar concentration (CMC) was estimated to be 10.5 mg l - 1. Our in vitro study shows that these NPs by themselves had negligible cytotoxicity to human pancreatic cancer (Panc-1) and human glioblastoma (U87) cell lines. Near infrared (NIR) microscopy and flow cytometry demonstrated that the cRGD conjugated PLGA-4-arm-PEG polymeric NPs were taken up more efficiently by U87MG glioma cells, over-expressing the αvβ3 integrin, when compared with the non-targeted NPs. Whole body imaging showed that the cRGD conjugated PLGA-4-arm-PEG branched polymeric NPs had the highest accumulation in the pancreatic tumor site of mice at 48 h post-injection. Physical, hematological, and pathological assays indicated low in vivo toxicity of this NP formulation. These studies on the ability of these bioconjugated PLGA-4-arm-PEG polymeric NPs suggest that the prepared polymeric NPs may serve as a promising platform for detection and targeted drug delivery for pancreatic cancer.

PLGA-soya lecithin based micelles for enhanced delivery of methotrexate: Cellular uptake, cytotoxic and pharmacokinetic evidences.

PubMed

Singh, Anupama; Thotakura, Nagarani; Kumar, Rajendra; Singh, Bhupinder; Sharma, Gajanand; Katare, Om Prakash; Raza, Kaisar

2017-02-01

Biocompatible and biodegradable polymers like PLGA have revolutionized the drug delivery approaches. However, poor drug loading and substantially high lipophilicity, pave a path for further tailing of this promising agent. In this regard, PLGA was feathered with biocompatible phospholipid and polymeric micelles were developed for delivery of Methotrexate (MTX) to cancer cells. The nanocarriers (114.6nm±5.5nm) enhanced the cytotoxicity of MTX by 2.13 folds on MDA-MB-231 cells. Confocal laser scanning microscopy confirmed the increased intracellular delivery. The carrier decreased the protein binding potential and enhanced the bioavailable fraction of MTX. Pharmacokinetic studies vouched substantial enhancement in AUC and bioresidence time, promising an ideal carrier to effectively deliver the drug to the site of action. The developed nanocarriers offer potential to deliver the drug in the interiors of cancer cells in an effective manner for improved therapeutic action. Copyright © 2016 Elsevier B.V. All rights reserved.

Charge-conversional poly(amino acid)s derivatives as a drug delivery carrier in response to the tumor environment.

PubMed

Yoon, Se Rim; Yang, Hee-Man; Park, Chan Woo; Lim, Sujin; Chung, Bong Hyun; Kim, Jong-Duk

2012-08-01

A charge-converting and pH-dependent nanocarrier was achieved by conjugating 2,3-dimethylmaleic anhydride (DMMA) to the amino group of an octadecyl grafted poly (2-hydroxyethyl aspartamide) (PHEA-g-C(18)-NH(2)) backbone, thereby forming a spherical micelle. PHEA, a poly(amino acid)s derivative, was derived from poly(succinimide), which is biocompatible and biodegradable. DMMA, a detachable component at the tumor site, was added, preventing aggregation with negative blood serum and enhancing the nanocarrier's cellular uptake. The polymeric micelle was comprehensively characterized and doxorubicin was encapsulated successively. The cellular uptake and anticancer therapeutic effect were evaluated by flow cytometry, confocal laser scanning microscopy, and a MTT assay. The properties of the nanocarrier can further be exploited to develop an early detection module for cancer. The present work is also expected to advance the study of designing smart carriers for drug and gene delivery. Copyright © 2012 Wiley Periodicals, Inc.

Evaluation of the interaction and drug release from alpha,beta-polyaspartamide derivatives to a biomembrane model.

PubMed

Castelli, F; Messina, C; Craparo, E F; Mandracchia, D; Pitarresi, G

2005-01-01

This article reports on a comparative study on the ability of various polymers, containing hydrophilic and/or hydrophobic groups, to interact with a biomembrane model using the differential scanning calorimetry (DSC) technique. Multilamellar vesicles of mixed dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidic acid (DMPA) were chosen as a model of cell membranes. The investigated samples were a water soluble polymer, the alpha,beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) and its derivatives partially functionalized with polyethylene glycol (PEG2000) to obtain PHEA-PEG2000, with hexadecylamine (C16) to obtain PHEA-C16, and with both compounds to obtain PHEA-PEG2000-C16. These polymers are potential candidates to prepare drug delivery systems. In particular, some samples give rise to polymeric micelles able to entrap hydrophobic drugs in an aqueous medium. The migration of drug molecules from these micelles to DMPC/DMPA vesicles also has been evaluated by DSC analysis, by using ketoprofen as a model drug.

Dual-Responsive pH and Temperature Sensitive Nanoparticles Based on Methacrylic Acid and Di(ethylene glycol) Methyl Ether Methacrylate for the Triggered Release of Drugs.

PubMed

Khine, Yee Yee; Jiang, Yanyan; Dag, Aydan; Lu, Hongxu; Stenzel, Martina H

2015-08-01

A series of thermo-and pH-responsive poly(methyl methacrylate)-block-poly[methacrylic acid-co-di(ethylene glycol) methyl ether methacrylate] PMMA-b-P[MAA-co-DEGMA] block copolymers were synthesized by RAFT polymerization and self-assembled into micelles. The molar ratio of MAA was altered from 0-12% in order to modulate the lower critical solution temperature (LCST) of PDEGMA. The release of the drug albendazole from the micelle was strongly dependent on the temperature and the LCST value of the polymer. Systems below the LCST released the drug slowly while increasing the temperature above the LCST or decreasing the pH value to 5 resulted in the burst-like release of the drug. ABZ delivered in this pH-responsive drug carrier had a higher toxicity than the free drug or the drug delivered in a non-responsive drug carrier. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hybrid Calcium Phosphate-Polymeric Micelles Incorporating Gadolinium Chelates for Imaging-Guided Gadolinium Neutron Capture Tumor Therapy.

PubMed

Mi, Peng; Dewi, Novriana; Yanagie, Hironobu; Kokuryo, Daisuke; Suzuki, Minoru; Sakurai, Yoshinori; Li, Yanmin; Aoki, Ichio; Ono, Koji; Takahashi, Hiroyuki; Cabral, Horacio; Nishiyama, Nobuhiro; Kataoka, Kazunori

2015-06-23

Gadolinium (Gd) chelates-loaded nanocarriers have high potential for achieving magnetic resonance imaging (MRI)-guided Gd neutron capture therapy (GdNCT) of tumors. Herein, we developed calcium phosphate micelles hybridized with PEG-polyanion block copolymers, and incorporated with the clinical MRI contrast agent Gd-diethylenetriaminepentaacetic acid (Gd-DTPA/CaP). The Gd-DTPA/CaP were nontoxic to cancer cells at the concentration of 100 μM based on Gd-DTPA, while over 50% of the cancer cells were killed by thermal neutron irradiation at this concentration. Moreover, the Gd-DTPA/CaP showed a dramatically increased accumulation of Gd-DTPA in tumors, leading to the selective contrast enhancement of tumor tissues for precise tumor location by MRI. The enhanced tumor-to-blood distribution ratio of Gd-DTPA/CaP resulted in the effective suppression of tumor growth without loss of body weight, indicating the potential of Gd-DTPA/CaP for safe cancer treatment.

Myelin basic protein is a glial microtubule-associated protein -- characterization of binding domains, kinetics of polymerization, and regulation by phosphorylation and a lipidic environment.

PubMed

Zienowicz, Agata; Bamm, Vladimir V; Vassall, Kenrick A; Harauz, George

2015-05-22

The 18.5-kDa splice isoform of myelin basic protein (MBP) predominates in the adult brain, adhering the cytoplasmic leaflets of the oligodendrocyte membrane together, but also assembling the cytoskeleton at leading edges of membrane processes. Here, we characterized MBP's role as a microtubule-assembly protein (MAP). Using light scattering and sedimentation assays we found that pseudo-phosphorylation of Ser54 (murine 18.5-kDa sequence) significantly enhanced the rate but not the final degree of polymerization. This residue lies within a short KPGSG motif identical to one in tau, a ubiquitous MAP important in neuronal microtubule assembly. Using polypeptide constructs, each comprising one of three major amphipathic α-helical molecular recognition fragments of 18.5-kDa MBP, we identified the N-terminal α1-peptide as sufficient to cause microtubule polymerization, the rate of which was significantly enhanced in the presence of dodecylphosphocholine (DPC) micelles to mimic a lipidic environment. Copyright © 2015 Elsevier Inc. All rights reserved.

Non-Surface Activity of Cationic Amphiphilic Diblock Copolymers

NASA Astrophysics Data System (ADS)

Ranjan Nayak, Rati; Yamada, Tasuku; Matsuoka, Hideki

2011-09-01

Cationic amphiphilic diblock copolymers containing quaternized poly (2-vinylpyridine) chain as a hydrophilic segment (PIp-b-PNMe2VP) were synthesized by living anionic polymerization. By IR measurement, we confirmed the quaternization of the polymer (PIp-b-PNMe2VP), and determined the degree of quaternization by conductometric titration. The surface tension experiment showed that the polymers are non-surface active in nature. The foam formation of the polymer solutions was also investigated with or without added salt. Almost no foam formation behavior was observed without added salt, while a little foam was observed in the presence of 1M NaCl. The critical micelle concentration (cmc) of the diblock copolymers with 3 different chain lengths was measured by the static light scattering method. The cmc values obtained in this study were much lower than the values obtained for anionic non-surface active diblock polymers studied previously. The hydrodynamic radii of the polymer micelle increased slightly in the presence of 1 M NaCl. The transmission electron microscopic images revealed spherical micelles in pure water. In the presence of salt, the cmc values increased as was the case for anionic polymers, which is unlike conventional surfactant systems but consistent with non-surface active anionic block copolymers. The microviscosity of the micelle core was evaluated using Coumarin-153 as a fluorescent anisotropy probe using steady-sate fluorescence depolarization. Non-surface activity has been proved to be universal for ionic amphiphilic block copolymers both for anionic and cationic. Hence, the origin of non-surface activity is not the charged state of water surface itself, but should be an image charge repulsion at the air/water interface.

Optimization of long circulating mixed polymeric micelles containing vinpocetine using simple lattice mixture design, in vitro and in vivo characterization.

PubMed

El-Dahmy, Rania Moataz; Elsayed, Ibrahim; Elshafeey, Ahmed Hassen; Gawad, Nabaweya Abdelaziz Abd El; El-Gazayerly, Omaima Naim

2014-12-30

The aim of this study was to increase the in vivo mean residence time of vinpocetine after IV injection utilizing long circulating mixed micellar systems. Mixed micelles were prepared using Pluronics L121, P123 and F127. The systems were characterized by testing their entrapment efficiency, particle size, polydispersity index, zeta potential, transmission electron microscopy and in vitro drug release. Simple lattice mixture design was planned for the optimization using Design-Expert(®) software. The optimized formula was lyophilized, sterilized and imaged by scanning electron microscope. Moreover, the in vivo behavior of the optimized formula was evaluated after IV injection in rabbits. The optimized formula, containing 68% w/w Pluronic L121 and 32% w/w Pluronic F127, had the highest desirability value (0.621). Entrapment efficiency, particle size, polydispersity index and zeta potential of the optimized formula were 50.74 ± 3.26%, 161.50 ± 7.39 nm, 0.21 ± 0.03 and -22.42 ± 1.72 mV, respectively. Lyophilization and sterilization did not affect the characteristics of the optimized formula. Upon in vivo investigation in rabbits, the optimized formula showed a significantly higher elimination half-life and mean residence time than the market product. Finally, mixed micelles could be considered as a promising long circulating nanocarrier for lipophilic drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Development of chitosan graft pluronic®F127 copolymer nanoparticles containing DNA aptamer for paclitaxel delivery to treat breast cancer cells

NASA Astrophysics Data System (ADS)

Thach Nguyen, Kim; Le, Duc Vinh; Do, Dinh Ho; Huan Le, Quang

2016-06-01

HER-2/ErbB2/Neu(HER-2), a member of the epidermal growth factor receptor family, is specifically overexpressed on the surface of breast cancer cells and serves a therapeutic target for breast cancer. In this study, we aimed to isolate DNA aptamer (Ap) that specifically bind to a HER-2 overexpressing SK-BR-3 human breast cancer cell line, using SELEX strategy. We developed a novel multifunctional composite micelle with surface modification of Ap for targeted delivery of paclitaxel. This binary mixed system consisting of Ap modified pluronic®F127 and chitosan could enhance PTX loading capacity and increase micelle stability. Polymeric micelles had a spherical shape and were self-assemblies of block copolymers of approximately 86.22 ± 1.45 nm diameter. PTX could be loaded with high encapsulation efficiency (83.28 ± 0.13%) and loading capacity (9.12 ± 0.34%). The release profile were 29%-35% in the first 12 h and 85%-93% after 12 d at pH 7.5 of receiving media. The IC50 doses by MTT assay showed the greater activity of nanoparticles loaded paclitaxel over free paclitaxel and killed cells up to 95% after 6 h. These results demonstrated unique assembly with the capacity to function as an efficient detection and delivery vehicle in the biological living system.

Real-time monitoring of anticancer drug release with highly fluorescent star-conjugated copolymer as a drug carrier.

PubMed

Qiu, Feng; Wang, Dali; Zhu, Qi; Zhu, Lijuan; Tong, Gangsheng; Lu, Yunfeng; Yan, Deyue; Zhu, Xinyuan

2014-04-14

Chemotherapy is one of the major systemic treatments for cancer, in which the drug release kinetics is a key factor for drug delivery. In the present work, a versatile fluorescence-based real-time monitoring system for intracellular drug release has been developed. First, two kinds of star-conjugated copolymers with different connections (e.g., pH-responsive acylhydrazone and stable ether) between a hyperbranched conjugated polymer (HCP) core and many linear poly(ethylene glycol) (PEG) arms were synthesized. Owing to the amphiphilic three-dimensional architecture, the star-conjugated copolymers could self-assemble into multimicelle aggregates from unimolecular micelles with excellent emission performance in the aqueous medium. When doxorubicin (DOX) as a model drug was encapsulated into copolymer micelles, the emission of star-conjugated copolymer and DOX was quenched. In vitro biological studies revealed that fluorescent intensities of both star-conjugated copolymer and DOX were activated when the drug was released from copolymeric micelles, resulting in the enhanced cellular proliferation inhibition against cancer cells. Importantly, pH-responsive feature of the star-conjugated copolymer with acylhydrazone linkage exhibited accelerated DOX release at a mildly acidic environment, because of the fast breakage of acylhydrazone in endosome or lysosome of tumor cells. Such fluorescent star-conjugated copolymers may open up new perspectives to real-time study of drug release kinetics of polymeric drug delivery systems for cancer therapy.

Precision synthesis of functional materials via RAFT polymerization and click-type chemical reactions

NASA Astrophysics Data System (ADS)

Flores, Joel Diez

2011-12-01

The need to tailor polymeric architectures with specific physico-chemical properties via the simplest, cleanest, and most efficient synthetic route possible has become the ultimate goal in polymer synthesis. Recent progress in macromolecular science, such as the discoveries of controlled/"living" free radical polymerization (CRP) methods, has brought about synthetic capabilities to prepare (co)polymers with advanced topologies, predetermined molecular weights, narrow molecular weight distributions, and precisely located functional groups. In addition, the establishment of click chemistry has redefined the selected few highly efficient chemical reactions that become highly useful in post-polymerization modification strategies. Hence, the ability to make well-defined topologies afforded by controlled polymerization techniques and the facile incorporation of functionalities along the chain via click-type reactions have yielded complex architectures, allowing the investigation of physical phenomena which otherwise could not be studied with systems prepared via conventional methods. The overarching theme of the research work described in this dissertation is the fusion of the excellent attributes of reversible addition-fragmentation chain transfer (RAFT) polymerization method, which is one of the CRP techniques, and click-type chemical reactions in the precision of synthesis of advanced functional materials. Chapter IV is divided into three sections. In Section I, the direct RAFT homopolymerization of 2-(acryloyloxy)ethyl isocyanate (AOI) and subsequent post-polymerization modifications are described. The polymerization conditions were optimized in terms of the choice of RAFT chain transfer agent (CTA), polymerization temperature and the reaction medium. Direct RAFT polymerization of AOI requires a neutral CTA, and relatively low reaction temperature to yield AOI homopolymers with low polydispersities. Efficient side-chain functionalization of PAOI homopolymers was achieved via reaction with model amine, thiol and alcohol compounds yielding urea, thiourethane and urethane derivatives, respectively. Reactions with amines and thiols (in the presence of base) were rapid, quantitative and efficient. However, the reaction with alcohols catalyzed by dibutyltin dilaurate (DBTDL) was relatively slow but proceeded to completion. Selective reaction pathways for the addition of difunctional ethanolamine and mercaptoethanol were also investigated. A related strategy is described in Section II wherein a hydroxyl-containing diblock copolymer precursor was transformed into a library of functional copolymers via two sequential post-polymerization modification reactions. A diblock copolymer scaffold, poly[(N,N-dimethylacrylamide)-b-( N-(2-hydroxyethyl)acrylamide] (PDMA-b-PHEA) was first prepared. The hydroxyl groups of the HEA block were then reacted with 2-(acryloyloxy)ethylisocyanate (AOI) and allylisocyanate (AI) resulting in acrylate- and allyl-functionalized copolymer precursors, respectively. The efficiencies of Michael-type and free radical thiol addition reactions were investigated using selected thiols having alkyl, aryl, hydroxyl, carboxylic acid, amine and amino acid functionalities. The steps of RAFT polymerization, isocyanate-hydroxyl coupling and thiol-ene addition are accomplished under mild conditions, thus offering facile and modular routes to synthesize functional copolymers. The synthesis and solution studies of pH- and salt-responsive triblock copolymer are described in Section III. This system is capable of forming self-locked micellar structures which may be controlled by changing solution pH as well as ionic strength. A triblock copolymer containing a permanently hydrophilic poly(N,N-dimethylacrylamide) (PDMA) outer block, a salt-sensitive zwitterionic poly(3[2-(N-methylacrylamido)ethyl dimethylammonio]propanesulfonate) (PMAEDAPS) middle block and a pH-responsive 3-acrylamido-3-methylbutanoic acid (PAMBA) core block was synthesized using aqueous RAFT polymerization. A facile formation of "self-locking" shell cross-linked micelles is achieved by changing solution pH and salt concentration. The reversible "self-locking" is attained from the interactions of zwitterionic groups in the middle block that constitutes the shell of the micelles. The structure slowly dissociates into unimers in 2-3 days at pH above the pKa of the PAMBA block.

Eye drop delivery of nano-polymeric micelle formulated genes with cornea-specific promoters.

PubMed

Tong, Yaw-Chong; Chang, Shwu-Fen; Liu, Chia-Yang; Kao, Winston W-Y; Huang, Chong Heng; Liaw, Jiahorng

2007-11-01

This study evaluates the eye drop delivery of genes with cornea-specific promoters, i.e., keratin 12 (K12) and keratocan (Kera3.2) promoters, by non-ionic poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) polymeric micelles (PM) to mouse and rabbit eyes, and investigates the underlying mechanisms. Three PM-formulated plasmids (pCMV-Lac Z, pK12-Lac Z and pKera3.2-Lac Z) containing the Lac Z gene for beta-galactosidase (beta-Gal) whose expression was driven by the promoter of either the cytomegalovirus early gene, the keratin 12 gene or the keratocan gene, were characterized by critical micelle concentration (CMC), dynamic light scattering (DLS), and atomic force microscopy (AFM). Transgene expression in ocular tissue after gene delivery was analyzed by 5-bromo-4-chloro-3-indolyl-beta-D-galactoside (X-Gal) color staining, 1,2-dioxetane beta-Gal enzymatic activity measurement, and real-time polymerase chain reaction (PCR) analysis. The delivery mechanisms of plasmid-PM on mouse and rabbit corneas were evaluated by EDTA and RGD (arginine-glycine-aspartic acid) peptide. The sizes of the three plasmid-PM complexes were around 150-200 nm with unimodal distribution. Enhanced stability was found for three plasmid-PM formulations after DNase I treatment. After six doses of eye drop delivery of pK12-Lac Z-PM three times a day, beta-Gal activity was significantly increased in both mouse and rabbit corneas. Stroma-specific Lac Z expression was only found in pKera3.2-Lac Z-PM-treated animals with pretreatment by 5 mM EDTA, an opener of junctions. Lac Z gene expression in both pK12-Lac Z-PM and pKera3.2-Lac Z-PM delivery groups was decreased by RGD peptide pretreatment. Cornea epithelium- and stroma-specific gene expression could be achieved using cornea-specific promoters of keratin 12 and keratocan genes, and the gene was delivered with PM formulation through non-invasive, eye drop in mice and rabbits. The transfection mechanism of plasmid-PM may involve endocytosis and particle size dependent paracellular transport. 2007 John Wiley & Sons, Ltd

Dimensional control of block copolymer nanofibers with a π-conjugated core: crystallization-driven solution self-assembly of amphiphilic poly(3-hexylthiophene)-b-poly(2-vinylpyridine).

PubMed

Gwyther, Jessica; Gilroy, Joe B; Rupar, Paul A; Lunn, David J; Kynaston, Emily; Patra, Sanjib K; Whittell, George R; Winnik, Mitchell A; Manners, Ian

2013-07-08

With the aim of accessing colloidally stable, fiberlike, π-conjugated nanostructures of controlled length, we have studied the solution self-assembly of two asymmetric crystalline-coil, regioregular poly(3-hexylthiophene)-b-poly(2-vinylpyridine) (P3HT-b-P2VP) diblock copolymers, P3HT23-b-P2VP115 (block ratio=1:5) and P3HT44-b-P2VP115 (block ratio=ca. 1:3). The self-assembly studies were performed under a variety of solvent conditions that were selective for the P2VP block. The block copolymers were prepared by using Cu-catalyzed azide-alkyne cycloaddition reactions of azide-terminated P2VP and alkyne end-functionalized P3HT homopolymers. When the block copolymers were self-assembled in a solution of a 50% (v/v) mixture of THF (a good solvent for both blocks) and an alcohol (a selective solvent for the P2VP block) by means of the slow evaporation of the common solvent; fiberlike micelles with a P3HT core and a P2VP corona were observed by transmission electron microscopy (TEM). The average lengths of the micelles were found to increase as the length of the hydrocarbon chain increased in the P2VP-selective alcoholic solvent (MeOH3 μm) fiberlike micelles were prepared by the dialysis of solutions of the block copolymers in THF against iPrOH. Furthermore the widths of the fibers were dependent on the degree of polymerization of the chain-extended P3HT blocks. The crystallinity and π-conjugated nature of the P3HT core in the fiberlike micelles was confirmed by a combination of UV/Vis spectroscopy, photoluminescence (PL) measurements, and wide-angle X-ray scattering (WAXS). Intense sonication (iPrOH, 1 h, 0 °C) of the fiberlike micelles formed by P3HT23-b-P2VP115 resulted in small (ca. 25 nm long) stublike fragments that were subsequently used as initiators in seeded growth experiments. Addition of P3HT23-b-P2VP115 unimers to the seeds allowed the preparation of fiberlike micelles with narrow length distributions (L(w)/L(n) < 1.11) and lengths from about 100-300 nm, that were dependent on the unimer-to-seed micelle ratio. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Polymeric drug delivery systems for intraoral site-specific chemoprevention of oral cancer.

PubMed

Desai, Kashappa Goud H

2018-04-01

Oral cancer is among the most prevalent cancers in the world. Moreover, it is one of the major health problems and causes of death in many regions of the world. The traditional treatment modalities include surgical removal, radiation therapy, systemic chemotherapy, or a combination of these methods. In recent decades, there has been significant interest in intraoral site-specific chemoprevention via local drug delivery using polymeric systems. Because of its easy accessibility and clear visibility, the oral mucosa is amenable for local drug delivery. A variety of polymeric systems-such as gels, tablets, films, patches, injectable systems (e.g., millicylindrical implants, microparticles, and in situ-forming depots), and nanosized carriers (e.g., polymeric nanoparticles, nanofibers, polymer-drug conjugates, polymeric micelles, nanoliposomes, nanoemulsions, and polymersomes)-have been developed and evaluated for the local delivery of natural and synthetic chemopreventive agents. The findings of in vitro, ex vivo, and in vivo studies and the positive outcome of clinical trials demonstrate that intraoral site-specific drug delivery is an attractive, highly effective and patient-friendly strategy for the management of oral cancer. Intraoral site-specific drug delivery provides unique therapeutic advantages when compared to systemic chemotherapy. Moreover, intraoral drug delivery systems are self-administrable and can be removed when needed, increasing patient compliance. This article covers important aspects and advances related to the design, development, and efficacy of polymeric systems for intraoral site-specific drug delivery. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1383-1413, 2018. © 2017 Wiley Periodicals, Inc.

Tumor-penetrating codelivery of siRNA and paclitaxel with ultrasound-responsive nanobubbles hetero-assembled from polymeric micelles and liposomes.

PubMed

Yin, Tinghui; Wang, Ping; Li, Jingguo; Wang, Yiru; Zheng, Bowen; Zheng, Rongqin; Cheng, Du; Shuai, Xintao

2014-07-01

Drug resistance is a big problem in systemic chemotherapy of hepatocellular carcinoma (HCC), and nanomedicines loaded with both chemotherapeutic agents (e.g. paclitaxel, PTX) and siRNA's targeting antiapoptosis genes (e.g. BCL-2) possess the advantages to simultaneously overcome the efflux pump-mediated drug resistance and antiapoptosis-related drug resistance. However, tumor-penetrating drug delivery with this type of nanomedicines is extremely difficult due to their relatively big size compared to the single drug-loaded nanomedicines. Aiming at address this problem, US-responsive nanobubbles encapsulating both anti-cancer drug paclitaxel (PTX) and siRNA (PTX-NBs/siRNA) for HCC treatment were developed by hetero-assembly of polymeric micelles and liposomes in the present study. Utilizing an external low-frequency US force imposed to the tumor site, effective tumor-penetrating codelivery of siRNA and PTX was achieved via tail vein injection of PTX-NBs/siRNA into nude mice bearing human HepG2 xerografts. Consequently, the PTX treatment-inducible antiapoptosis in HepG2 cells was effectively suppressed by the codelivered siRNA targeting an antiapoptosis gene (BCL-2 siRNA) during chemotherapy. Owing to the synergistic anti-cancer effect of two therapeutic agents, tumor growth was completely inhibited using low-dose PTX in animal study. Our results highlight the great potential of this type of US-responsive hetero-assemblies carrying both anti-cancer drug and siRNA as an effective nanomedicinal system for HCC therapy. Copyright © 2014 Elsevier Ltd. All rights reserved.

Intranasal brain-targeted clonazepam polymeric micelles for immediate control of status epilepticus: in vitro optimization, ex vivo determination of cytotoxicity, in vivo biodistribution and pharmacodynamics studies.

PubMed

Nour, Samia A; Abdelmalak, Nevine S; Naguib, Marianne J; Rashed, Hassan M; Ibrahim, Ahmed B

2016-11-01

Clonazepam (CZ) is an anti-epileptic drug used mainly in status epilepticus (SE). The drug belongs to Class II according to BCS classification with very limited solubility and high permeability and it suffers from extensive first-pass metabolism. The aim of the present study was to develop CZ-loaded polymeric micelles (PM) for direct brain delivery allowing immediate control of SE. PM were prepared via thin film hydration (TFH) technique adopting a central composite face-centered design (CCFD). The seventeen developed formulae were evaluated in terms of entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and in vitro release. For evaluating the in vivo behavior of the optimized formula, both biodistrbution using 99m Tc-radiolabeled CZ and pharmacodynamics studies were done in addition to ex vivo cytotoxicty. At a drug:Pluronic® P123:Pluronic® L121 ratio of 1:20:20 (PM7), a high EE, ZP, Q8h, and a low PDI was achieved. The biodistribution studies revealed that the optimized formula had significantly higher drug targeting efficiency (DTE = 242.3%), drug targeting index (DTI = 144.25), and nose-to-brain direct transport percentage (DTP = 99.30%) and a significant prolongation of protection from seizures in comparison to the intranasally administered solution with minor histopathological changes. The declared results reveal the ability of the developed PM to be a strong potential candidate for the emergency treatment of SE.

Relating structure and flow of soft colloids

NASA Astrophysics Data System (ADS)

Kundu, S. K.; Gupta, S.; Stellbrink, J.; Willner, L.; Richter, D.

2013-11-01

To relate the complex macroscopic flow of soft colloids to details of its microscopic equilibrium and non-equilibrium structure is still one big challenge in soft matter science. We investigated several well-defined colloidal model systems like star polymers or diblock copolymer micelles by linear/non-linear rheology, static/dynamic light scattering (SLS/DLS) and small angle neutron scattering (SANS). In addition, in-situ SANS experiments during shear (Rheo-SANS) revealed directly shear induced structural changes on a microscopic level. Varying the molecular architecture of the individual colloidal particle as well as particle-particle interactions and covering at the same time a broad concentration range from the very dilute to highly concentrated, glassy regime, we could separate contributions from intra- and inter-particle softness. Both can be precisely "tuned" by varying systematically the functionality, 6 ≤ f≤ 64, for star polymers or aggregation number, 30 ≤ N agg ≤ 1000 for diblock copolymer micelles, as well as the degree of polymerization of the individual polymer arm 100 ≤ D p ≤ 3000. In dilute solutions, the characteristic shear rate at which deformation of the soft colloid is observed can be related to the Zimm time of the polymeric corona. In concentrated solutions, we validated a generalized Stokes-Einstein approach to describe the increase in macroscopic viscosity and mesoscopic self diffusion coefficient on approaching the glassy regime. Both can be explained in terms of an ultra-soft interaction potential. Moreover, non-equilibrium structure factors are obtained by Rheo-SANS. All experimental results are in excellent quantitative agreement with recent theoretical predictions.

Using PEGylated magnetic nanoparticles to describe the EPR effect in tumor for predicting therapeutic efficacy of micelle drugs.

PubMed

Chen, Ling; Zang, Fengchao; Wu, Haoan; Li, Jianzhong; Xie, Jun; Ma, Ming; Gu, Ning; Zhang, Yu

2018-01-25

Micelle drugs based on a polymeric platform offer great advantages over liposomal drugs for tumor treatment. Although nearly all of the nanomedicines approved in the clinical use can passively target to the tumor tissues on the basis of an enhanced permeability and retention (EPR) effect, the nanodrugs have shown heterogenous responses in the patients. This phenomenon may be traced back to the EPR effect of tumor, which is extremely variable in the individuals from extensive studies. Nevertheless, there is a lack of experimental data describing the EPR effect and predicting its impact on therapeutic efficacy of nanoagents. Herein, we developed 32 nm magnetic iron oxide nanoparticles (MION) as a T 2 -weighted contrast agent to describe the EPR effect of each tumor by in vivo magnetic resonance imaging (MRI). The MION were synthesized by a thermal decomposition method and modified with DSPE-PEG2000 for biological applications. The PEGylated MION (Fe 3 O 4 @PEG) exhibited high r 2 of 571 mM -1 s -1 and saturation magnetization (M s ) of 94 emu g -1 Fe as well as long stability and favorable biocompatibility through the in vitro studies. The enhancement intensities of the tumor tissue from the MR images were quantitatively measured as TNR (Tumor/Normal tissue signal Ratio) values, which were correlated with the delay of tumor growth after intravenous administration of the PLA-PEG/PTX micelle drug. The results demonstrated that the group with the smallest TNR values (TNR < 0.5) displayed the best tumor inhibitory effect. In addition, there was a superior correlation between TNR value and relative tumor delay in individual mice. These analysis results indicated that the TNR value of the tumor region enhanced by Fe 3 O 4 @PEG (d = 32 nm) could be used to predict the therapeutic efficacy of the micelle drugs (d ≤ 32 nm) in a certain period of time. Fe 3 O 4 @PEG has a potential to serve as an ideal MRI contrast agent to visualize the EPR effect in patients for accurate medication guidance of micelle drugs in the future treatment of tumors.

Investigations on clonazepam-loaded polymeric micelle-like nanoparticles for safe drug administration during pregnancy.

PubMed

Sezgin-Bayindir, Zerrin; Elcin, Ayse Eser; Parmaksiz, Mahmut; Elcin, Yasar Murat; Yuksel, Nilufer

2018-03-01

Medication during pregnancy is often a necessity for women to treat their acute or chronic diseases. The goal of this study is to evaluate the potential of micelle-like nanoparticles (MNP) for providing safe drug usage in pregnancy and protect both foetus and mother from medication side effects. Clonazepam-loaded MNP were prepared from copolymers [polystyrene-poly(acrylic acid) (PS-PAA), poly(ethylene glycol)-b-poly(lactic acid) (PEG-PLA) and distearyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-poly(ethylene glycol) (PEG-DSPE)] with varying monomer ratios and their drug-loading efficiency, drug release ratio, particle size, surface charge and morphology were characterised. The cellular transport and cytotoxicity experiments were conducted on clonazepam and MNP formulations using placenta-choriocarcinoma-BeWo and brain-endothelial-bEnd3 cells. Clonazepam-loaded PEG 5000 -PLA 4500 MNP reduced the drug transport through BeWo cells demonstrating that MNP may lower foetal drug exposure, thus reduce the drug side effects. However, lipofectamine modified MNP improved the transport of clonazepam and found to be promising for brain and in-utero-specific drug treatment.

Triblock copolymers encapsulated poly (aryl benzyl ether) dendrimer zinc(II) phthalocyanine nanoparticles for enhancement in vitro photodynamic efficacy.

PubMed

Huang, Yide; Yu, Huizhen; Lv, Huafei; Zhang, Hong; Ma, Dongdong; Yang, Hongqin; Xie, Shusen; Peng, Yiru

2016-12-01

A novel series of nanoparticles formed via an electrostatic interaction between the periphery of negatively charged 1-2 generation aryl benzyl ether dendrimer zinc (II) phthalocyanines and positively charged poly(L-lysin) segment of triblock copolymer, poly(L-lysin)-block-poly(ethylene glycol)-block-poly(L-lysin), was developed for the use as an effective photosensitizers in photodynamic therapy. The dynamic light scattering, atomic force microscopy showed that two nanoparticles has a relevant size of 80-150nm. The photophysical properties and singlet oxygen quantum yields of free dendrimer phthalocyanines and nanoparticles exhibited generation dependence. The intracellular uptake of dendrimer phthalocyanines in Hela cells was significantly elevated as they were incorporated into the micelles, but was inversely correlated with the generation of dendrimer phthalocyanines. The photocytotoxicity of dendrimer phthalocyanines incorporated into polymeric micelles was also increased. The presence of nanoparticles induced efficient cell death. Using a mitochondrial-sepcific dye rhodamine 123 (Rh123), our fluorescence microscopic result indicated that nanoparticles localized to the mitochondria. Copyright © 2016 Elsevier B.V. All rights reserved.

General overview of lipid-polymer hybrid nanoparticles, dendrimers, micelles, liposomes, spongosomes and cubosomes.

PubMed

Wakaskar, Rajesh R

2018-04-01

In recent years, the wider use of nanotechnology has attracted greater attention from scientists in multi-disciplinary fields. Nanotechnological research has come a long way in the past decade, with major advances being made, both in terms of diagnostic and therapeutic potential of nanoparticles. Areas covered: Some of the prominently discussed nanoparticles in this day and age are polymeric micelles, liposomes, lipid-polymer hybrid nanoparticles, dendrimers, spongosomes and cubosomes. This review attempts to focus on the conventional advantages and exemplary features that these particles possess, thus making them some of the most ideal vehicles for drug delivery. Expert opinion: Particulate systems, which have been extensively studied in this article, have been employed to enhance the pharmacokinetic and pharmacodynamic characteristics of various hydrophobic and hydrophilic drug moieties, thus attempting to prolong the blood circulation times and increase their efficacy over unmodified drug molecules. These modification techniques have enabled these drug molecules to be delivered to the pharmacological sites of action at an optimised controlled rate, thus trying to minimise the potential for any toxicity resulting from the non-specific distribution of drug to various organs.

Zonisamide-loaded triblock copolymer nanomicelles as a novel drug delivery system for the treatment of acute spinal cord injury

PubMed Central

Li, JingLun; Deng, JiaoJiao; Yuan, JinXian; Fu, Jie; Li, XiaoLing; Tong, AiPing; Wang, YueLong; Chen, YangMei; Guo, Gang

2017-01-01

Spinal cord injury (SCI) commonly leads to lifelong disability due to the limited regenerative capacity of the adult central nervous system. Nanomicelles can be used as therapeutic systems to provide effective treatments for SCI. In this study, a novel triblock monomethyl poly(ethylene glycol)-poly(l-lactide)-poly(trimethylene carbonate) copolymer was successfully synthesized. Next, polymeric nanomicelles loaded with zonisamide (ZNS), a Food and Drug Administration-approved antiepileptic drug, were prepared and characterized. The ZNS-loaded micelles (ZNS-M) were further utilized for the treatment of SCI in vitro and in vivo. The obtained ZNS-M were ~50 nm in diameter with good solubility and dispersibility. Additionally, these controlled-release micelles showed significant antioxidative and neuron-protective effects in vitro. Finally, our results indicated that ZNS-M treatment could promote motor function recovery and could increase neuron and axon density in a hemisection SCI model. In summary, these results may provide an experimental basis for the use of ZNS-M as a clinically applicable therapeutic drug for the treatment of SCI in the future. PMID:28408816

Characterization of chlorophyll derivatives in micelles of polymeric surfactants aiming photodynamic applications

NASA Astrophysics Data System (ADS)

Gerola, Adriana Passarella; de Morais, Flavia Amanda Pedroso; Costa, Paulo Fernando A.; Kimura, Elza; Caetano, Wilker; Hioka, Noboru

2017-02-01

The spectrophotometric properties of chlorophylls' derivatives (Chls) formulated in the Pluronics® F-127 and P-123 were evaluated and the results have shown that the Chls were efficiently solubilized in these drug delivery systems as monomers. The relative location of the Chls in the Pluronics® was estimated from the Stokes shift and micropolarity of the micellar environment. Chls with phytyl chain were located in the micellar core, where the micropolarity is similar to ethanol, while phorbides' derivatives (without phytyl chain) were located in the outer shell of the micelle, i.e., more polar environment. In addition, the thermal stability of the micellar formulations was evaluated through electronic absorption, fluorescence emission and resonance light scattering with lowering the temperature. The Chls promote the stability of the micelles at temperatures below the Critical Micellar Temperature (CMT) of these surfactants. For F-127 formulations, the water molecules drive through inside the nano-structure at temperatures below the CMT, which increased the polarity of this microenvironment and directly affected the spectrophotometric properties of the Chls with phytyl chain. The properties of the micellar microenvironment of P-123, with more hydrophobic core due to the small PEO/PPO fraction, were less affected by lowering the temperature than for F-127. These results enable us to better understand the Chls behavior in micellar copolymers and allowed us to design new drug delivery system that maintains the photosensitizer's properties for photodynamic applications.

Membrane-micelle model for humus in soils and sediments and its relation to humification

USGS Publications Warehouse

Wershaw, Robert L.

1994-01-01

Humification, the process whereby biomass consisting of dead plant and animal remains is converted into soil organic matter (humus), is one of the basic processes of the carbon cycle. The organic compounds that make up plant and animal tissue are thermodynamically unstable in the oxidizing atmosphere at the surface of the Earth. After the organisms in which they are incorporated die, the compounds are converted back to carbon dioxide and water by degradation reactions catalyzed by enzymes secreted by micro-organisms. However, not all the organic compounds in the dead biomass are immediately converted; some of the material is only partially oxidized. The residue left after partial oxidative degradation of the dead biomass is the source of the organic compounds that accumulate in soils and sediments as humus. Previously, humification was thought to involve a conversion of degradation products by a series of polymerization reactions into new types of polymeric species that are different from the precursor molecular species in the original biomass. However, it is proposed here that the depolymerization and oxidation reactions that take place during the enzymatic degradation of biopolymers produce amphiphiles--molecules that have a polar (hydrophilic) part and a nonpolar (hydrophobic) part. These amphiphiles that result from the partial oxidative degradation of dead biomass assemble spontaneously into ordered aggregates in which the hydrophobic parts of the molecules form the interiors and the hydrophilic parts of the molecules make up the exterior surfaces of the aggregates. These ordered aggregates constitute the humus in soils and sediments. Humus ordered aggregates most likely exist as bilayer membranes coating mineral grains and as micelles in solution.

Convection-enhanced delivery of SN-38-loaded polymeric micelles (NK012) enables consistent distribution of SN-38 and is effective against rodent intracranial brain tumor models.

PubMed

Zhang, Rong; Saito, Ryuta; Mano, Yui; Sumiyoshi, Akira; Kanamori, Masayuki; Sonoda, Yukihiko; Kawashima, Ryuta; Tominaga, Teiji

2016-10-01

Convection-enhanced delivery (CED) of therapeutic agents is a promising local delivery technique that has been extensively studied as a treatment for CNS diseases over the last two decades. One continuing challenge of CED is accurate and consistent delivery of the agents to the target. The present study focused on a new type of therapeutic agent, NK012, a novel SN-38-loaded polymeric micelle. Local delivery profiles of NK012 and SN-38 were studied using rodent brain and intracranial rodent brain tumor models. First, the cytotoxicity of NK012 against glioma cell lines was determined in vitro. Proliferations of glioma cells were significantly reduced after exposure to NK012. Then, the distribution and local toxicity after CED delivery of NK012 and SN-38 were evaluated in vivo. Volume of distribution of NK012 after CED was much larger than that of SN-38. Histological examination revealed minimum brain tissue damage in rat brains after delivery of 40 µg NK012 but severe damage with SN-38 at the same dose. Subsequently, the efficacy of NK012 delivered via CED was tested in 9L and U87MG rodent orthotopic brain tumor models. CED of NK012 displayed excellent efficacy in the 9L and U87MG orthotopic brain tumor models. Furthermore, NK012 and gadolinium diamide were co-delivered via CED to monitor the NK012 distribution using MRI. Volume of NK012 distribution evaluated by histology and MRI showed excellent agreement. CED of NK012 represents an effective treatment option for malignant gliomas. MRI-guided CED of NK012 has potential for clinical application.

Synthesis, characterisation, and in vitro cellular uptake kinetics of nanoprecipitated poly(2-methacryloyloxyethyl phosphorylcholine)- b-poly(2-(diisopropylamino)ethyl methacrylate) (MPC-DPA) polymeric nanoparticle micelles for nanomedicine applications

NASA Astrophysics Data System (ADS)

Salvage, Jonathan P.; Smith, Tia; Lu, Tao; Sanghera, Amendeep; Standen, Guy; Tang, Yiqing; Lewis, Andrew L.

2016-10-01

Nanoscience offers the potential for great advances in medical technology and therapies in the form of nanomedicine. As such, developing controllable, predictable, and effective, nanoparticle-based therapeutic systems remains a significant challenge. Many polymer-based nanoparticle systems have been reported to date, but few harness materials with accepted biocompatibility. Phosphorylcholine (PC) based biomimetic materials have a long history of successful translation into effective commercial medical technologies. This study investigated the synthesis, characterisation, nanoprecipitation, and in vitro cellular uptake kinetics of PC-based polymeric nanoparticle micelles (PNM) formed by the biocompatible and pH responsive block copolymer poly(2-methacryloyloxyethyl phosphorylcholine)- b-poly(2-(diisopropylamino)ethyl methacrylate) (MPC-DPA). Atom transfer radical polymerisation (ATRP), and gel permeation chromatography (GPC) were used to synthesise and characterise the well-defined MPC100-DPA100 polymer, revealing organic GPC, using evaporative light scatter detection, to be more accurate than aqueous GPC for this application. Subsequent nanoprecipitation investigations utilising photon correlation spectroscopy (PCS) revealed PNM size increased with polymer concentration, and conferred Cryo-stability. PNM diameters ranged from circa 64-69 nm, and increased upon hydrophobic compound loading, circa 65-71 nm, with loading efficiencies of circa 60 % achieved, whilst remaining monodisperse. In vitro studies demonstrated that the PNM were of low cellular toxicity, with colony formation and MTT assays, utilising V79 and 3T3 cells, yielding comparable results. Investigation of the in vitro cellular uptake kinetics revealed rapid, 1 h, cellular uptake of MPC100-DPA100 PNM delivered fluorescent probes, with fluorescence persistence for 48 h. This paper presents the first report of these novel findings, which highlight the potential of the system for nanomedicine application development.

Formulation and in vivo assessment of terconazole-loaded polymeric mixed micelles enriched with Cremophor EL as dual functioning mediator for augmenting physical stability and skin delivery.

PubMed

Abd-Elsalam, Wessam H; El-Zahaby, Sally A; Al-Mahallawi, Abdulaziz M

2018-11-01

The aim of the current study was to formulate terconazole (TCZ) loaded polymeric mixed micelles (PMMs) incorporating Cremophor EL as a stabilizer and a penetration enhancer. A 2 3 full factorial design was performed using Design-Expert® software for the optimization of the PMMs which were formulated using Pluronic P123 and Pluronic F127 together with Cremophor EL. To confirm the role of Cremophor EL, PMMs formulation lacking Cremophor EL was prepared for the purpose of comparison. Results showed that the optimal PMMs formulation (F7, where the ratio of total Pluronics to drug was 40:1, the weight ratio of Pluronic P123 to Pluronic F127 was 4:1, and the percentage of Cremophor EL in aqueous phase was 5%) had a high micellar incorporation efficiency (92.98 ± 0.40%) and a very small micellar size (33.23 ± 8.00 nm). Transmission electron microscopy revealed that PMMs possess spherical shape and good dispersibility. The optimal PMMs exhibited superior physical stability when compared with the PMMs formulation of the same composition but lacking Cremophor EL. Ex vivo studies demonstrated that the optimal PMMs formula markedly improved the dermal TCZ delivery compared to PMMs lacking Cremophor EL and TCZ suspension. In addition, it was found that the optimal PMMs exhibited a greater extent of TCZ deposition in the rat dorsal skin relative to TCZ suspension. Moreover, histopathological studies revealed the safety of the optimal PMMs upon topical application to rats. Consequently, PMMs enriched with Cremophor EL, as a stable nano-system, could be promising for the skin delivery of TCZ.

Facile preparation of well-defined AB2 Y-shaped miktoarm star polypeptide copolymer via the combination of ring-opening polymerization and click chemistry.

PubMed

Rao, Jingyi; Zhang, Yanfeng; Zhang, Jingyan; Liu, Shiyong

2008-10-01

Well-defined AB2 Y-shaped miktoarm star polypeptide copolymer, PZLL-b-(PBLG)2, was synthesized via a combination of ring-opening polymerization (ROP) of alpha-amino acid N-carboxyanhydride (NCA) and click chemistry, where PZLL is poly(epsilon-benzyloxycarbonyl-L-lysine) and PBLG is poly(gamma-benzyl-L-glutamate). First, two types of primary-amine-containing initiators, N-aminoethyl 3,5-bis(propargyloxyl)-benzamide and 3-azidopropylamine, were synthesized and employed for the ROP of NCA, leading to the formation of dialkynyl-terminated PZLL and azide-terminated PBLG, dialkynyl-PZLL and PBLG-N3, respectively. The subsequent copper(I)-catalyzed cycloaddition reaction between dialkynyl-PZLL and slightly excess PBLG-N3 led to facile preparation of PZLL-b-(PBLG)2 Y-shaped miktoarm star polypeptide copolymer. The excess PBLG-N3 was scavenged off by reacting with alkynyl-functionalized Wang resin. The obtained Y-shaped miktoarm star polypeptide copolymer was characterized by gel permeation chromatograph (GPC), Fourier transform-infrared spectroscopy (FT-IR), and (1)H NMR. Moreover, after the hydrolysis of protecting benzyl and benzyloxycarbonyl groups of PZLL-b-(PBLG)2, water-soluble pH-responsive Y-shaped miktoarm star polypeptide copolymer, PLL-b-(PLGA)2, was obtained, where PLL is poly(L-lysine) and PLGA is poly(L-glutamic acid). It can self-assemble into PLGA-core micelles at acidic pH and PLL-core micelles at alkaline pH, accompanied with the coil-to-helix transition of PLGA and PLL sequences, respectively. The spontaneous pH-responsive supramolecular assembly of PLL-b-(PLGA)2 miktoarm star polypeptide copolymer has been investigated via a combination of (1)H NMR, laser light scattering (LLS), transmission electron microscopy (TEM), and circular dichroism (CD) spectroscopy.

Polymeric nanoparticles for targeted treatment in oncology: current insights

PubMed Central

Prabhu, Rashmi H; Patravale, Vandana B; Joshi, Medha D

2015-01-01

Chemotherapy, a major strategy for cancer treatment, lacks the specificity to localize the cancer therapeutics in the tumor site, thereby affecting normal healthy tissues and advocating toxic adverse effects. Nanotechnological intervention has greatly revolutionized the therapy of cancer by surmounting the current limitations in conventional chemotherapy, which include undesirable biodistribution, cancer cell drug resistance, and severe systemic side effects. Nanoparticles (NPs) achieve preferential accumulation in the tumor site by virtue of their passive and ligand-based targeting mechanisms. Polymer-based nanomedicine, an arena that entails the use of polymeric NPs, polymer micelles, dendrimers, polymersomes, polyplexes, polymer–lipid hybrid systems, and polymer–drug/protein conjugates for improvement in efficacy of cancer therapeutics, has been widely explored. The broad scope for chemically modifying the polymer into desired construct makes it a versatile delivery system. Several polymer-based therapeutic NPs have been approved for clinical use. This review provides an insight into the advances in polymer-based targeted nanocarriers with focus on therapeutic aspects in the field of oncology. PMID:25678788

Complexation of β-cyclodextrin with dual molecular probes bearing fluorescent and paramagnetic moieties linked by short polyether chains.

PubMed

Mocanu, S; Matei, I; Ionescu, S; Tecuceanu, V; Marinescu, G; Ionita, P; Culita, D; Leonties, A; Ionita, Gabriela

2017-10-18

Electron paramagnetic resonance (EPR) and fluorescence spectroscopies provide molecular-level insights on the interaction of paramagnetic and fluorescent species with the microenvironment. A series of dual molecular probes bearing fluorescent and paramagnetic moieties linked by flexible short polyether chains have been synthesized. These new molecular probes open the possibility to investigate various multi-component systems such as host-guest systems, polymeric micelles, gels and protein solutions by using EPR and fluorescence spectroscopies concertedly. The EPR and fluorescence spectra of these compounds show that the dependence of the rotational correlation time and fluorescence quantum yield on the chain length of the linker is not linear, due to the flexibility of the polyether linker. The quenching effect of the nitroxide moiety on the fluorescence intensity of the pyrene group varies with the linker length and flexibility. The interaction of these dual molecular probes with β-cyclodextrin, in solution and in polymeric gels, was evaluated and demonstrated by analysis of EPR and fluorescence spectra.

Novel self-assembled gels and materials synthesis in unconventional environments

NASA Astrophysics Data System (ADS)

Irvin, Glen Clifford, Jr.

This thesis deals specifically with the fabrication of novel nanophase and polymer materials using novel microstructured mediums. Enzymatic polymerization in a new microemulsion system using dense carbon dioxide and fluorinated surfactants was carried out. The morphology, molecular weight, and chemical structure of the polymer are characterized through electron microscopy, HPLC, FTIR, and 1HNMR. Structural characteristics indicate similarity to polymers formed in AOT-inverse micelles. Spectroscopic information of the polymerization system on a molecular level has been performed. The results indicate strong hydrogen bonding interactions between the monomer, water, and perfluorinated surfactant implying the partitioning of the monomer to the surfactant headgroup region. An extension of the microemulsion environment is found with novel microemulsion based gels. The gels contain both lecithin and AOT surfactants where roughly equal volumes of hydrocarbon and water forms a three-dimensional gel network. This microemulsion system is unique from a fundamental scientific and practical interest. Analysis of the system microstructures using 1HNMR, 13CNMR 31PNNM, Rheology, SAXS, SANS, and conductivity is presented. Nanomaterial templated syntheses were conducted and are discussed. A new technique was developed for the rapid production of clathrate hydrates either in aqueous or water-in-microemulsion environments. The systems devised for this technology have significantly greater interfacial contact between water and gas molecules (clathrate hydrate constituents). The rapid clathrate hydrate technique was utilized for synthesis of nanoclusters in aqueous and reverse micelle based systems using the remarkable phenomenon of clathrate hydrate formation. Conversion of water to crystalline ice-like (clathrate hydrate) form is exploited to arrest particle growth, thereby restricting particle size to the nanometer range. The technique is used to generate high synthesis rates of nanoclusters (specifically ferrites) in aqueous solution. By controlling process conditions, ferrite particles with spherical or high aspect ratio acicular morphologies are obtained. Characterization of magnetic materials produced using this new technique was detailed with XRD, SQUID, and TEM. An extension of the rapid hydrate technique to AOT/water/Isooctane microemulsions found that for the same [water]/[AOT] ratio, nanoclusters of smaller size could be formed simply by subjecting the reversed micelles to hydrate forming conditions. Analysis of a model semiconductor (PbS) is presented using UV-VIS, XRD, EDAX, TEM, and Electron Diffraction.

Formulation and evaluation of mixed polymeric micelles of quercetin for treatment of breast, ovarian, and multidrug resistant cancers.

PubMed

Patra, Arjun; Satpathy, Swaha; Shenoy, Anitha K; Bush, Jason A; Kazi, Mohsin; Hussain, Muhammad Delwar

2018-01-01

Quercetin (QCT), a naturally occurring flavonoid has a wide array of pharmacological properties such as anticancer, antioxidant and anti-inflammatory activities. QCT has low solubility in water and poor bioavailability, which limited its use as a therapeutic molecule. Polymeric micelles (PMs) is a novel drug delivery system having characteristics like smaller particle size, higher drug loading, sustained drug release, high stability, increased cellular uptake and improved therapeutic potential. In the present study, we have formulated and characterized mixed PMs (MPMs) containing QCT for increasing its anticancer potential. The MPMs were prepared by thin film hydration method, and their physicochemical properties were characterized. The in vitro anticancer activity of the MPMs were tested in breast (MCF-7 and MDA-MB-231, epithelial and metastatic cancer cell lines, respectively), and ovarian (SKOV-3 and NCI/ADR, epithelial and multi-drug resistant cell lines, respectively) cancer. The optimal MPM formulations were obtained from Pluronic polymers, P123 and P407 with molar ratio of 7:3 (A16); and P123, P407 and TPGS in the molar ratio of 7:2:1 (A22). The size of the particles before lyophilization (24.83±0.44 nm) and after lyophilisation (37.10±4.23 nm), drug loading (8.75±0.41%), and encapsulation efficiency (87.48±4.15%) for formulation A16 were determined. For formulation A22, the particle size before lyophilization, after lyophilization, drug loading and encapsulation efficiency were 26.37±2.19 nm, 45.88±13.80 nm, 9.01±0.11% and 90.07±1.09%, respectively. The MPMs exhibited sustained release of QCT compared to free QCT as demonstrated from in vitro release experiments. The solubility of QCT was markedly improved compared to pure QCT. The MPMs were highly stable in aqueous media as demonstrated by their low critical micelle concentration. The concentration which inhibited 50% growth (IC 50 ) values of both micellar preparations in all the cancer cell lines were significantly less compared to free QCT. Both the MPMs containing QCT could be used for effective delivery to different type of cancer and may be considered for further development.

Particle Based Technologies for Osteoarthritis Detection and Therapy

PubMed Central

Kavanaugh, Taylor E.; Werfel, Thomas A.; Cho, Hongsik; Hasty, Karen A.; Duvall, Craig L.

2015-01-01

Osteoarthritis (OA) is a disease characterized by degradation of joints with the development of painful osteophytes in the surrounding tissues. Currently, there are a limited number of treatments for this disease and many of these only provide temporary, palliative relief. In this review, we discuss polymer drug delivery systems that can provide targeted and sustained delivery of imaging and therapeutic agents to OA-affected sites. We focus on technologies such as polymeric micelles and nano- / micro-particles, liposomes, and dendrimers for their potential treatment and/or diagnosis of OA. Several promising studies are highlighted, motivating the continued development of delivery technologies to improve treatments for OA. PMID:25990835

What nanomedicine in the clinic right now really forms nanoparticles?

PubMed

Svenson, Sonke

2014-01-01

Some researchers believe nanomedicine will revolutionize healthcare and medicine through transformative new therapeutic tools. Nanocarriers, utilized to transport actives to the target site, are constructed from a wide range of materials. Nanocarriers can be grouped into self-assembling (liposomes, micelles), processed (nanoparticles, emulsions), and chemically bound (dendrimers, silica-based carriers, carbon nanotubes) structures. A review of nanomedicines on the market and in clinical translation reveals that the vast majority is based on liposomes, polymeric micelles, and nanoparticles. The increasing presence of these novel nanomedicines raises the question what nanomedicines in the clinic right now really form nanoparticles, i.e., are improvements we see from nanomedicines structure-related or do they result from improved formulations? Do we even have sufficient data to address this question? The formation of nanocarriers is usually confirmed in vitro but little if any in vivo (let alone clinical) information is available. Given the large number of nanomedicines on the market and under clinical evaluation one clearly cannot expect to find a 'one size fits all' answer. Therefore, two case studies are discussed: the paclitaxel formulation Taxol® and its nanomedicine companions LEP-ETU (liposome), Genexol®-PM and NK105 (micelles), and Abraxane® (nanoparticle). Published pharmacokinetic data is utilized to find differences indicating nanocarrier delivery. The second case study involves structurally related camptothecin-polymer conjugates CRLX101 (nanoparticles) and XMT-1001 (prodrug). Structural differences are evaluated to discuss the different aggregation behavior. This opinion can only serve as first attempt to find a more general answer; clearly more data is needed from future studies. © 2014 Wiley Periodicals, Inc.

Dendritic brushes under theta and poor solvent conditions

NASA Astrophysics Data System (ADS)

Gergidis, Leonidas N.; Kalogirou, Andreas; Charalambopoulos, Antonios; Vlahos, Costas

2013-07-01

The effects of solvent quality on the internal stratification of polymer brushes formed by dendron polymers up to third generation were studied by means of molecular dynamics simulations with Langevin thermostat. The distributions of polymer units, of the free ends, the radii of gyration, and the back folding probabilities of the dendritic spacers were studied at the macroscopic states of theta and poor solvent. For high grafting densities we observed a small decrease in the height of the brush as the solvent quality decreases. The internal stratification in theta solvent was similar to the one we found in good solvent, with two and in some cases three kinds of populations containing short dendrons with weakly extended spacers, intermediate-height dendrons, and tall dendrons with highly stretched spacers. The differences increase as the grafting density decreases and single dendron populations were evident in theta and poor solvent. In poor solvent at low grafting densities, solvent micelles, polymeric pinned lamellae, spherical and single chain collapsed micelles were observed. The scaling dependence of the height of the dendritic brush at high density brushes for both solvents was found to be in agreement with existing analytical results.

Fluorination of phthalocyanine substituents: Improved photoproperties and enhanced photodynamic efficacy after optimal micellar formulations.

PubMed

Pucelik, Barbara; Gürol, Ilke; Ahsen, Vefa; Dumoulin, Fabienne; Dąbrowski, Janusz M

2016-11-29

A fluorinated phthalocyanine and its non-fluorinated analogue were selected to evaluate the potential enhancement of fluorination on photophysical, photochemical and redox properties as well as on biological activity in cellular and animal models. Due to the pharmacological relevance, the affinity of these phthalocyanines towards biological membranes (logP ow ) as well as their primary interaction with human serum albumin (HSA) or low-density lipoprotein (LDL) were determined. Water-dispersible drug formulation of phthalocyanines via Pluronic ® -based triblock copolymer micelles was prepared to avoid self-aggregation effects and to improve their delivery. The obtained results demonstrate that phthalocyanines incorporation into tunable-polymeric micelles significantly enhanced their cellular uptake and their photocytotoxicity. The improved biodistribution and photodynamic efficacy of the phthalocyanines-triblock copolymer conjugates was also confirmed in vivo in CT26 bearing BALB/c mice. PDT with both compounds led to tumor growth inhibition in all treated animals. Fluorinated phthalocyanine 2 turned out to be the most effective anticancer agent as the tumors of 20% of mice treated regressed completely and did not appear for over one year after treatment. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Development of materials from copolyacrylates via atom transfer radical polymerization

NASA Astrophysics Data System (ADS)

Jones, Melody Mersadez

Homopolymerization of 2-(trimethylsilyl)ethyl acrylate, 3,3-dimethylbutyl acrylate, methyl acrylate, and methyl methacrylate using atom transfer radical polymerization (ATRP) is reported. In addition, polymethyl acrylate and polymethyl methacrylate were used as macroinitiators for diblock copolymerizations (via ATRP) with various monomers to yield pMA-b-TMSEA, pMMA-b-TMSEA, and pMMA-b-GMA copolymers; these results are also reported. Controlled polymerizations were performed using the CuBr/hexamethyltriethylenetetramine catalyst system in combination with methyl bromopropionate as the initiator. The protected acid block copolymers pMA-b-TMSEA and pMMA-b-TMSEA were deprotected to afford acrylic and meth acrylic acid block copolymers pMA-b-AA and pMMA-b-AA. Methylene chloride was used to micellize the amphiphilic copolymers in order to obtain the critical micelle concentration of the polymers (CMCpMA-b-AA = 10 mg/mL, CMCpMMA-b-AA = 0.4 mg/mL). The majority of polymerization were done in bulk; however, since poly(trimethylsilyl)ethyl acrylate displayed polydispersity (Mn = 11459, PDI = 1.437) on the high end of the acceptable range, various solvents were utilized to decrease the polymerization rate and afford low polydispersity materials. This differs from the ATRP of polymethyl acrylate or polymethyl methacrylate using this catalytic system, which do not require the addition of a solvent to obtain well-defined polymers. Also, for this polymerization system three different temperatures (60°C, 90°C, and 120°C) were used, in order to reduce the concentration of radicals and the contribution of termination. The homopolymers and protected acid block copolymers were characterized by gel permeation chromatography to determine the relative molecular weights. Differential scanning calorimetry was used to obtain the glass transition temperature of all polymers. Characterization using NMR (1H and 13C) and FTIR confirmed homopolymerization of 3,3-dimethylbutyl acrylate, 2-(trimethylsilyl)ethyl acrylate and complete cleavage of the (trimethylsilyl)ethyl group from the protected acid copolymers.

Targeted cutaneous delivery of ciclosporin A using micellar nanocarriers and the possible role of inter-cluster regions as molecular transport pathways.

PubMed

Lapteva, Maria; Santer, Verena; Mondon, Karine; Patmanidis, Ilias; Chiriano, Gianpaolo; Scapozza, Leonardo; Gurny, Robert; Möller, Michael; Kalia, Yogeshvar N

2014-12-28

Oral administration of ciclosporin A (CsA) is indicated in the treatment of severe recalcitrant plaque psoriasis. However, CsA is both nephro- and hepatotoxic and its systemic administration also exposes the patient to other severe side effects. Although topical delivery of CsA, targeted directly to psoriatic skin, would offer significant advantages, there are no topical formulations approved for dermatological use. The aim of this work was to formulate CsA loaded polymeric micelles using the biodegradable and biocompatible MPEG-dihexPLA diblock copolymer and to evaluate their potential for delivering the drug selectively into the skin without concomitant transdermal permeation. Micelle formulations were characterised with respect to drug content, size and morphology. Micelle and drug penetration pathways were subsequently visualised with confocal laser scanning microscopy (CLSM) using fluorescein labelled CsA (Fluo-CsA) and Nile-Red (NR) labelled copolymer. Visualisation studies typically use fluorescent dyes as "model drugs"; however, these may have different physicochemical properties to the drug molecule under investigation. Therefore, in this study it was decided to chemically modify CsA and to use this structurally similar fluorescent analogue to visualise molecular distribution and transport pathways. Molecular modelling techniques and experimental determination of log D served as molecular scale and macroscopic methods to compare the lipophilicity of CsA and Fluo-CsA. The spherical, homogeneous and nanometre-scale micelles (with Zav from 25 to 52 nm) increased the aqueous solubility of CsA by 518-fold. Supra-therapeutic amounts of CsA were delivered to human skin (1.4±0.6 μg/cm2, cf. a statistically equivalent 1.1±0.5 μg/cm2 for porcine skin) after application of the formulation with the lowest CsA and copolymer content (1.67±0.03 mg/ml of CsA and 5mg/ml of copolymer) for only 1h without concomitant transdermal permeation. Fluo-CsA was successfully synthesised, characterised and incorporated into fluorescent NR-MPEG-dihexPLA micelles; its conformation was not modified by the addition of fluorescein and its log D, measured from pH4 to 8, was equivalent to that of CsA. Fluo-CsA and NR-MPEG-dihexPLA copolymer were subsequently visualised in skin by CLSM. The images indicated that micelles were preferentially deposited between corneocytes and in the inter-cluster regions (i.e. between the clusters of corneocytes). Fluo-CsA skin penetration was deeper in these structures, suggesting that inter-cluster penetration is probably the preferred transport pathway responsible for the increased cutaneous delivery of CsA. Copyright © 2014 Elsevier B.V. All rights reserved.

Oral bioavailability of curcumin: problems and advancements.

PubMed

Liu, Weidong; Zhai, Yingjie; Heng, Xueyuan; Che, Feng Yuan; Chen, Wenjun; Sun, Dezhong; Zhai, Guangxi

2016-09-01

Curcumin is a natural compound of Curcuma longa L. and has shown many pharmacological activities such as anti-inflammatory, anti-oxidant in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, neuroprotective activities and protects against myocardial infarction. Particularly, curcumin has also demonstrated favorite anticancer efficacy. But limiting factors such as its extremely low oral bioavailability hampers its application as therapeutic agent. Therefore, many technologies have been developed and applied to overcome this limitation. This review described the main physicochemical properties of curcumin and summarized the recent studies in the design and development of oral delivery systems for curcumin to enhance the solubility and oral bioavailability, including liposomes, nanoparticles and polymeric micelles, phospholipid complexes, and microemulsions.

[Drug delivery systems using nano-sized drug carriers].

PubMed

Nakayama, Masamichi; Okano, Teruo

2005-07-01

Nanotechnology has attracted great attention all over the world in recent several years and has led to the establishment of the novel technical field of "nanomedicine" through collaboration with advanced medical technology. Particularly, site-specific drug targeting using particle drug carrier systems has made substantial progress and been actively developed. This review explains the essential factors (size and chemical character) of drug carriers to allow long circulation in the bloodstream avoiding the reticuloendothelial system, and shows the present status and future perspective of several types of nano-carrier systems (water-soluble polymer, liposome and polymeric micelle). We also introduce the novel concept of multi-targeting system (combination of two or more targeting methodologies) for ideal drug therapies.

The efficacy of nimodipine drug delivery using mPEG-PLA micelles and mPEG-PLA/TPGS mixed micelles.

PubMed

Huang, Shuling; Yu, Xiaohong; Yang, Linlin; Song, Fenglan; Chen, Gang; Lv, Zhufen; Li, Tiao; Chen, De; Zhu, Wanhua; Yu, Anan; Zhang, Yongming; Yang, Fan

2014-10-15

In order to develop and compare mPEG-PLA micelles and mPEG-PLA/TPGS mixed micelles, with the intention to develop a highly efficient formulation for nimodipine (NIM), NIM-loaded micelles and mixed micelles were made and their pharmacokinetics were studied. Single factor experiments and orthogonal experiments were designed to optimize the final preparation process, characterizations and drug release behaviors were studied. Pharmacokinetics of NIM micelles, NIM mixed micelles were researched and were compared to NIM solution. Micelles and mixed micelles were prepared by solvent evaporation method, with relatively high drug loading efficiency and within nano-particle size range. The CMC value of mPEG-PLA was lower than that of mPEG-PLA/TPGS. The results of FTIR and TEM confirmed the spherical core-shell structure of micelles as well as mixed micelles, and the encapsulation of NIM inside the cores. In vitro release showed that micelles and mixed micelles had sustained release effect in the forms of passive diffusion and dissolution process, respectively. Following intraperitoneal administration (5mg/kg), micelles and mixed micelles were absorbed faster than solution, and with larger MRT(0-t), smaller CLz and larger AUC(0-t) as compared to that of solution, which showed micelles and mixed micelles had higher retention, slower elimination and higher bioavailability. This experiment also showed that mixed micelles released NIM more stably than micelles. By evaluate the bioequivalence, NIM micelles and NIM mixed micelles were testified non-bioequivalent to NIM solution. Micelles and mixed micelles could sustain the NIM concentrations more efficiently in plasma as compared to solution. Mixed micelles were the best ones since they had high loading content and released more stably. Thus, apprehending micelles and mixed micelles were suited as poor aqueous solubility drug carriers, and mixed micelles were better due to their high loading content and more stable release. Copyright © 2014 Elsevier B.V. All rights reserved.

Revisiting structure-property relationship of pH-responsive polymers for drug delivery applications.

PubMed

Bazban-Shotorbani, Salime; Hasani-Sadrabadi, Mohammad Mahdi; Karkhaneh, Akbar; Serpooshan, Vahid; Jacob, Karl I; Moshaverinia, Alireza; Mahmoudi, Morteza

2017-05-10

pH-responsive polymers contain ionic functional groups as pendants in their structure. The total number of charged groups on polymer chains determines the overall response of the system to changes in the external pH. This article reviews various pH-responsive polymers classified as polyacids (e.g., carboxylic acid based polymers, sulfonamides, anionic polysaccharides, and anionic polypeptides) and polybases (e.g., polyamines, pyridine and imidazole containing polymers, cationic polysaccharides, and cationic polypeptides). We correlate the pH variations in the body at the organ level (e.g., gastrointestinal tract and vaginal environment), tissue level (e.g., cancerous and inflamed tissues), and cellular level (e.g., sub-cellular organelles), with the intrinsic properties of pH-responsive polymers. This knowledge could help to select more effective ('smart') polymeric systems based on the biological target. Considering the pH differences in the body, various drug delivery systems can be designed by utilizing smart biopolymeric compounds with the required pH-sensitivity. We also review the pharmaceutical application of pH-responsive polymeric carriers including hydrogels, polymer-drug conjugates, micelles, dendrimers, and polymersomes. © 2016.

Modeling of hyaluronic acid containing anti-cancer drugs-loaded polylactic-co-glycolic acid bioconjugates for targeted delivery to cancer cells

NASA Astrophysics Data System (ADS)

Gul-e-Saba, Adulphakdee, A.; Madthing, A.; Zafar, M. N.; Abdullah, M. A.

2012-09-01

Molecular modeling of hyaluronan (HA), polylactic-co-glycolic acid (PLGA), polyethylene glycol-bis-amine (PEG-bis-amine), Curcumin, Cisplatin and the conjugate HA-PEG-PLGA containing Curcumin/Cisplatin were performed using Discovery Studio 2.5 to better understand issues and constraints related to targeted delivery of potent anticancer drugs to cancer cells. HA, a versatile biopolymer is a ligand of cancer cell receptor, CD44 that can be particularly useful in a receptor-mediated cellular uptake of drug-incorporated nanoparticles. Biocompatible and biodegradable polymers, PLGA and PEG, serve as polymeric micelles for controlled-release of drug. Curcumin as a natural anticancer agent has poor solubility that limits its use in drug therapeutics, while platinum-based Cisplatin exhibits systemic cytotoxicity. These can be overcome via drug delivery in polymeric biocompatible vehicles. The PLGA-PEG-HA conjugate shows the total measurement of 105 bond length with average bond length of 1.274163 Å. The conjugation between PEG and HA occurs at C8-O1 atoms and can be manipulated to improve properties.

Crizotinib-loaded polymeric nanoparticles in lung cancer chemotherapy.

PubMed

Jiang, Zhi-Ming; Dai, Shou-Ping; Xu, Yong-Qing; Li, Tao; Xie, Jian; Li, Chong; Zhang, Zhong-Hui

2015-07-01

The study describes the development of polylactide-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS)-based nanosystem as a carrier of crizotinib (CZT) to achieve superior anticancer efficacy in lung cancer therapy. We have demonstrated that block copolymer and hydrophobic drug is capable of self-assembling into a very stable nanocarrier, with suitable properties that allow their application for cancer drug delivery. Drug release study showed a sustained release pattern as a result of entrapment in the hydrophobic core of micelles. CZT/PT NP showed a noticeable cytotoxic effect in NCIH3122 lung cancer cells in a dose-dependent manner. Furthermore, morphological imaging and Live/Dead assay revealed a superior anticancer efficacy for nanoformulations. The polymeric nanoparticle showed a predominant presence in the cytoplasmic region of cell, indicating a typical endocytosis-mediated cellular uptake. The annexin V/PI staining-based apoptosis assay showed a remarkable ~40 % apoptosis (early and late apoptosis cells) comparing to only ~25 % apoptosis by free CZT. Taken together, Vitamin E TPGS-modified PLA nanoparticles would be a potential drug delivery system to increase the chemotherapeutic efficacy of CZT in lung cancer chemotherapy.

Nanotheranostics: Emerging Strategies for Early Diagnosis and Therapy of Brain Cancer

PubMed Central

Sonali; Viswanadh, Matte Kasi; Singh, Rahul Pratap; Agrawal, Poornima; Mehata, Abhishesh Kumar; Pawde, Datta Maroti; Narendra; Sonkar, Roshan; Muthu, Madaswamy Sona

2018-01-01

Nanotheranostics have demonstrated the development of advanced platforms that can diagnose brain cancer at early stages, initiate first-line therapy, monitor it, and if needed, rapidly start subsequent treatments. In brain nanotheranostics, therapeutic as well as diagnostic entities are loaded in a single nanoplatform, which can be further developed as a clinical formulation for targeting various modes of brain cancer. In the present review, we concerned about theranostic nanosystems established till now in the research field. These include gold nanoparticles, carbon nanotubes, magnetic nanoparticles, mesoporous silica nanoparticles, quantum dots, polymeric nanoparticles, upconversion nanoparticles, polymeric micelles, solid lipid nanoparticles and dendrimers for the advanced detection and treatment of brain cancer with advanced features. Also, we included the role of three-dimensional models of the BBB and cancer stem cell concept for the advanced characterization of nanotheranostic systems for the unification of diagnosis and treatment of brain cancer. In future, brain nanotheranostics will be able to provide personalized treatment which can make brain cancer even remediable or at least treatable at the primary stages. PMID:29291164

Immune activation with peptide assemblies carrying Lewis y tumor-associated carbohydrate antigen.

PubMed

Yamazaki, Yuji; Watabe, Naoki; Obata, Hiroaki; Hara, Eri; Ohmae, Masashi; Kimura, Shunsaku

2017-02-01

Molecular assemblies varying morphologies in a wide range from spherical micelle, nanosheet, curved sheet, nanotube and vesicle were prepared and loaded with Lewis y (Le y ) tumor-associated carbohydrate antigen on the assembly surface. The molecular assemblies were composed of poly(sarcosine) m -block-poly(L-lactic acid) 30 (m = 15 or 50, Lactosome), poly(sarcosine) m -block-(D/L-Leu-Aib) n (m = 22 or 30, n = 6 or 8) and their combinations. The molecular assemblies carrying Le y on the surface were administered in BALB/c nu/nu mice. The major epitopes of the molecular assemblies are commonly Le y and poly(sarcosine). IgM productions upon administrations of the molecular assemblies were assayed by ELISA, showing that anti-poly(sarcosine) IgM was highly produced by Lactosome of spherical micelle but with a negligible amount of anti-Le y IgM. On the other hand, the nanosheet of the interdigitated monolayer triggered the production of anti-Le y IgM but with less anti-poly(sarcosine) IgM production. Taken together, IgM specificity differs according to the molecular environment of the epitopes in the molecular assemblies. The antigenicity of poly(sarcosine) was augmented in polymeric micelle providing loose environment for B cells to penetrate in, whereas a high density of Le y on the molecular assembly was required for anti-Le y IgM production. The antigenicity of Le y is therefore dependent on the molecular assemblies on which Le y is displayed on the surface. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

Combinatorial resveratrol and quercetin polymeric micelles mitigate doxorubicin induced cardiotoxicity in vitro and in vivo.

PubMed

Cote, Brianna; Carlson, Lisa Janssen; Rao, Deepa A; Alani, Adam W G

2015-09-10

Doxorubicin hydrochloride (ADR) is an anthracycline antibiotic used to treat various cancers. However, due to its extensive cardiotoxic side effects a lifetime cumulative dose limit of 450-550 mg/m2 exists. The postulated mechanism of the cardiotoxicity is generation of reactive oxygen and nitrogen species. Natural products like resveratrol (RES), and quercetin (QUE) are known free radical scavengers and have shown cardioprotective effects. However, concurrent dosing of these natural products with ADR is limited due to their low solubility, and low oral bioavailability. We hypothesize that the combination of RES and QUE in Pluronic® F127 micelles (mRQ) when co-administered with ADR, will be cardioprotective in vitro and in vivo, while maintaining or increasing the efficacy of ADR against cancer cell lines in vitro. We prepared mRQ micelles capable of retaining 1.1mg/mL and 1.42 mg/mL of RES and QUE respectively. The in vitro release of RES and QUE from the micelles followed first order kinetics over 48h. In vitro cell viability and combination index analysis studies in human ovarian cancer cells (SKOV-3) and rat cardiomyocytes (H9C2) showed that RES:QUE: ADR at 10:10:1 ratio was synergistic in SKOV-3 cells and antagonistic in H9C2 cells. Caspase 3/7 activity studies indicated that mRQ did not interfere with ADR caspase activity in SKOV-3 cells but significantly decreased it in H9C2 cells. The generation of reactive oxygen species (ROS) in SKOV-3 and H9C2 cells in the presence of mRQ also indicated no changes in ROS activity in SKOV-3 cells but significant scavenging in H9C2 cells. Healthy mice were exposed to acute doses of ADR and ADR with mRQ. Based on biochemical estimations the presence of mRQ with ADR conferred full cardioprotection in these mice. Concurrent administration of mRQ with ADR at 10:10:1 ratio provides a viable strategy to mitigate acute ADR induced cardiotoxicity. Copyright © 2015 Elsevier B.V. All rights reserved.

Polymer Self-Assembly into Unique Fractal Nanostructures in Solution by a One-Shot Synthetic Procedure.

PubMed

Shin, Suyong; Gu, Ming-Long; Yu, Chin-Yang; Jeon, Jongseol; Lee, Eunji; Choi, Tae-Lim

2018-01-10

A fractal nanostructure having a high surface area is potentially useful in sensors, catalysts, functional coatings, and biomedical and electronic applications. Preparation of fractal nanostructures on solid substrates has been reported using various inorganic or organic compounds. However, achieving such a process using polymers in solution has been extremely challenging. Here, we report a simple one-shot preparation of polymer fractal nanostructures in solution via an unprecedented assembly mechanism controlled by polymerization and self-assembly kinetics. This was possible only because one monomer was significantly more reactive than the other, thereby easily forming a diblock copolymer microstructure. Then, the second insoluble block containing poly(p-phenylenevinylene) (PPV) without any side chains spontaneously underwent self-assembly during polymerization by an in situ nanoparticlization of conjugated polymers (INCP) method. The formation of fractal structures in solution was confirmed by various imaging techniques such as atomic force microscopy, transmission electron microscopy (TEM), and cryogenic TEM. The diffusion-limited aggregation theory was adopted to explain the branching patterns of the fractal nanostructures according to the changes in polymerization conditions such as the monomer concentration and the presence of additives. Finally, after detailed kinetic analyses, we proposed a plausible mechanism for the formation of unique fractal nanostructures, where the gradual formation and continuous growth of micelles in a chain-growth-like manner were accounted for.

Advanced drug and gene delivery systems based on functional biodegradable polycarbonates and copolymers.

PubMed

Chen, Wei; Meng, Fenghua; Cheng, Ru; Deng, Chao; Feijen, Jan; Zhong, Zhiyuan

2014-09-28

Biodegradable polymeric nanocarriers are one of the most promising systems for targeted and controlled drug and gene delivery. They have shown several unique advantages such as excellent biocompatibility, prolonged circulation time, passive tumor targeting via the enhanced permeability and retention (EPR) effect, and degradation in vivo into nontoxic products after completing their tasks. The current biodegradable drug and gene delivery systems exhibit, however, typically low in vivo therapeutic efficacy, due to issues of low loading capacity, inadequate in vivo stability, premature cargo release, poor uptake by target cells, and slow release of therapeutics inside tumor cells. To overcome these problems, a variety of advanced drug and gene delivery systems has recently been designed and developed based on functional biodegradable polycarbonates and copolymers. Notably, polycarbonates and copolymers with diverse functionalities such as hydroxyl, carboxyl, amine, alkene, alkyne, halogen, azido, acryloyl, vinyl sulfone, pyridyldisulfide, and saccharide, could be readily obtained by controlled ring-opening polymerization. In this paper, we give an overview on design concepts and recent developments of functional polycarbonate-based nanocarriers including stimuli-sensitive, photo-crosslinkable, or active targeting polymeric micelles, polymersomes and polyplexes for enhanced drug and gene delivery in vitro and in vivo. These multifunctional biodegradable nanosystems might be eventually developed for safe and efficient cancer chemotherapy and gene therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Advanced targeted therapies in cancer: Drug nanocarriers, the future of chemotherapy.

PubMed

Pérez-Herrero, Edgar; Fernández-Medarde, Alberto

2015-06-01

Cancer is the second worldwide cause of death, exceeded only by cardiovascular diseases. It is characterized by uncontrolled cell proliferation and an absence of cell death that, except for hematological cancers, generates an abnormal cell mass or tumor. This primary tumor grows thanks to new vascularization and, in time, acquires metastatic potential and spreads to other body sites, which causes metastasis and finally death. Cancer is caused by damage or mutations in the genetic material of the cells due to environmental or inherited factors. While surgery and radiotherapy are the primary treatment used for local and non-metastatic cancers, anti-cancer drugs (chemotherapy, hormone and biological therapies) are the choice currently used in metastatic cancers. Chemotherapy is based on the inhibition of the division of rapidly growing cells, which is a characteristic of the cancerous cells, but unfortunately, it also affects normal cells with fast proliferation rates, such as the hair follicles, bone marrow and gastrointestinal tract cells, generating the characteristic side effects of chemotherapy. The indiscriminate destruction of normal cells, the toxicity of conventional chemotherapeutic drugs, as well as the development of multidrug resistance, support the need to find new effective targeted treatments based on the changes in the molecular biology of the tumor cells. These novel targeted therapies, of increasing interest as evidenced by FDA-approved targeted cancer drugs in recent years, block biologic transduction pathways and/or specific cancer proteins to induce the death of cancer cells by means of apoptosis and stimulation of the immune system, or specifically deliver chemotherapeutic agents to cancer cells, minimizing the undesirable side effects. Although targeted therapies can be achieved directly by altering specific cell signaling by means of monoclonal antibodies or small molecules inhibitors, this review focuses on indirect targeted approaches that mainly deliver chemotherapeutic agents to molecular targets overexpressed on the surface of tumor cells. In particular, we offer a detailed description of different cytotoxic drug carriers, such as liposomes, carbon nanotubes, dendrimers, polymeric micelles, polymeric conjugates and polymeric nanoparticles, in passive and active targeted cancer therapy, by enhancing the permeability and retention or by the functionalization of the surface of the carriers, respectively, emphasizing those that have received FDA approval or are part of the most important clinical studies up to date. These drug carriers not only transport the chemotherapeutic agents to tumors, avoiding normal tissues and reducing toxicity in the rest of the body, but also protect cytotoxic drugs from degradation, increase the half-life, payload and solubility of cytotoxic agents and reduce renal clearance. Despite the many advantages of all the anticancer drug carriers analyzed, only a few of them have reached the FDA approval, in particular, two polymer-protein conjugates, five liposomal formulations and one polymeric nanoparticle are available in the market, in contrast to the sixteen FDA approval of monoclonal antibodies. However, there are numerous clinical trials in progress of polymer-protein and polymer-drug conjugates, liposomal formulations, including immunoliposomes, polymeric micelles and polymeric nanoparticles. Regarding carbon nanotubes or dendrimers, there are no FDA approvals or clinical trials in process up to date due to their unresolved toxicity. Moreover, we analyze in detail the more promising and advanced preclinical studies of the particular case of polymeric nanoparticles as carriers of different cytotoxic agents to active and passive tumor targeting published in the last 5 years, since they have a huge potential in cancer therapy, being one of the most widely studied nano-platforms in this field in the last years. The interest that these formulations have recently achieved is stressed by the fact that 90% of the papers based on cancer therapeutics with polymeric nanoparticles have been published in the last 6 years (PubMed search). Copyright © 2015 Elsevier B.V. All rights reserved.

Self assembled dual responsive micelles stabilized with protein for co-delivery of drug and siRNA in cancer therapy.

PubMed

Aji Alex, M R; Nehate, Chetan; Veeranarayanan, Srivani; Kumar, D Sakthi; Kulshreshtha, Ritu; Koul, Veena

2017-07-01

Design of safe and efficient vehicles for the combinatorial delivery of drugs and genetic agents is an emerging requisite for achieving enhanced therapeutic effect in cancer. Even though several nanoplatforms have been explored for the co-delivery of drugs and genetic materials the translation of these systems to clinical phase is still a challenge, mainly due to tedious synthesis procedures, lack of serum stability, inefficient scalability etc. Here in, we report development of reduction and pH sensitive polymeric graft of low molecular weight poly (styrene -alt -maleic anhydride) and evaluation of its efficacy in co-delivering drug and siRNA. The polymer was modified with suitable components, which could help in overcoming various systemic and cellular barriers for successful co-delivery of drugs and nucleic acids to cancer cells, using simple chemical reactions. The polymeric derivative could easily self assemble in water to form smooth, spherical micellar structures, indicating their scalability. Doxorubicin and PLK-1 siRNA were selected as model drug and nucleic acid, respectively. Doxorubicin could be loaded in the self assembling micelles with an optimum loading content of ∼8.6% w/w and efficient siRNA complexation was achieved with polymer/siRNA weight ratios >40. The polyplexes were stabilized in physiological saline by coating with bovine serum albumin (BSA). Stable drug loaded nanoplexes, for clinical administration, could be easily formulated by gently dispersing them in physiological saline containing appropriate amount of albumin. Drug release from the nanoplexes was significantly enhanced at low pH (5) and in the presence of 10 mM glutathione (GSH) showing their dual stimuli sensitive nature. In vitro cell proliferation assay and in vivo tumor regression study have shown synergistic effect of the drug loaded nanoplexes in inhibiting cancer cell proliferation. Facile synthesis steps, scalability and ease of formulation depict excellent clinical translation potential of the proposed nanosystem. Copyright © 2017 Elsevier Ltd. All rights reserved.

Curcumin-carboxymethyl chitosan (CNC) conjugate and CNC/LHR mixed polymeric micelles as new approaches to improve the oral absorption of P-gp substrate drugs.

PubMed

Ni, Jiang; Tian, Fengchun; Dahmani, Fatima Zohra; Yang, Hui; Yue, Deren; He, Shuwang; Zhou, Jianping; Yao, Jing

2016-11-01

The low oral bioavailability of numerous drugs has been mostly attributed to the significant effect of P-gp-mediated efflux on intestinal drug transport. Herein, we developed mixed polymeric micelles (MPMs) comprised of curcumin-carboxymethyl chitosan (CNC) conjugate, as a potential inhibitor of P-gp-mediated efflux and gastrointestinal absorption enhancer, and low-molecular-weight heparin-all-trans-retinoid acid (LHR) conjugate, as loading material, with the aim to improve the oral absorption of P-gp substrate drugs. CNC conjugate was synthesized by chemical bonding of curcumin (Cur) and carboxymethyl chitosan (CMCS) taking advantage of the inhibition of intestinal P-gp-mediated secretion by Cur and the intestinal absorption enhancement by CMCS. The chemical structure of CNC conjugate was characterized by 1 H NMR with a degree of substitution of Cur of 4.52-10.20%. More importantly, CNC conjugate markedly improved the stability of Cur in physiological pH. Cyclosporine A-loaded CNC/LHR MPMs (CsA-CNC/LHR MPMs) were prepared by dialysis method, with high drug loading 25.45% and nanoscaled particle size (∼200 nm). In situ single-pass perfusion studies in rats showed that both CsA + CNC mixture and CsA-CNC/LHR MPMs achieved significantly higher K a and P eff than CsA suspension in the duodenum and jejunum segments (p <  0.01), which was comparable to verapamil coperfusion effect. Similarly, CsA + CNC mixture and CsA-CNC/LHR MPMs significantly increased the oral bioavailability of CsA as compared to CsA suspension. These results suggest that CNC conjugate might be considered as a promising gastrointestinal absorption enhancer, while CNC/LHR MPMs had the potential to improve the oral absorption of P-gp substrate drugs.

Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study.

PubMed

Chen, Ling-Chun; Chen, Ying-Chen; Su, Chia-Yu; Hong, Chung-Shu; Ho, Hsiu-O; Sheu, Ming-Thau

2016-01-01

Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic(®) P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60 ± 5.02 nm, 0.589 ± 0.198, 96.87% ± 9.04%, and 12.18% ± 1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17-7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration-time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core-shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability.

Development and characterization of self-assembling lecithin-based mixed polymeric micelles containing quercetin in cancer treatment and an in vivo pharmacokinetic study

PubMed Central

Chen, Ling-Chun; Chen, Ying-Chen; Su, Chia-Yu; Hong, Chung-Shu; Ho, Hsiu-O; Sheu, Ming-Thau

2016-01-01

Quercetin (Que) is known to have biological benefits including an anticancer effect, but low water solubility limits its clinical application. The aim of this study was to develop a lecithin-based mixed polymeric micelle (LMPM) delivery system to improve the solubility and bioavailability of Que. The optimal Que-LMPM, composed of Que, lecithin, Pluronic® P123, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy[poly(ethylene glycol)-2000] in a proportion of 3:1:17.5:2.5 (w/w), was prepared by a thin-film method. The average size, polydispersion index, encapsulating efficiency, and drug loading of Que-LMPM were 61.60±5.02 nm, 0.589±0.198, 96.87%±9.04%, and 12.18%±1.11%, respectively. The solubility of Que in the Que-LMPM system increased to 5.81 mg/mL, compared to that of free Que in water of 0.17–7.7 μg/mL. The Que-LMPM system presented a sustained-release property in vitro. The in vitro cytotoxicity assay showed that the 50% inhibitory concentration values toward MCF-7 breast cancer cells for free Que, blank LMPMs, and Que-LMPMs were >200, >200, and 110 μM, respectively, indicating the nontoxicity of the LMPM carrier, but the LMPM formulation enhanced the cytotoxicity of Que against MCF-7 cells. A cellular uptake assay also confirmed the intake of Que-LMPM by MCF-7 cells. An in vivo pharmacokinetic study demonstrated that Que-LMPMs had higher area under the concentration–time curve and a longer half-life, leading to better bioavailability compared to a free Que injection. Due to their nanosize, core–shell structure, and solubilization potential, LMPMs were successfully developed as a drug delivery system for Que to improve its solubility and bioavailability. PMID:27143878

An Open-Label, Randomized, Parallel, Phase III Trial Evaluating the Efficacy and Safety of Polymeric Micelle-Formulated Paclitaxel Compared to Conventional Cremophor EL-Based Paclitaxel for Recurrent or Metastatic HER2-Negative Breast Cancer.

PubMed

Park, In Hae; Sohn, Joo Hyuk; Kim, Sung Bae; Lee, Keun Seok; Chung, Joo Seop; Lee, Soo Hyeon; Kim, Tae You; Jung, Kyung Hae; Cho, Eun Kyung; Kim, Yang Soo; Song, Hong Suk; Seo, Jae Hong; Ryoo, Hun Mo; Lee, Sun Ah; Yoon, So Young; Kim, Chul Soo; Kim, Yong Tai; Kim, Si Young; Jin, Mi Ryung; Ro, Jungsil

2017-07-01

Genexol-PM is a Cremophor EL-free formulation of low-molecular-weight, non-toxic, and biodegradable polymeric micelle-bound paclitaxel. We conducted a phase III study comparing the clinical efficacy and toxicity of Genexol-PM with conventional paclitaxel (Genexol). Patients were randomly assigned (1:1) to receive Genexol-PM 260 mg/m 2 or Genexol 175 mg/m 2 intravenously every 3 weeks. The primary outcome was the objective response rate (ORR). The study enrolled 212 patients, of whom 105 were allocated to receive Genexol-PM. The mean received dose intensity of Genexol-PM was 246.8±21.3 mg/m 2 (95.0%), and that of Genexol was 168.3±10.6 mg/m 2 (96.2%). After a median follow-up of 24.5 months (range, 0.0 to 48.7 months), the ORR of Genexol-PM was 39.1% (95% confidence interval [CI], 31.2 to 46.9) and the ORR of Genexol was 24.3% (95% CI, 17.5 to 31.1) (p non-inferiority =0.021, p superiority =0.016). The two groups did not differ significantly in overall survival (28.8 months for Genexol-PM vs. 23.8 months for Genexol; p=0.52) or progression-free survival (8.0 months for Genexol-PM vs. 6.7 months for Genexol; p=0.26). In both groups, the most common toxicities were neutropenia, with 68.6% occurrence in the Genexol-PM group versus 40.2% in the Genexol group (p < 0.01). The incidences of peripheral neuropathy of greater than grade 2 did not differ significantly between study treatments. Compared with standard paclitaxel, Genexol-PM demonstrated non-inferior and even superior clinical efficacy with a manageable safety profile in patients with metastatic breast cancer.

pH-sensitive polymeric cisplatin-ion complex with styrene-maleic acid copolymer exhibits tumor-selective drug delivery and antitumor activity as a result of the enhanced permeability and retention effect.

PubMed

Saisyo, Atsuyuki; Nakamura, Hideaki; Fang, Jun; Tsukigawa, Kenji; Greish, Khaled; Furukawa, Hiroyuki; Maeda, Hiroshi

2016-02-01

Cisplatin (CDDP) is widely used to treat various cancers. However, its distribution to normal tissues causes serious adverse effects. For this study, we synthesized a complex of styrene-maleic acid copolymer (SMA) and CDDP (SMA-CDDP), which formed polymeric micelles, to achieve tumor-selective drug delivery based on the enhanced permeability and retention (EPR) effect. SMA-CDDP is obtained by regulating the pH of the reaction solution of SMA and CDDP. The mean SMA-CDDP particle size was 102.5 nm in PBS according to electrophoretic light scattering, and the CDDP content was 20.1% (w/w). The release rate of free CDDP derivatives from the SMA-CDDP complex at physiological pH was quite slow (0.75%/day), whereas it was much faster at pH 5.5 (4.4%/day). SMA-CDDP thus had weaker in vitro toxicity at pH 7.4 but higher cytotoxicity at pH 5.5. In vivo pharmacokinetic studies showed a 5-fold higher tumor concentration of SMA-CDDP than of free CDDP. SMA-CDDP had more effective antitumor potential but lower toxicity than did free CDDP in mice after i.v. administration. Administration of parental free CDDP at 4 mg/kg×3 caused a weight loss of more than 5%; SMA-CDDP at 60 mg/kg (CDDP equivalent)×3 caused no significant weight change but markedly suppressed S-180 tumor growth. These findings together suggested using micelles of the SMA-CDDP complex as a cancer chemotherapeutic agent because of beneficial properties-tumor-selective accumulation and relatively rapid drug release at the acidic pH of the tumor-which resulted in superior antitumor effects and fewer side effects compared with free CDDP. Copyright © 2015 Elsevier B.V. All rights reserved.

Lx2-32c–loaded polymeric micelles with small size for intravenous drug delivery and their inhibitory effect on tumor growth and metastasis in clinically associated 4T1 murine breast cancer

PubMed Central

Chen, Li-qing; Huang, Wei; Gao, Zhong-gao; Fang, Wei-shuo; Jin, Ming-ji

2016-01-01

Lx2-32c is a novel taxane derivative with a strong antitumor activity. In this study, we developed Lx2-32c–loaded polymeric micelles (Lx2-32c-PMs) with small size and investigated their antitumor efficacy against tumor growth and metastasis on 4T1 murine breast cancer cell line with Cremophor EL–based Lx2-32c solution as the control. In this study, copolymer monomethoxy polyethylene glycol2000–polylactide1300 was used to prepare Lx2-32c-PMs by film hydration method, and their physicochemical properties were characterized as well, according to morphology, particle size, zeta potential, in vitro drug release, and reconstitution stability. Under confocal laser scanning microscopy, it was observed that Lx2-32c-PMs could be effectively taken up by 4T1 cells in a time-dependent manner. Cell Counting Kit-8 assay showed that the IC50 of Lx2-32c-PMs was 0.3827 nM. Meanwhile, Lx2-32c-PMs had better ability to promote apoptosis and induce G2/M cycle block and polyploidy formation, compared with Lx2-32c solution. More importantly, in vivo animal studies showed that compared to Lx2-32c solution, Lx2-32c-PMs possessed better ability not only to effectively inhibit the tumor growth, but also to significantly suppress spontaneous and postoperative metastasis to distant organs in 4T1 orthotopic tumor-bearing mice. Consequently, Lx2-32c-PMs have significantly prolonged the survival lifetime of tumor-bearing mice. Thus, our study reveals that Lx2-32c-PMs had favorable antitumor activity and exhibited a good prospect for application in the field of antitumor therapy. PMID:27799769

The effect of solute concentration on hindered gradient diffusion in polymeric gels

NASA Astrophysics Data System (ADS)

Buck, Kristan K. S.; Dungan, Stephanie R.; Phillips, Ronald J.

1999-10-01

The effect of solute concentration on hindered diffusion of sphere-like colloidal solutes in stiff polymer hydrogels is examined theoretically and experimentally. In the theoretical development, it is shown that the presence of the gel fibres enhances the effect of concentration on the thermodynamic driving force for gradient diffusion, while simultaneously reducing the effect of concentration on the hydrodynamic drag. The result is that gradient diffusion depends more strongly on solute concentration in gels than it does in pure solution, by an amount that depends on the partition coefficient and hydraulic permeability of the gel solute system. Quantitative calculations are made to determine the concentration-dependent diffusivity correct to first order in solute concentration. In order to compare the theoretical predictions with experimental data, rates of diffusion have been measured for nonionic micelles and globular proteins in solution and agarose hydrogels at two gel concentrations. The measurements were performed by using holographic interferometry, through which one monitors changes in refractive index as gradient diffusion takes place within a transparent gel. If the solutes are modelled as spheres with short-range repulsive interactions, then the experimentally measured concentration dependence of the diffusivities of both the protein and micelles is in good agreement with the theoretical predictions.

Solubilization of poorly water-soluble compounds using amphiphilic phospholipid polymers with different molecular architectures.

PubMed

Mu, Mingwei; Konno, Tomohiro; Inoue, Yuuki; Ishihara, Kazuhiko

2017-10-01

To achieve stable and effective solubilization of poorly water-soluble bioactive compounds, water-soluble and amphiphilic polymers composed of hydrophilic 2-methacryloyloxyethyl phosphorylcholine (MPC) units and hydrophobic n-butyl methacrylate (BMA) units were prepared. MPC polymers having different molecular architectures, such as random-type monomer unit sequences and block-type sequences, formed polymer aggregates when they were dissolved in aqueous media. The structure of the random-type polymer aggregate was loose and flexible. On the other hand, the block-type polymer formed polymeric micelles, which were composed of very stable hydrophobic poly(BMA) cores and hydrophilic poly(MPC) shells. The solubilization of a poorly water-soluble bioactive compound, paclitaxel (PTX), in the polymer aggregates was observed, however, solubilizing efficiency and stability were strongly depended on the polymer architecture; in other words, PTX stayed in the poly(BMA) core of the polymer micelle formed by the block-type polymer even when plasma protein was present in the aqueous medium. On the other hand, when the random-type polymer was used, PTX was transferred from the polymer aggregate to the protein. We conclude that water-soluble and amphiphilic MPC polymers are good candidates as solubilizers for poorly water-soluble bioactive compounds. Copyright © 2017 Elsevier B.V. All rights reserved.

Synthesis and Characterization of Fatty Acid/Amino Acid Self-Assemblies

PubMed Central

Gajowy, Joanna; Bolikal, Durgadas; Kohn, Joachim; El Fray, Miroslawa

2014-01-01

In this paper, we discuss the synthesis and self-assembling behavior of new copolymers derived from fatty acid/amino acid components, namely dimers of linoleic acid (DLA) and tyrosine derived diphenols containing alkyl ester pendent chains, designated as “R” (DTR). Specific pendent chains were ethyl (E) and hexyl (H). These poly(aliphatic/aromatic-ester-amide)s were further reacted with poly(ethylene glycol) (PEG) and poly(ethylene glycol methyl ether) of different molecular masses, thus resulting in ABA type (hydrophilic-hydrophobic-hydrophilic) triblock copolymers. We used Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopies to evaluate the chemical structure of the final materials. The molecular masses were estimated by gel permeation chromatography (GPC) measurements. The self-organization of these new polymeric systems into micellar/nanospheric structures in aqueous environment was evaluated using ultraviolet/visible (UV-VIS) spectroscopy, dynamic light scattering (DLS) and transmission electron microscopy (TEM). The polymers were found to spontaneously self-assemble into nanoparticles with sizes in the range 196–239 nm and critical micelle concentration (CMC) of 0.125–0.250 mg/mL. The results are quite promising and these materials are capable of self-organizing into well-defined micelles/nanospheres encapsulating bioactive molecules, e.g., vitamins or antibacterial peptides for antibacterial coatings on medical devices. PMID:25347356

Efficient Cisplatin Pro-Drug Delivery Visualized with Sub-100 nm Resolution: Interfacing Engineered Thermosensitive Magnetomicelles with a Living System

DOE PAGES

Vitol, Elina A.; Rozhkova, Elena A.; Rose, Volker; ...

2014-06-06

Temperature-responsive magnetic nanomicelles can serve as thermal energy and cargo carriers with controlled drug release functionality. In view of their potential biomedical applications, understanding the modes of interaction between nanomaterials and living systems and evaluation of efficiency of cargo delivery is of the utmost importance. In this paper, we investigate the interaction between the hybrid magnetic nanomicelles engineered for controlled platinum complex drug delivery and a biological system at three fundamental levels: subcellular compartments, a single cell and whole living animal. Nanomicelles with polymeric P(NIPAAm-co-AAm)-b-PCL core-shell were loaded with a hydrophobic Pt(IV) complex and Fe 3O 4 nanoparticles though self-assembly.more » The distribution of a platinum complex on subcellular level is visualized using hard X-ray fluorescence microscopy with unprecedented level of detail at sub-100 nm spatial resolution. We then study the cytotoxic effects of platinum complex-loaded micelles in vitro on a head and neck cancer cell culture model SQ20B. In conclusion, by employing the magnetic functionality of the micelles and additionally loading them with a near infrared fluorescent dye, we magnetically target them to a tumor site in a live animal xenografted model which allows to visualize their biodistribution in vivo.« less

Ultrasound enhanced release of therapeutics from drug-releasing implants based on titania nanotube arrays.

PubMed

Aw, Moom Sinn; Losic, Dusan

2013-02-25

A non-invasive and external stimulus-driven local drug delivery system (DDS) based on titania nanotube (TNT) arrays loaded with drug encapsulated polymeric micelles as drug carriers and ultrasound generator is described. Ultrasound waves (USW) generated by a pulsating sonication probe (Sonotrode) in phosphate buffered saline (PBS) at pH 7.2 as the medium for transmitting pressure waves, were used to release drug-loaded nano-carriers from the TNT arrays. It was demonstrated that a very rapid release in pulsatile mode can be achieved, controlled by several parameters on the ultrasonic generator. This includes pulse length, time, amplitude and power intensity. By optimization of these parameters, an immediate drug-micelles release of 100% that spans a desirable time of 5-50 min was achieved. It was shown that stimulated release can be generated and reproduced at any time throughout the TNT-Ti implant life, suggesting considerable potential of this approach as a feasible and tunable ultrasound-mediated drug delivery system in situ via drug-releasing implants. It is expected that this concept can be translated from an in vitro to in vivo regime for therapeutic applications using drug-releasing implants in orthopedic and coronary stents. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Highly robust crystalsome via directed polymer crystallization at curved liquid/liquid interface

PubMed Central

Wang, Wenda; Qi, Hao; Zhou, Tian; Mei, Shan; Han, Lin; Higuchi, Takeshi; Jinnai, Hiroshi; Li, Christopher Y.

2016-01-01

Lipids and amphiphilic block copolymers spontaneously self-assemble in water to form a plethora of micelles and vesicles. They are typically fluidic in nature and often mechanically weak for applications such as drug delivery and gene therapeutics. Mechanical properties of polymeric materials could be improved by forming crystalline structures. However, most of the self-assembled micelles and vesicles have curved surfaces and precisely tuning crystallization within a nanoscale curved space is challenging, as the curved geometry is incommensurate with crystals having three-dimensional translational symmetry. Herein, we report using a miniemulsion crystallization method to grow nanosized, polymer single-crystal-like capsules. We coin the name crystalsome to describe this unique structure, because they are formed by polymer lamellar crystals and their structure mimics liposomes and polymersomes. Using poly(L-lactic acid) (PLLA) as the model polymer, we show that curved water/p-xylene interface formed by the miniemulsion process can guide the growth of PLLA single crystals. Crystalsomes with the size ranging from ∼148 nm to over 1 μm have been formed. Atomic force microscopy measurement demonstrate a two to three orders of magnitude increase in bending modulus compared with conventional polymersomes. We envisage that this novel structure could shed light on investigating spherical crystallography and drug delivery. PMID:26837260

Self-assembly of nanocomposite materials

DOEpatents

Brinker, C. Jeffrey; Sellinger, Alan; Lu, Yunfeng

2001-01-01

A method of making a nanocomposite self-assembly is provided where at least one hydrophilic compound, at least one hydrophobic compound, and at least one amphiphilic surfactant are mixed in an aqueous solvent with the solvent subsequently evaporated to form a self-assembled liquid crystalline mesophase material. Upon polymerization of the hydrophilic and hydrophobic compounds, a robust nanocomposite self-assembled material is formed. Importantly, in the reaction mixture, the amphiphilic surfactant has an initial concentration below the critical micelle concentration to allow formation of the liquid-phase micellar mesophase material. A variety of nanocomposite structures can be formed, depending upon the solvent evaporazation process, including layered mesophases, tubular mesophases, and a hierarchical composite coating composed of an isotropic worm-like micellar overlayer bonded to an oriented, nanolaminated underlayer.

Synthesis of sharply thermo and PH responsive PMA-b-PNIPAM-b-PEG-b-PNIPAM-b-PMA by RAFT radical polymerization and its schizophrenic micellization in aqueous solutions.

PubMed

Ahmadkhani, Lida; Abbasian, Mojtaba; Akbarzadeh, Abolfazl

2017-01-01

Sharply thermo- and pH-responsive pentablock terpolymer with a core-shell-corona structure was prepared by RAFT polymerization of N-isopropylacrylamide and methacrylic acid monomers using PEG-based benzoate-type of RAFT agent. The PEG-based RAFT agent could be easily synthesized by dihydroxyl-capped PEG with 4-cyano-4-(thiobenzoyl) sulfanylpentanoic acids, using esterification reaction. This pentablock terpolymer was characterized by 1 H NMR, FT-IR, and GPC. The PDI was obtained by GPC, indicating that the molecular weight distribution was narrow and the polymerization was well controlled. The thermo- and pH-responsive micellization of the pentablock terpolymer in aqueous solution was investigated using fluorescence spectroscopy technique, UV-vis transmittance, and TEM. The LCST of pentablock terpolymer increased (over 50 °C) compared to the NIPAM homopolymer (~32 °C), due to the incorporation of the hydrophilic PEG and PMA blocks in pentablock terpolymer (PNIPAM block as the core, PEG the block and the hydrophilic PMA block as the shell and the corona). Also, pH-dependent phase transition behavior shows at a pH value of about ~5.8, according to pKa of MAA. Thus, in acidic solution at room temperature, the pentablock terpolymer self-assembled to form core-shell-corona micelles, with the hydrophobic PMA block as the core, the PNIPAM block and the hydrophilic PEG block as the shell and the corona, respectively.

Nanopatterned submicron pores as a shield for nonspecific binding in surface plasmon resonance-based sensing.

PubMed

Raz, Sabina Rebe; Marchesini, Gerardo R; Bremer, Maria G E G; Colpo, Pascal; Garcia, Cesar Pascual; Guidetti, Guido; Norde, Willem; Rossi, Francois

2012-11-21

We present a novel approach to tackle the most common drawback of using surface plasmon resonance for analyte screening in complex biological matrices--the nonspecific binding to the sensor chip surface. By using a perforated membrane supported by a polymeric gel structure at the evanescent wave penetration depth, we have fabricated a non-fouling sieve above the sensing region. The sieve shields the evanescent wave from nonspecific interactions which interfere with SPR sensing by minimizing the fouled area of the polymeric gel and preventing the translocation of large particles, e.g. micelles or aggregates. The nanopatterned macropores were fabricated by means of colloidal lithography and plasma enhanced chemical vapor deposition of a polyethylene oxide-like film on top of a polymeric gel matrix commonly used in surface plasmon resonance analysis. The sieve was characterized using surface plasmon resonance imaging, contact angle, atomic force microscopy and scanning electron microscopy. The performance of the sieve was studied using an immunoassay for detection of antibiotic residues in full fat milk and porcine serum. The non-fouling membrane presented pores in the 92-138 nm range organized in a hexagonal crystal lattice with a clearance of about 5% of the total surface. Functionally, the membrane with the nanopatterned macropores showed significant improvements in immunoassay robustness and sensitivity in untreated complex samples. The utilization of the sensor built-in sieve for measurements in complex matrices offers reduction in pre-analytical sample preparation steps and thus shortens the total analysis time.

Recent developments in curcumin and curcumin based polymeric materials for biomedical applications: A review.

PubMed

Mahmood, Kashif; Zia, Khalid Mahmood; Zuber, Mohammad; Salman, Mahwish; Anjum, Muhammad Naveed

2015-11-01

Turmeric (Curcuma longa) is a popular Indian spice that has been used for centuries in herbal medicines for the treatment of a variety of ailments such as rheumatism, diabetic ulcers, anorexia, cough and sinusitis. Curcumin (diferuloylmethane) is the main curcuminoid present in turmeric and responsible for its yellow color. Curcumin has been shown to possess significant anti-inflammatory, anti-oxidant, anti-carcinogenic, anti-mutagenic, anticoagulant and anti-infective effects. This review summarizes and discusses recently published papers on the key biomedical applications of curcumin based materials. The highlighted studies in the review provide evidence of the ability of curcumin to show the significant vitro antioxidant, diabetic complication, antimicrobial, neuroprotective, anti-cancer activities and detection of hypochlorous acid, wound healing, treatment of major depression, healing of paracentesis, and treatment of carcinoma and optical detection of pyrrole properties. Hydrophobic nature of this polyphenolic compound along with its rapid metabolism, physicochemical and biological instability contribute to its poor bioavailability. To redress these problems several approaches have been proposed like encapsulation of curcumin in liposomes and polymeric micelles, inclusion complex formation with cyclodextrin, formation of polymer-curcumin conjugates, etc. Copyright © 2015 Elsevier B.V. All rights reserved.

"Non-equilibrium" block copolymer micelles with glassy cores: a predictive approach based on theory of equilibrium micelles.

PubMed

Nagarajan, Ramanathan

2015-07-01

Micelles generated in water from most amphiphilic block copolymers are widely recognized to be non-equilibrium structures. Typically, the micelles are prepared by a kinetic process, first allowing molecular scale dissolution of the block copolymer in a common solvent that likes both the blocks and then gradually replacing the common solvent by water to promote the hydrophobic blocks to aggregate and create the micelles. The non-equilibrium nature of the micelle originates from the fact that dynamic exchange between the block copolymer molecules in the micelle and the singly dispersed block copolymer molecules in water is suppressed, because of the glassy nature of the core forming polymer block and/or its very large hydrophobicity. Although most amphiphilic block copolymers generate such non-equilibrium micelles, no theoretical approach to a priori predict the micelle characteristics currently exists. In this work, we propose a predictive approach for non-equilibrium micelles with glassy cores by applying the equilibrium theory of micelles in two steps. In the first, we calculate the properties of micelles formed in the mixed solvent while true equilibrium prevails, until the micelle core becomes glassy. In the second step, we freeze the micelle aggregation number at this glassy state and calculate the corona dimension from the equilibrium theory of micelles. The condition when the micelle core becomes glassy is independently determined from a statistical thermodynamic treatment of diluent effect on polymer glass transition temperature. The predictions based on this "non-equilibrium" model compare reasonably well with experimental data for polystyrene-polyethylene oxide diblock copolymer, which is the most extensively studied system in the literature. In contrast, the application of the equilibrium model to describe such a system significantly overpredicts the micelle core and corona dimensions and the aggregation number. The non-equilibrium model suggests ways to obtain different micelle sizes for the same block copolymer, by the choices we can make of the common solvent and the mode of solvent substitution. Published by Elsevier Inc.

AKT2 siRNA delivery with amphiphilic-based polymeric micelles show efficacy against cancer stem cells.

PubMed

Rafael, Diana; Gener, Petra; Andrade, Fernanda; Seras-Franzoso, Joaquin; Montero, Sara; Fernández, Yolanda; Hidalgo, Manuel; Arango, Diego; Sayós, Joan; Florindo, Helena F; Abasolo, Ibane; Schwartz, Simó; Videira, Mafalda

2018-11-01

Development of RNA interference-based therapies with appropriate therapeutic window remains a challenge for advanced cancers. Because cancer stem cells (CSC) are responsible of sustaining the metastatic spread of the disease to distal organs and the progressive gain of resistance of advanced cancers, new anticancer therapies should be validated specifically for this subpopulation of cells. A new amphihilic-based gene delivery system that combines Pluronic ® F127 micelles with polyplexes spontaneously formed by electrostatic interaction between anionic siRNA and cationic polyethylenimine (PEI) 10K, was designed (PM). Resultant PM gather the requirements for an efficient and safe transport of siRNA in terms of its physicochemical characteristics, internalization capacity, toxicity profile and silencing efficacy. PM were loaded with a siRNA against AKT2, an important oncogene involved in breast cancer tumorigenesis, with a special role in CSC malignancy. Efficacy of siAKT2-PM was validated in CSC isolated from two breast cancer cell lines: MCF-7 and Triple Negative MDA-MB-231 corresponding to an aggressive subtype of breast cancer. In both cases, we observed significant reduction on cell invasion capacity and strong inhibition of mammosphere formation after treatment. These results prompt AKT2 inhibition as a powerful therapeutic target against CSC and pave the way to the appearance of more effective nanomedicine-based gene therapies aimed to prevent CSC-related tumor recurrence.

Phospholipid micelle-based magneto-plasmonic nanoformulation for magnetic field-directed, imaging-guided photo-induced cancer therapy.

PubMed

Ohulchanskyy, Tymish Y; Kopwitthaya, Atcha; Jeon, Mansik; Guo, Moran; Law, Wing-Cheung; Furlani, Edward P; Kim, Chulhong; Prasad, Paras N

2013-11-01

We present a magnetoplasmonic nanoplatform combining gold nanorods (GNR) and iron-oxide nanoparticles within phospholipid-based polymeric nanomicelles (PGRFe). The gold nanorods exhibit plasmon resonance absorbance at near infrared wavelengths to enable photoacoustic imaging and photothermal therapy, while the Fe3O4 nanoparticles enable magnetophoretic control of the nanoformulation. The fabricated nanoformulation can be directed and concentrated by an external magnetic field, which provides enhancement of a photoacoustic signal. Application of an external field also leads to enhanced uptake of the magnetoplasmonic formulation by cancer cells in vitro. Under laser irradiation at the wavelength of the GNR absorption peak, the PGRFe formulation efficiently generates plasmonic nanobubbles within cancer cells, as visualized by confocal microscopy, causing cell destruction. The combined magnetic and plasmonic functionalities of the nanoplatform enable magnetic field-directed, imaging-guided, enhanced photo-induced cancer therapy. In this study, a nano-formulation of gold nanorods and iron oxide nanoparticles is presented using a phospholipid micelle-based delivery system for magnetic field-directed and imaging-guided photo-induced cancer therapy. The gold nanorods enable photoacoustic imaging and photothermal therapy, while the Fe3O4 nanoparticles enable magnetophoretic control of the formulation. This and similar systems could enable more precise and efficient cancer therapy, hopefully in the near future, after additional testing. Copyright © 2013 Elsevier Inc. All rights reserved.

pH-Sensitive polymer assisted self-aggregation of bis(pyrene) in living cells in situ with turn-on fluorescence

NASA Astrophysics Data System (ADS)

Duan, Zhongyu; Gao, Yu-Juan; Qiao, Zeng-Ying; Qiao, Shenglin; Wang, Yongmei; Hou, Chunyuan; Wang, Lei; Wang, Hao

2015-09-01

Supramolecular self-assemblies with various nanostructures in organic and aqueous solutions have been prepared with desired functions. However, in situ construction of self-assembled superstructures in physiological conditions to achieve expected biological functions remains a challenge. Here, we report a supramolecular system to realize the in situ formation of nanoaggregates in living cells. The bis(pyrene) monomers were dispersed inside of hydrophobic domains of pH-sensitive polymeric micelles and delivered to the lysosomes of cells. In the acidic lysosomes, the bis(pyrene) monomers were released and self-aggregated with turn-on fluorescence. We envision this strategy for in situ construction of supramolecular nanostructures in living cells will pave the way for molecular diagnostics in the future.

Tumor-targeted nanomedicines for cancer theranostics

PubMed Central

Lammers, Twan; Shi, Yang

2017-01-01

Chemotherapeutic drugs have multiple drawbacks, including severe side effects and suboptimal therapeutic efficacy. Nanomedicines assist in improving the biodistribution and the target accumulation of chemotherapeutic drugs, and are therefore able to enhance the balance between efficacy and toxicity. Multiple different types of nanomedicines have been evaluated over the years, including liposomes, polymer-drug conjugates and polymeric micelles, which rely on strategies such as passive targeting, active targeting and triggered release for improved tumor-directed drug delivery. Based on the notion that tumors and metastases are highly heterogeneous, it is important to integrate imaging properties in nanomedicine formulations in order to enable non-invasive and quantitative assessment of targeting efficiency. By allowing for patient pre-selection, such next generation nanotheranostics are useful for facilitating clinical translation and personalizing nanomedicine treatments. PMID:27865762

Protein composition of different sized casein micelles in milk after the binding of lactoferrin or lysozyme.

PubMed

Anema, Skelte G; de Kruif, C G Kees

2013-07-24

Casein micelles with bound lactoferrin or lysozyme were fractionated into sizes ranging in radius from ∼50 to 100 nm. The κ-casein content decreased markedly and the αS-casein/β-casein content increased slightly as micelle size increased. For lactoferrin, higher levels were bound to smaller micelles. The lactoferrin/κ-casein ratio was constant for all micelle sizes, whereas the lactoferrin/αS-casein and lactoferrin/β-casein ratio decreased with increasing micelle size. This indicates that the lactoferrin was binding to the surface of the casein micelles. For lysozyme, higher levels bound to larger casein micelles. The lysozyme/αS-casein and lysozyme/β-casein ratios were nearly constant, whereas the lysozyme/κ-casein ratio increased with increasing micelle size, indicating that lysozyme bound to αS-casein and β-casein in the micelle core. Lactoferrin is a large protein that cannot enter the casein protein mesh; therefore, it binds to the micelle surface. The smaller lysozyme can enter the protein mesh and therefore binds to the more charged αS-casein and β-casein.

Association of denatured whey proteins with casein micelles in heated reconstituted skim milk and its effect on casein micelle size.

PubMed

Anema, Skelte G; Li, Yuming

2003-02-01

When skim milk at pH 6.55 was heated (75 to 100 degrees C for up to 60 min), the casein micelle size, as monitored by photon correlation spectroscopy, was found to increase during the initial stages of heating and tended to plateau on prolonged heating. At any particular temperature, the casein micelle size increased with longer holding times, and, at any particular holding time, the casein micelle size increased with increasing temperature. The maximum increase in casein micelle size was about 30-35 nm. The changes in casein micelle size were poorly correlated with the level of whey protein denaturation. However, the changes in casein micelle size were highly correlated with the levels of denatured whey proteins that were associated with the casein micelles. The rate of association of the denatured whey proteins with the casein micelles was considerably slower than the rate of denaturation of the whey proteins. Removal of the whey proteins from the skim milk resulted in only small changes in casein micelle size during heating. Re-addition of beta-lactoglobulin to the whey-protein-depleted milk caused the casein micelle size to increase markedly on heat treatment. The changes in casein micelle size induced by the heat treatment of skim milk may be a consequence of the whey proteins associating with the casein micelles. However, these associated whey proteins would need to occlude a large amount of serum to account for the particle size changes. Separate experiments showed that the viscosity changes of heated milk and the estimated volume fraction changes were consistent with the particle size changes observed. Further studies are needed to determine whether the changes in size are due to the specific association of whey proteins with the micelles or whether a low level of aggregation of the casein micelles accompanies this association behaviour. Preliminary studies indicated lower levels of denatured whey proteins associated with the casein micelles and smaller changes in casein micelle size occurred as the pH of the milk was increased from pH 6.5 to pH 6.7.

Enzymatic- and temperature-sensitive controlled release of ultrasmall superparamagnetic iron oxides (USPIOs).

PubMed

Yu, Shann S; Scherer, Randy L; Ortega, Ryan A; Bell, Charleson S; O'Neil, Conlin P; Hubbell, Jeffrey A; Giorgio, Todd D

2011-02-27

Drug and contrast agent delivery systems that achieve controlled release in the presence of enzymatic activity are becoming increasingly important, as enzymatic activity is a hallmark of a wide array of diseases, including cancer and atherosclerosis. Here, we have synthesized clusters of ultrasmall superparamagnetic iron oxides (USPIOs) that sense enzymatic activity for applications in magnetic resonance imaging (MRI). To achieve this goal, we utilize amphiphilic poly(propylene sulfide)-bl-poly(ethylene glycol) (PPS-b-PEG) copolymers, which are known to have excellent properties for smart delivery of drug and siRNA. Monodisperse PPS polymers were synthesized by anionic ring opening polymerization of propylene sulfide, and were sequentially reacted with commercially available heterobifunctional PEG reagents and then ssDNA sequences to fashion biofunctional PPS-bl-PEG copolymers. They were then combined with hydrophobic 12 nm USPIO cores in the thin-film hydration method to produce ssDNA-displaying USPIO micelles. Micelle populations displaying complementary ssDNA sequences were mixed to induce crosslinking of the USPIO micelles. By design, these crosslinking sequences contained an EcoRV cleavage site. Treatment of the clusters with EcoRV results in a loss of R2 negative contrast in the system. Further, the USPIO clusters demonstrate temperature sensitivity as evidenced by their reversible dispersion at ~75°C and re-clustering following return to room temperature. This work demonstrates proof of concept of an enzymatically-actuatable and thermoresponsive system for dynamic biosensing applications. The platform exhibits controlled release of nanoparticles leading to changes in magnetic relaxation, enabling detection of enzymatic activity. Further, the presented functionalization scheme extends the scope of potential applications for PPS-b-PEG. Combined with previous findings using this polymer platform that demonstrate controlled drug release in oxidative environments, smart theranostic applications combining drug delivery with imaging of platform localization are within reach. The modular design of these USPIO nanoclusters enables future development of platforms for imaging and drug delivery targeted towards proteolytic activity in tumors and in advanced atherosclerotic plaques.

Responsive micellar films of amphiphilic block copolymer micelles: control on micelle opening and closing.

PubMed

Chen, Zhiquan; He, Changcheng; Li, Fengbin; Tong, Ling; Liao, Xingzhi; Wang, Yong

2010-06-01

We reported the deliberate control on the micelle opening and closing of amphiphilic polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) micellar films by exposing them to selective solvents. We first treated the micellar films with polar solvents including ethanol and water (pH = 4, 8, and 12) that have different affinities to P2VP. We observed opening of the micelles in all the cases. Both the size of opened pores and the opening rate are dependent on the solvency of different solvents for P2VP. We then explored the closing behavior of the opened micelles using solvents having different affinities to PS. We found that the opened micelles were recovered to their initial closed micelle forms. The recovery was accompanied by a slow micelle disassociation process which gradually reduced the micelle size. The rates of the micelle closing and disassociation are also dependent on the solvency of different solvents for PS.

Molecular dynamics simulation and NMR investigation of the association of the β-blockers atenolol and propranolol with a chiral molecular micelle

NASA Astrophysics Data System (ADS)

Morris, Kevin F.; Billiot, Eugene J.; Billiot, Fereshteh H.; Hoffman, Charlene B.; Gladis, Ashley A.; Lipkowitz, Kenny B.; Southerland, William M.; Fang, Yayin

2015-08-01

Molecular dynamics simulations and NMR spectroscopy were used to compare the binding of two β-blocker drugs to the chiral molecular micelle poly-(sodium undecyl-(L)-leucine-valine). The molecular micelle is used as a chiral selector in capillary electrophoresis. This study is part of a larger effort to understand the mechanism of chiral recognition in capillary electrophoresis by characterizing the molecular micelle binding of chiral compounds with different geometries and charges. Propranolol and atenolol were chosen because their structures are similar, but their chiral interactions with the molecular micelle are different. Molecular dynamics simulations showed both propranolol enantiomers inserted their aromatic rings into the molecular micelle core and that (S)-propranolol associated more strongly with the molecular micelle than (R)-propranolol. This difference was attributed to stronger molecular micelle hydrogen bonding interactions experienced by (S)-propranolol. Atenolol enantiomers were found to bind near the molecular micelle surface and to have similar molecular micelle binding free energies.

pH and redox-responsive mixed micelles for enhanced intracellular drug release.

PubMed

Cai, Mengtan; Zhu, Kun; Qiu, Yongbin; Liu, Xinrong; Chen, Yuanwei; Luo, Xianglin

2014-04-01

In order to prepare pH and redox sensitive micelles, amphiphilic copolymers of poly (epsilon-caprolactone)-b-poly(2-(diethylamino) ethyl methacrylate) (PCL-PDEA) and disulfide-linked poly(ethyl glycol)-poly(epsilon-caprolactone) (mPEG-SS-PCL) were synthesized. The double-sensitive micelles were prepared simply by solvent-evaporating method with the mixed two copolymers. The pH sensitivity of the mixed micelles was confirmed by the change of micelle diameter/diameter distribution measured by dynamic lighting scattering (DLS) and the redox sensitivity of the mixed micelles was testified by the change of micellar morphous observed by scanning electron microscope (SEM). In vitro drug release showed that drug-loaded mixed micelles (mass ratio 5:5) could achieve above 90% of drug release under low pH and reducing condition within 10h. Moreover, the drug-loaded mixed micelles (mass ratio 5:5) showed the largest cellular toxicity compared with other drug-loaded micelles, while blank mixed micelles exhibited no toxicity. These results meant that the mixed micelles composed by the two amphiphilic copolymers can enhance intracellular drug release. It is concluded that the newly developed mixed micelles can serve as a potential drug delivery system for anticancer drugs. Copyright © 2014 Elsevier B.V. All rights reserved.

Reduction-sensitive micelles self-assembled from amphiphilic chondroitin sulfate A-deoxycholic acid conjugate for triggered release of doxorubicin.

PubMed

Liu, Hongxia; Wu, Shuqin; Yu, Jingmou; Fan, Dun; Ren, Jin; Zhang, Lei; Zhao, Jianguo

2017-06-01

Reduction-sensitive chondroitin sulfate A (CSA)-based micelles were developed. CSA was conjugated with deoxycholic acid (DOCA) via a disulfide linkage. The bioreducible conjugate (CSA-ss-DOCA) can form self-assembled micelles in aqueous medium. The critical micelle concentration (CMC) of CSA-ss-DOCA conjugate is 0.047mg/mL, and its mean diameter is 387nm. The anticancer drug doxorubicin (DOX) was chosen as a model drug, and was effectively encapsulated into the micelles with high loading efficiency. Reduction-sensitive micelles and reduction-insensitive control micelles displayed similar DOX release behavior in phosphate buffered saline (PBS, pH7.4). Notably, DOX release from the reduction-sensitive micelles in vitro was accelerated in the presence of 20mM glutathione-containing PBS environment. Moreover, DOX-loaded CSA-ss-DOCA (CSA-ss-DOCA/DOX) micelles exhibited intracellular reduction-responsive characteristics in human gastric cancer HGC-27 cells determined by confocal laser scanning microscopy (CLSM). Furthermore, CSA-ss-DOCA/DOX micelles demonstrated higher antitumor efficacy than reduction-insensitive control micelles in HGC-27 cells. These results suggested that reduction-sensitive CSA-ss-DOCA micelles had the potential as intracellular targeted carriers of anticancer drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Development and evaluation of N-naphthyl-N,O-succinyl chitosan micelles containing clotrimazole for oral candidiasis treatment.

PubMed

Tonglairoum, Prasopchai; Woraphatphadung, Thisirak; Ngawhirunpat, Tanasait; Rojanarata, Theerasak; Akkaramongkolporn, Prasert; Sajomsang, Warayuth; Opanasopit, Praneet

2017-03-01

Clotrimazole (CZ)-loaded N-naphthyl-N,O-succinyl chitosan (NSCS) micelles have been developed as an alternative for oral candidiasis treatment. NSCS was synthesized by reductive N-amination and N,O-succinylation. CZ was incorporated into the micelles using various methods, including the dropping method, the dialysis method, and the O/W emulsion method. The size and morphology of the CZ-loaded micelles were characterized using dynamic light scattering measurements (DLS) and a transmission electron microscope (TEM), respectively. The drug entrapment efficiency, loading capacity, release characteristics, and antifungal activity against Candida albicans were also evaluated. The CZ-loaded micelles prepared using different methods differed in the size of micelles. The micelles ranged in size from 120 nm to 173 nm. The micelles prepared via the O/W emulsion method offered the highest percentage entrapment efficiency and loading capacity. The CZ released from the CZ-loaded micelles at much faster rate compared to CZ powder. The CZ-loaded NSCS micelles can significantly hinder the growth of Candida cells after contact. These CZ-loaded NSCS micelles offer great antifungal activity and might be further developed to be a promising candidate for oral candidiasis treatment.

Effect of counterions on the shape, hydration, and degree of order at the interface of cationic micelles: the triflate case.

PubMed

Lima, Filipe S; Cuccovia, Iolanda M; Horinek, Dominik; Amaral, Lia Q; Riske, Karin A; Schreier, Shirley; Salinas, Roberto K; Bastos, Erick L; Pires, Paulo A R; Bozelli, José Carlos; Favaro, Denize C; Rodrigues, Ana Clara B; Dias, Luís Gustavo; El Seoud, Omar A; Chaimovich, Hernan

2013-04-02

Specific ion effects in surfactant solutions affect the properties of micelles. Dodecyltrimethylammonium chloride (DTAC), bromide (DTAB), and methanesulfonate (DTAMs) micelles are typically spherical, but some organic anions can induce shape or phase transitions in DTA(+) micelles. Above a defined concentration, sodium triflate (NaTf) induces a phase separation in dodecyltrimethylammonium triflate (DTATf) micelles, a phenomenon rarely observed in cationic micelles. This unexpected behavior of the DTATf/NaTf system suggests that DTATf aggregates have unusual properties. The structural properties of DTATf micelles were analyzed by time-resolved fluorescence quenching, small-angle X-ray scattering, nuclear magnetic resonance, and electron paramagnetic resonance and compared with those of DTAC, DTAB, and DTAMs micelles. Compared to the other micelle types, the DTATf micelles had a higher average number of monomers per aggregate, an uncommon disk-like shape, smaller interfacial hydration, and restricted monomer chain mobility. Molecular dynamic simulations supported these observations. Even small water-soluble salts can profoundly affect micellar properties; our data demonstrate that the -CF3 group in Tf(-) was directly responsible for the observed shape changes by decreasing interfacial hydration and increasing the degree of order of the surfactant chains in the DTATf micelles.

Effect of hydrostatic pressure on gas solubilization in micelles.

PubMed

Meng, Bin; Ashbaugh, Henry S

2015-03-24

Molecular dynamics simulations of anionic sodium decylsulfate and nonionic pentaethylene glycol monodecyl ether micelles in water have been performed to examine the impact of hydrostatic pressure on argon solubilization as a function of pressure. The potential-of-mean force between the micelles and argon demonstrates that nonpolar gases are attracted to the interiors of both micelles. The affinity of argon for micelle interiors, however, decreases with increasing pressure as a result of the comparatively higher molar volume of argon inside assemblies. We evaluate solubility enhancement coefficients, which describe the drop in the solute chemical potential as a function of the micellized surfactant concentration, to quantify the impact of micellization on gas solubilization. While argon is similarly attracted to the hydrophobic cores of both micelles, the gas is more effectively sequestered within nonionic micelles compared with anionic micelles as a result of salting out by charged head groups and accompanying counterions. The solubility enhancement coefficients of both micelles decrease with increasing pressure, reflecting the changing forces observed in the potentials-of-mean force. An analytical liquid drop model is proposed to describe the pressure dependence of argon solubilization within micelles that captures the simulation solubility enhancement coefficients after fitting an effective micelle radius for each surfactant.

Novel micelle carriers for cyclosporin A topical ocular delivery: in vivo cornea penetration, ocular distribution and efficacy studies.

PubMed

Di Tommaso, Claudia; Bourges, Jean-Louis; Valamanesh, Fatemeh; Trubitsyn, Gregory; Torriglia, Alicia; Jeanny, Jean-Claude; Behar-Cohen, Francine; Gurny, Robert; Möller, Michael

2012-06-01

Cornea transplantation is one of the most performed graft procedures worldwide with an impressive success rate of 90%. However, for "high-risk" patients with particular ocular diseases in addition to the required surgery, the success rate is drastically reduced to 50%. In these cases, cyclosporin A (CsA) is frequently used to prevent the cornea rejection by a systemic treatment with possible systemic side effects for the patients. To overcome these problems, it is a challenge to prepare well-tolerated topical CsA formulations. Normally high amounts of oils or surfactants are needed for the solubilization of the very hydrophobic CsA. Furthermore, it is in general difficult to obtain ocular therapeutic drug levels with topical instillations due to the corneal barriers that efficiently protect the intraocular structures from foreign substances thus also from drugs. The aim of this study was to investigate in vivo the effects of a novel CsA topical aqueous formulation. This formulation was based on nanosized polymeric micelles as drug carriers. An established rat model for the prevention of cornea graft rejection after a keratoplasty procedure was used. After instillation of the novel formulation with fluorescent labeled micelles, confocal analysis of flat-mounted corneas clearly showed that the nanosized carriers were able to penetrate into all corneal layers. The efficacy of a 0.5% CsA micelle formulation was tested and compared to a physiological saline solution and to a systemic administration of CsA. In our studies, the topical CsA treatment was carried out for 14 days, and the three parameters (a) cornea transparency, (b) edema, and (c) neovascularization were evaluated by clinical observation and scoring. Compared to the control group, the treated group showed a significant higher cornea transparency and significant lower edema after 7 and 13 days of the surgery. At the end point of the study, the neovascularization was reduced by 50% in the CsA-micelle treated animals. The success rate of cornea graft transplantation was 73% in treated animals against 25% for the control group. This result was as good as observed for a systemic CsA treatment in the same animal model. This new formulation has the same efficacy like a systemic treatment but without the serious CsA systemic side effects. Ocular drug levels of transplanted and healthy rat eyes were dosed by UPLC/MS and showed a high CsA value in the cornea (11710 ± 7530 ng(CsA)/g(tissue) and 6470 ± 1730 ng(CsA)/g(tissue), respectively). In conclusion, the applied formulation has the capacity to overcome the ocular surface barriers, the micelles formed a drug reservoir in the cornea from, where a sustained release of CsA can take place. This novel formulation for topical application of CsA is clearly an effective and well-tolerated alternative to the systemic treatment for the prevention of corneal graft rejection. Copyright © 2012 Elsevier B.V. All rights reserved.

Glycopolymer micelles with reducible ionic cores for hepatocytes-targeting delivery of DOX.

PubMed

Wang, Yanxia; Zhang, Xinge; Yu, Peien; Li, Chaoxing

2013-01-30

A novel galactose-decorated cross-linked micelles (cl-micelles) with ionic cores using cystamine (Cys) as a biodegradable cross-linker was prepared by using block ionomer complexes of poly(ethylene glycol)-b-poly(2-acryloxyethyl-galactose)-b-poly(acrylic acid) (PEG-b-PAEG-b-PAA) and Ca(2+) (PEG-b-PAEG-b-PAA cl-micelles/Cys). Doxorubicin (DOX) was successfully incorporated into the ionic cores of such micelles via electrostatic interactions. Proton nuclear magnetic resonance spectrum and Fourier transform infrared spectrometer indicated galactose ligands were exposed at the micellar surface. The micelles were spherical in shape, with an average size of 100nm. The in vitro release studies confirmed that DOX-loaded PEG-b-PAEG-b-PAA cl-micelles/Cys accomplished rapid drug release under reducing condition. Remarkably, PEG-b-PAEG-b-PAA cl-micelles/Cys efficiently delivered and released DOX into the cell nucleus of HepG2 cells, and the intensity of fluorescence observed in HepG2 cells was stronger than that incubated with the micelles without galactose ligands. In contrast, little fluorescence was observed in NIH3T3 cells after incubation with PEG-b-PAEG-b-PAA cl-micelles/Cys. Interestingly, cytotoxicity assays showed that DOX-loaded PEG-b-PAEG-b-PAA cl-micelles/Cys retained higher cell inhibition efficiency in HepG2 cells as compared with NIH3T3 cells, and were more potent than the micelles without galactose ligands and the micelles with non degradable cross-links. These results indicate that PEG-b-PAEG-b-PAA cl-micelles/Cys have great potential in liver tumor-targeted chemotherapy. Copyright © 2012 Elsevier B.V. All rights reserved.

Biodegradable self-assembled PEG-PCL-PEG micelles for hydrophobic honokiol delivery: I. Preparation and characterization

NASA Astrophysics Data System (ADS)

Gong, ChangYang; Wei, XiaWei; Wang, XiuHong; Wang, YuJun; Guo, Gang; Mao, YongQiu; Luo, Feng; Qian, ZhiYong

2010-05-01

This study aims to develop self-assembled poly(ethylene glycol)-poly(ɛ-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) micelles to encapsulate hydrophobic honokiol (HK) in order to overcome its poor water solubility and to meet the requirement of intravenous administration. Honokiol loaded micelles (HK-micelles) were prepared by self-assembly of PECE copolymer in aqueous solution, triggered by its amphiphilic characteristic assisted by ultrasonication without any organic solvents, surfactants and vigorous stirring. The particle size of the prepared HK-micelles measured by Malvern laser particle size analyzer were 58 nm, which is small enough to be a candidate for an intravenous drug delivery system. Furthermore, the HK-micelles could be lyophilized into powder without any adjuvant, and the re-dissolved HK-micelles are stable and homogeneous with particle size about 61 nm. Furthermore, the in vitro release profile showed a significant difference between the rapid release of free HK and the much slower and sustained release of HK-micelles. Moreover, the cytotoxicity results of blank micelles and HK-micelles showed that the PECE micelle was a safe carrier and the encapsulated HK retained its potent antitumor effect. In short, the HK-micelles were successfully prepared by an improved method and might be promising carriers for intravenous delivery of HK in cancer chemotherapy, being effective, stable, safe (organic solvent and surfactant free), and easy to produce and scale up.

Preparation and in vivo/in vitro evaluation of formononetin phospholipid/vitamin E TPGS micelles.

PubMed

Cheng, Xudong; Yan, Hongmei; Jia, Xiaobin; Zhang, Zhenhai

2016-01-01

To enhance the formononetin (FN) antitumor effect, we developed a passive targeting FN-contained formulation. FN-contained Vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS or TPGS)/phospholipid micelles were prepared by the solvent injection method. Particle size, polydispersity, zeta potential, encapsulation efficiency, drug release profile, and micelles morphology were evaluated and characterized by various methods including high-performance liquid chromatography, dynamic light scattering, and transmission electron microscopy. Cellular uptake of micelles was evaluated with fluorescence imaging coupled with HPLC method. Cytotoxicity of FN micelles and free FN was compared using MTT method. In vivo imaging was employed to assess the accumulation of DiR micelles and free DiR at tumor site. The antitumor effect of FN micelles was examined in tumor-bearing mice. The results showed that prepared FN micelles had an average particle diameter of 111.91 ± 5.82 nm with good stability. FN micelles enhanced the cellular uptake and improved cell cytotoxicity than free FN. Furthermore, DiR micelles quickly accumulated at the tumor site than free DiR. FN micelles significantly improved tumor inhibition rate compared to that observed with free FN in tumor-bearing mice with great biosafety. Thus, FN micelles demonstrated a clear treatment advantage and provided an ideal drug administration system to improve the antitumor effect of FN.

Secondary structure and dynamics study of the intrinsically disordered silica-mineralizing peptide P 5 S 3 during silicic acid condensation and silica decondensation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zerfaß, Christian; Buchko, Garry W.; Shaw, Wendy J.

The silica forming repeat R5 of sil1 from Cylindrotheca fusiformis was the blueprint for the design of P5S3, a 50-residue peptide which can be produced in large amounts by recombinant bacterial expression. It contains five protein kinase A target sites and is highly cationic due to 10 lysine and 10 arginine residues. In the presence of supersaturated ortho silicic acid P5S3 strongly enhances silica-formation whereas it retards the dissolution of amorphous silica (SiO2) at globally undersaturated concentrations. The secondary structure of P5S3 during these different functions was studied by circular dichroism (CD), complemented by nuclear magnetic resonance (NMR) studies ofmore » the peptide in the absence of silicate. The NMR studies of dual-labeled (13C, 15N) P5S3 revealed a disordered structure at pH 2.8 and 4.5. Within the pH range of 4.5 to 9.5, the CD data verified the disordered secondary structure but also suggested the presence of some polyproline II character in the absence of silicic acid. Upon silicic acid polymerization and during dissolution of preformed silica, the CD spectrum of P5S3 indicated partial transition into an α-helical conformation which was transient during silica-dissolution. Consequently, the secondary structural changes observed for P5S3 correlate with the presence of oli-gomeric/polymeric silicic acid, presumably due to P5S3-silicic acid interactions. These interactions appear, at least in part, ionic in nature since dodecylsulfate micelles, which are negatively charged, cause similar conformational shifts to P5S3 in the absence of silica while ß-D-dodecyl maltoside micelles, which are neutral, do not. Thus, P5S3 influences both the condensation of silicic acid into silica and its decondensation back to silicic acid. Moreover, the dynamics of these pro-cesses may be indirectly monitored by following structural changes to P5S3 with CD spectroscopy.« less

The effect of varying the introduction mode of reactants on electrical, physical and thermal stability properties of polypyrrole synthesized with CTAB

NASA Astrophysics Data System (ADS)

Vahidi, K.; Jalili, Y. Seyed; Salar Elahi, A.

2017-10-01

Electrical and physical properties of conducting polymers are generally enhanced via modifications in the chemical structure of the final product, there appears to be a void in facile physical means to improve the materials' properties without utilizing additives which remain in the final product as impurity. In this research, we presented the effect of altering the introduction method of reactants in emulsion polymerization of PPy with CTAB on the electrical, physical and stability properties of the final product. Three samples were prepared: one via a conventional non-emulsion polymerization method as a reference sample, the second in which the reactants were added simultaneously and the goal sample in which the monomer/surfactant mixture was allowed to be stirred separately then it was added dropwise to the oxidant solution. UV-vis, FTIR, 4-point Van Derr Paw probe, FESEM and contact angle measurements were used to investigate optical, electrical, physical, heat stability and solubility properties of the samples. The results indicate that since in the final sample a higher portion of the reaction occurred on the hydrophobic interior of the micelles, the final material had a lower number of structural and chemical defects which leads to higher conjugation lengths and thus higher properties such as a 9-fold difference in conductivity and improved solubility and thermal stability. The novelty of this work lies in the simplicity of the alterations that have been made, both in terms of optimization of the synthetic route which had been thoroughly investigated and also in terms of the differences that our work poses compared to that of the others; namely: the parameters have been thoroughly studied and analyzed but not the method of addition as in our experiments the sequence of addition and the method of addition of the reactants were altered to observe their effect on the physical and the electronic properties which has led to the conclusion that in case of drop-wise addition, a larger portion of the reaction occurs inside the micelles hence giving rise to inhibition of the defect-producing chemical bonds which is supported by the analysis in our investigations.

Influence of succinylation on the conformation of yak casein micelles.

PubMed

Yang, Min; Cui, Na; Fang, Yan; Shi, Ying; Yang, Jitao; Wang, Jiangyu

2015-07-15

Succinylation modifies the physicochemical characteristics and improves the functional properties of proteins. This study assessed the effects of succinylation on the conformation of yak casein micelles with seven degree of modification. The results revealed that succinylation contributed to the dissociation of casein micelles. With the increase of succinylated degree, soluble nitrogen and minerals content increased, while casein micelle size and polydispersity index of micelles decreased. Succinylation affected the spatial conformation of yak casein micelles: turn decreased, ß-sheet and α-helix increased, and irregular structure were non-significantly affected. The intrinsic and ANS fluorescence intensity decreased and the maximum emission wavelength shifted red with increasing succinylation. Based on the results, the structure of yak casein micelles was characteristic of the sub-micelle model. Copyright © 2015 Elsevier Ltd. All rights reserved.

Thermoresponsive complex amphiphilic block copolymer micelles investigated by laser light scattering.

PubMed

Zhao, Fang; Xie, Dinghai; Zhang, Guangzhao; Pispas, Stergios

2008-05-22

Poly(isoprene)-block-poly(ethylene oxide) (PI-b-PEO) diblock copolymers form micelles in water. The introduction of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (PEO-b-PPO-b-PEO) triblock copolymer leads to the formation of mixed micelles through hydrophobic interaction. The dimension of the mixed micelles varies with the weight ratio (r) of PEO-b-PPO-b-PEO to PI-b-PEO. By use of laser light scattering, we have investigated the temperature dependence of the structural evolution of the micelles at different r. At r<10, the size of the mixed micelles decreases with temperature. At r>10, due to the excessive PEO-b-PPO-b-PEO chains in solution, as temperature increases, the mixed micelles aggregate into larger micelle clusters.

Thermodynamics of micelle formation in a water-alcohol solution of sodium tetradecyl sulfate

NASA Astrophysics Data System (ADS)

Shilova, S. V.; Tret'yakova, A. Ya.; Barabanov, V. P.

2016-01-01

The effects of addition of ethanol and propan-1-ol on sodium tetradecyl sulfate micelle formation in an aqueous solution are studied via microprobe fluorescence microscopy and conductometry. The critical micelle concentration, quantitative characteristics of micelles, and thermodynamic parameters of micelle formation are determined. Addition of 5-15 vol % of ethanol or 5-10 vol % of propan-1-ol is shown to result in a lower critical micelle concentration than in the aqueous solution, and in the formation of mixed spherical micelles whose sizes and aggregation numbers are less than those for the systems without alcohol. The contribution from the enthalpy factor to the free energy of sodium tetradecyl sulfate micelle formation is found to dominate in mixed solvents, in contrast to aqueous solutions.

Rennet-induced coagulation properties of yak casein micelles: A comparison with cow casein micelles.

PubMed

Zhang, Yan; Li, Yuan; Wang, Pengjie; Tian, Yanbao; Liang, Qi; Ren, Fazheng

2017-12-01

It is essential for yak cheese processing to understand the rennet-induced coagulation properties of gel formation from casein micelles. We have previously discovered that yak milk requires a longer incubation time but forms stronger gels compared with cow milk. In this study, we are aiming to understand the rennet-induced coagulation properties of yak casein micelles comparing with cow casein micelles. Rheological analyses revealed that the gelling times of yak and cow casein micelles were 11.6±0.5 and 8.7±0.4min (P<0.05) respectively, but yak casein gel had a higher elastic modulus G' (6.5±0.2Pa) than cow casein gel (2.5±0.2Pa; P<0.05). This is consistent with the results obtained by micro-rheology. Confocal laser scanning microscopic images (CLSM) and cryo-scanning electron microscopic images (cryo-SEM) showed that yak casein gel was more homogeneous and had smaller pore size than cow casein gels. Yak casein micelles had higher calcium (26.00mM), phosphate (19.90mM) and β-casein (relative 32%) concentrations. In addition, yak casein micelles were larger (Z-average 218.6nm) than cow casein micelles, and contained lower κ-casein (relative 13%). By comparison with cow casein micelles, yak casein micelle composition corresponding to their micellar calcium phosphate and κ-casein content may greatly contribute to the longer coagulation time and denser gel structure. An initial slower caseinomacropeptide (CMP) release rate and the slower rate of aggregation between para-casein micelles contributed to a more homogeneous yak gel network. Higher colloidal calcium phosphate is crucial for yak casein micelle aggregation and gel firmness because sufficient colloidal calcium phosphates can firmly glue sub-micelles and links casein micelles. This study provides valuable information for yak cheese production. Copyright © 2017. Published by Elsevier Ltd.

Casein polymorphism heterogeneity influences casein micelle size in milk of individual cows.

PubMed

Day, L; Williams, R P W; Otter, D; Augustin, M A

2015-06-01

Milk samples from individual cows producing small (148-155 nm) or large (177-222 nm) casein micelles were selected to investigate the relationship between the individual casein proteins, specifically κ- and β-casein phenotypes, and casein micelle size. Only κ-casein AA and β-casein A1A1, A1A2 and A2A2 phenotypes were found in the large casein micelle group. Among the small micelle group, both κ-casein and β-casein phenotypes were more diverse. κ-Casein AB was the dominant phenotype, and 3 combinations (AA, AB, and BB) were present in the small casein micelle group. A considerable mix of β-casein phenotypes was found, including B and I variants, which were only found in the small casein micelle group. The relative amount of κ-casein to total casein was significantly higher in the small micelle group, and the nonglycosylated and glycosylated κ-casein contents were higher in the milks with small casein micelles (primarily with κ-casein AB and BB variants) compared with the large micelle group. The ratio of glycosylated to nonglycosylated κ-casein was higher in the milks with small casein micelles compared with the milks with large casein micelles. This suggests that although the amount of κ-casein (both glycosylated and nonglycosylated) is associated with micelle size, an increased proportion of glycosylated κ-casein could be a more important and favorable factor for small micelle size. This suggests that the increased spatial requirement due to addition of the glycosyl group with increasing extent of glycosylation of κ-casein is one mechanism that controls casein micelle assembly and growth. In addition, increased electrostatic repulsion due to the sialyl residues on the glycosyl group could be a contributory factor. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

The fabrication of nanopatterns with Au nanoparticles-embedded micelles via nanoimprint lithography.

PubMed

Lee, Jung-Pil; Kim, Eun-Uk; Koh, Haeng-Deog; Kang, Nam-Goo; Jung, Gun-Young; Lee, Jae-Suk

2009-09-09

We fabricated nanopatterns with Au nanoparticles-embedded micelles (Au-micelles) by self-assembly of block copolymers via nanoimprint lithography. The micelle structure prepared by self-assembled block copolymers was used as a template for the synthesis of Au nanoparticles (Au NPs). Au NPs were synthesized in situ inside the micelles of polystyrene-block-poly(2-vinylpyridine) (PS- b-P2VP). Au-micelles were arranged on the trenches of the polymer template, which was imprinted by nanoimprint lithography. The fabrication of line-type and dot-type nanopatterns was carried out by the combined method. In addition, multilayer nanopatterns of the Au-micelles were also proposed.

Calculations of critical micelle concentration by dissipative particle dynamics simulations: the role of chain rigidity.

PubMed

Lee, Ming-Tsung; Vishnyakov, Aleksey; Neimark, Alexander V

2013-09-05

Micelle formation in surfactant solutions is a self-assembly process governed by complex interplay of solvent-mediated interactions between hydrophilic and hydrophobic groups, which are commonly called heads and tails. However, the head-tail repulsion is not the only factor affecting the micelle formation. For the first time, we present a systematic study of the effect of chain rigidity on critical micelle concentration and micelle size, which is performed with the dissipative particle dynamics simulation method. Rigidity of the coarse-grained surfactant molecule was controlled by the harmonic bonds set between the second-neighbor beads. Compared to flexible molecules with the nearest-neighbor bonds being the only type of bonded interactions, rigid molecules exhibited a lower critical micelle concentration and formed larger and better-defined micelles. By varying the strength of head-tail repulsion and the chain rigidity, we constructed two-dimensional diagrams presenting how the critical micelle concentration and aggregation number depend on these parameters. We found that the solutions of flexible and rigid molecules that exhibited approximately the same critical micelle concentration could differ substantially in the micelle size and shape depending on the chain rigidity. With the increase of surfactant concentration, primary micelles of more rigid molecules were found less keen to agglomeration and formation of nonspherical aggregates characteristic of flexible molecules.

Interaction of lactoferrin and lysozyme with casein micelles.

PubMed

Anema, Skelte G; de Kruif, C G Kees

2011-11-14

On addition of lactoferrin (LF) to skim milk, the turbidity decreases. The basic protein binds to the caseins in the casein micelles, which is then followed by a (partial) disintegration of the casein micelles. The amount of LF initially binding to casein micelles follows a Langmuir adsorption isotherm. The kinetics of the binding of LF could be described by first-order kinetics and similarly the disintegration kinetics. The disintegration was, however, about 10 times slower than the initial adsorption, which allowed investigating both phenomena. Kinetic data were also obtained from turbidity measurements, and all data could be described with one equation. The disintegration of the casein micelles was further characterized by an activation energy of 52 kJ/mol. The initial increase in hydrodynamic size of the casein micelles could be accounted for by assuming that it would go as the cube root of the mass using the adsorption and disintegration kinetics as determined from gel electrophoresis. The results show that LF binds to casein micelles and that subsequently the casein micelles partly disintegrate. All micelles behave in a similar manner as average particle size decreases. Lysozyme also bound to the casein micelles, and this binding followed a Langmuir adsorption isotherm. However, lysozyme did not cause the disintegration of the casein micelles.

Enhancement of bioavailability by formulating rhEPO ionic complex with lysine into PEG-PLA micelle

NASA Astrophysics Data System (ADS)

Shi, Yanan; Sun, Fengying; Wang, Dan; Zhang, Renyu; Dou, Changlin; Liu, Wanhui; Sun, Kaoxiang; Li, Youxin

2013-10-01

A composite micelle of ionic complex encapsulated into poly(ethylene glycol)-poly( d, l-lactide) (PEG-PLA) di-block copolymeric micelles was used for protein drug delivery to improve its pharmacokinetic performance. In this study, recombinant human erythropoietin (rhEPO, as a model protein) was formulated with lysine into composite micelles at a diameter of 71.5 nm with narrow polydispersity indices (PDIs < 0.3). Only a trace amount of protein was in aggregate form. The zeta potential of the spherical micelles was ranging from -0.54 to 1.39 mv, and encapsulation efficiency is high (80 %). The stability of rhEPO was improved significantly in composite micelles in vitro. Pharmacokinetic studies in rats showed significant, enhanced plasma retention of the composite micelles in comparison with native rhEPO. Areas under curve (AUCs) of the rhEPO released from the composite micelles were 4.5- and 2.3-folds higher than those of the native rhEPO and rhEPO-loaded PEG-PLA micelle, respectively. In addition, the composite micelles exhibited good biocompatibility using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay with human embryonic kidney (HEK293T) cells. All these features are preferable for utilizing the composite micelles as a novel protein delivery system.

Mesoscale crystallization of calcium phosphate nanostructures in protein (casein) micelles.

PubMed

Thachepan, Surachai; Li, Mei; Mann, Stephen

2010-11-01

Aqueous micelles of the multi-protein calcium phosphate complex, casein, were treated at 60°C and pH 7 over several months. Although partial dissociation of the micelles into 12 nm sized amorphous calcium phosphate (ACP)/protein nanoparticles occurred within a period of 14 days, crystallization of the ACP nanoclusters into bundles of hydroxyapatite (HAP) nanofilaments was not observed until after 12 weeks. The HAP nanofilaments were formed specifically within the partially disrupted protein micelles suggesting a micelle-mediated pathway of mesoscale crystallization. Similar experiments using ACP-containing synthetic micelles prepared from ß-casein protein alone indicated that co-aligned bundles of HAP nanofilaments were produced within the protein micelle interior after 24 hours at temperatures as low as 35°C. The presence of Mg²(+) ions in the casein micelles, as well as a possible synergistic effect associated with the multi-protein nature of the native aggregates, could account for the marked inhibition in mesoscale crystallization observed in the casein micelles compared with the single-component b-casein constructs.

Modular Design Features of a Peptide Amphiphile Micelle Vaccine Platform and Their Impact on an Immune Response

NASA Astrophysics Data System (ADS)

Barrett, John Christopher

Inducing a strong and specific immune response is the hallmark of a successful vaccine. Nanoparticles have emerged as promising vaccine delivery devices to discover and elicit immune responses. Modular platforms are attractive for their engineerability and broad potential applications. Fine-tuning a nanoparticle vaccine to create an immune response with specific antibody and other cellular responses is influenced by many factors such as shape, size and composition. Peptide amphiphile micelles are a unique biomaterials platform that can function as a modular vaccine delivery system, enabling control over many of these important factors. Peptide amphiphiles (PAs) consist of a hydrophilic peptide antigen conjugated to a hydrophobic lipid tail. The PAs then self-assemble into micelles, with the micelle characteristics determined by the chemical composition of the PA and micelle preparation methods. PA micelles contain a large design space, so it is important to have a basic understanding of how each design feature can affect the platform's interaction with the immune system. In this dissertation, the structure, composition, and biodistribution properties of PA micelles are evaluated for their ability to impact an immune response against a Group A Streptococcus B cell antigen (J8). Through structural design and physical characterization, micelles are shown to self-assemble into either short rod-like or long cylindrical shapes. Analyzing these shape effects on the immune response showed that cylindrical micelles induced higher antibody titers than rod-like micelles, providing evidence that the cylindrical micelle shape is important to induce immune responses and a possible mechanism of action. Shape was also seen to impact the activation profile of dendritic cells, B cells and T cells. Assembly into cylindrical micelles also stabilizes the secondary structure of peptide antigens, which may impact the immune response raised. In composition, the hydrophobic/hydrophilic interface of PA micelles enabled the precise entrapment of amphiphilic adjuvants which were found to not alter micelle formation or shape. These heterogeneous micelles significantly enhanced murine antibody responses when compared to animals vaccinated with non-adjuvanted micelles or soluble J8 peptide supplemented with a classical adjuvant. PAs were also shown to traffic more efficiently to the lymph node than free peptide. Characterization of these design features and their impact on an immune response provides a valuable foundation of knowledge to apply when expanding the peptide amphiphile micelle platform to other vaccine applications.

Mesoscale crystallization of calcium phosphate nanostructures in protein (casein) micelles

NASA Astrophysics Data System (ADS)

Thachepan, Surachai; Li, Mei; Mann, Stephen

2010-11-01

Aqueous micelles of the multi-protein calcium phosphate complex, casein, were treated at 60 °C and pH 7 over several months. Although partial dissociation of the micelles into 12 nm sized amorphous calcium phosphate (ACP)/protein nanoparticles occurred within a period of 14 days, crystallization of the ACP nanoclusters into bundles of hydroxyapatite (HAP) nanofilaments was not observed until after 12 weeks. The HAP nanofilaments were formed specifically within the partially disrupted protein micelles suggesting a micelle-mediated pathway of mesoscale crystallization. Similar experiments using ACP-containing synthetic micelles prepared from β-casein protein alone indicated that co-aligned bundles of HAP nanofilaments were produced within the protein micelle interior after 24 hours at temperatures as low as 35 °C. The presence of Mg2+ ions in the casein micelles, as well as a possible synergistic effect associated with the multi-protein nature of the native aggregates, could account for the marked inhibition in mesoscale crystallization observed in the casein micelles compared with the single-component β-casein constructs.Aqueous micelles of the multi-protein calcium phosphate complex, casein, were treated at 60 °C and pH 7 over several months. Although partial dissociation of the micelles into 12 nm sized amorphous calcium phosphate (ACP)/protein nanoparticles occurred within a period of 14 days, crystallization of the ACP nanoclusters into bundles of hydroxyapatite (HAP) nanofilaments was not observed until after 12 weeks. The HAP nanofilaments were formed specifically within the partially disrupted protein micelles suggesting a micelle-mediated pathway of mesoscale crystallization. Similar experiments using ACP-containing synthetic micelles prepared from β-casein protein alone indicated that co-aligned bundles of HAP nanofilaments were produced within the protein micelle interior after 24 hours at temperatures as low as 35 °C. The presence of Mg2+ ions in the casein micelles, as well as a possible synergistic effect associated with the multi-protein nature of the native aggregates, could account for the marked inhibition in mesoscale crystallization observed in the casein micelles compared with the single-component β-casein constructs. Electronic supplementary information (ESI) available: Particle size histograms, TEM, EDX and electron diffraction data. See DOI: 10.1039/c0nr00158a

Enhanced transmucosal delivery of itraconazole by thiolated d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate micelles for the treatment of Candida albicans.

PubMed

Suksiriworapong, Jiraphong; Mingkwan, Thawanrat; Chantasart, Doungdaw

2017-11-01

This study aimed to investigate the transmucosal delivery of itraconazole (ITZ) by thiolated d-ɑ-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS-Cys) micelles. TPGS-Cys polymer was successfully synthesized by the simple coupling between carboxyl-activated TPGS and Cys as confirmed by NMR and FTIR techniques. Afterwards, the TPGS/TPGS-Cys micelles were prepared using the blend of TPGS and TPGS-Cys at 10:0, 7:3, 5:5, 3:7 and 0:10mass ratios. All micelles had the size ranged from 8 to 10nm with narrow size distribution and showed spherical in shape. The surface of the 10:0 TPGS micelles exhibited negatively charge while, the TPGS-Cys micelles demonstrated the slightly positive surface charge. The critical micelle concentration, loading capacity and release profiles of TPGS/TPGS-Cys micelles were comparable to the TPGS micelles. The release of ITZ from all micelles was biphasic and sustained in simulated saliva fluid over 48h. The 3:7 and 0:10 TPGS/TPGS-Cys micelles had a good mucoadhesive property. Meanwhile, only 0:10 TPGS/TPGS-Cys micelles enhanced the permeability through buccal mucosa and potentiated the antifungal activity of ITZ against Candida albicans by at least 1.35 folds as compared to ITZ alone. Therefore, this formulation can be further developed for the transmucosal delivery of ITZ for the treatment of C. albicans. Copyright © 2017 Elsevier B.V. All rights reserved.

Spray-dried casein-based micelles as a vehicle for solubilization and controlled delivery of flutamide: formulation, characterization, and in vivo pharmacokinetics.

PubMed

Elzoghby, Ahmed O; Helmy, Maged W; Samy, Wael M; Elgindy, Nazik A

2013-08-01

Novel casein (CAS)-based micelles loaded with the poorly soluble anti-cancer drug, flutamide (FLT), were successfully developed in a powdered form via spray-drying technique. Genipin (GNP) was used to crosslink CAS micelles as demonstrated by color variation of the micelles. Drug solubilization was enhanced by incorporation within the hydrophobic micellar core which was confirmed by solubility study and UV spectra. Spherical core-shell micelles were obtained with a particle size below 100 nm and zeta potential around -30 mV. At low drug loading, FLT was totally incorporated within micellar core as revealed by thermal analysis. However, at higher loading, excess non-incorporated drug at micelle surface caused a significant reduction in the surface charge density. Turbidity measurements demonstrated the high physical stability of micelles for 2 weeks dependent on GNP-crosslinking degree. In a dry powdered form, the micelles were stable for 6 months with no significant changes in drug content or particle size. A sustained drug release from CAS micelles up to 5 days was observed. After i.v. administration into rats, CAS micelles exhibited a prolonged plasma circulation of FLT compared to drug solution. Furthermore, a more prolonged drug systemic circulation was observed for GNP-crosslinked micelles. Overall, this study reports the application of spray-dried natural protein-based micelles for i.v. delivery of hydrophobic anti-cancer drugs such as FLT. Copyright © 2013 Elsevier B.V. All rights reserved.

Structure formation in binary mixtures of surfactants: vesicle opening-up to bicelles and octopus-like micelles

NASA Astrophysics Data System (ADS)

Noguchi, Hiroshi

Micelle formation in binary mixtures of surfactants is studied using a coarse-grained molecular simulation. When a vesicle composed of lipid and detergent types of molecules is ruptured, a disk-shaped micelle, the bicelle, is typically formed. It is found that cup-shaped vesicles and bicelles connected with worm-like micelles are also formed depending on the surfactant ratio and critical micelle concentration. The obtained octopus shape of micelles agree with those observed in the cryo-TEM images reported in [S. Jain and F. S. Bates, Macromol. 37, 1511 (2004).]. Two types of connection structures between the worm-like micelles and the bicelles are revealed.

Loading and release mechanisms of a biocide in polystyrene-block-poly(acrylic acid) block copolymer micelles.

PubMed

Vyhnalkova, Renata; Eisenberg, Adi; van de Ven, Theo G M

2008-07-24

The kinetics of loading of polystyrene197-block-poly(acrylic acid)47 (PS197-b-PAA47) micelles, suspended in water, with thiocyanomethylthiobenzothiazole biocide and its subsequent release were investigated. Loading of the micelles was found to be a two-step process. First, the surface of the PS core of the micelles is saturated with biocide, with a rate determined by the transfer of solid biocide to micelles during transient micelle-biocide contacts. Next, the biocide penetrates as a front into the micelles, lowering the Tg in the process (non-Fickian case II diffusion). The slow rate of release is governed by the height of the energy barrier that a biocide molecule must overcome to pass from PS into water, resulting in a uniform biocide concentration within the micelle, until Tg is increased to the point that diffusion inside the micelles becomes very slow. Maximum loading of biocide into micelles is approximately 30% (w/w) and is achieved in 1 h. From partition experiments, it can be concluded that the biocide has a similar preference for polystyrene as for ethylbenzene over water, implying that the maximum loading is governed by thermodynamics.

The influence of polarity of additive molecules on micelle structures of polystyrene-block-poly(4-vinylpyridine) in the fabrication of nano-porous templates.

PubMed

Chua, Kee Sze; Koh, Ai Peng; Lam, Yeng Ming

2010-11-01

Block copolymers are useful for in situ synthesis of nanoparticles as well as producing nanoporous templates. As such, the effects of precursors on the block copolymer micelle structure is important. In this study, we investigate the effects of polarity of molecules introduced into block copolymer micelle cores on the micelle structure. The molecular dipole moment of the additive molecules has been evaluated and their effects on the block copolymer micelles investigated using light scattering spectroscopy, small-angle X-ray scattering, transmission electron microscopy and atomic force microscopy. The molecule with the largest dipole moment resulted in spherical structures with a polydispersity of less than 0.06 in a fully translational diffusion system. Surprisingly, the less polar additive molecules produced elongated micelles and the aspect ratio increases with decreasing polarity. The change in structure from spherical to elongated structure was attributed to P4VP chain extension, where compounds with polarity most similar to P4VP induce the most chain extension. The second virial coefficients of the solutions with elongated micelles are lower than that for spherical micelle systems by up to one order in magnitude, indicating a strong tendency for micelles to coalesce. On rinsing the spin-cast films, pores were obtained from spherical micelles and ridges from elongated micelles, suggesting a viable alternative for morphology modification using mild conditions where external annealing treatments to the film are not preferred. The knowledge of polarity effects of additive molecules on micelle structure has wider implications for supramolecular block copolymer systems where, depending on the application requirements, changes to the shape of the micelle structure can be induced or avoided. Copyright 2010 Elsevier Inc. All rights reserved.

The use of polyion complex micelles to enhance the oral delivery of salmon calcitonin and transport mechanism across the intestinal epithelial barrier.

PubMed

Li, Na; Li, Xin-Ru; Zhou, Yan-Xia; Li, Wen-Jing; Zhao, Yong; Ma, Shu-Jin; Li, Jin-Wen; Gao, Ya-Jie; Liu, Yan; Wang, Xing-Lin; Yin, Dong-Dong

2012-12-01

The objective of the present study was to demonstrate the effect of polyanionic copolymer mPEG-grafted-alginic acid (mPEG-g-AA)-based polyion complex (PIC) micelles on enhancing the oral absorption of salmon calcitonin (sCT) in vivo and in vitro and identify the transepithelial transport mechanism of PIC micelles across the intestinal barrier. mPEG-g-AA was first successfully synthesized and characterized in cytotoxicity. The PIC micelles were approximately of 72 nm in diameter with a narrow distribution. The extremely significant enhancement of hypocalcemia efficacy of sCT-loaded PIC micelles in rats was evidenced by intraduodenal administration in comparison with sCT solution. The presence of mPEG-grafted-chitosan in PIC micelles had no favorable effect on this action in the referred content. In the Caco-2 transport studies, PIC micelles could significantly increase the permeability of sCT across Caco-2 monolayers without significantly affecting transepithelial electrical resistance values during the transport study. No evident alterations in the F-actin cytoskeleton were detected by confocal microscope observation following treatment of the cell monolayers with PIC micelles, which further certified the incapacity of PIC micelles to open the intercellular tight junctions. In addition, TEM observations showed that the intact PIC micelles were transported across the everted gut sac. These suggested that the transport of PIC micelles across Caco-2 cell monolayers involve a predominant transcytosis mechanism via endocytosis rather than paracellular pathway. Furthermore, PIC micelles were localized in both the cytoplasm and the nuclei observed by CLSM. Therefore, PIC micelles might be a potentially applicable tool for enhancing the oral absorption of cationic peptide and protein drugs. Copyright © 2012 Elsevier Ltd. All rights reserved.

Lecithin in mixed micelles attenuates the cytotoxicity of bile salts in Caco-2 cells.

PubMed

Tan, Ya'nan; Qi, Jianping; Lu, Yi; Hu, Fuqiang; Yin, Zongning; Wu, Wei

2013-03-01

This study was designed to investigate the cytotoxicity of bile salt-lecithin mixed micelles on the Caco-2 cell model. Cell viability and proliferation after mixed micelles treatments were evaluated with the MTT assay, and the integrity of Caco-2 cell monolayer was determined by quantitating the transepithelial electrical resistance and the flux of tracer, FITC-dextran 4400. The apoptosis induced by mixed micelles treatments was investigated with the annexin V/PI protocol. The particle size of mixed micelles was all smaller than 100 nm. The mixed micelles with lower than 0.2mM sodium deoxycholate (SDC) had no significant effects on cell viability and proliferation. When the level of SDC was higher than 0.4mM and the lecithin/SDC ratio was lower than 2:1, the mixed micelles caused significant changes in cell viability and proliferation. Furthermore, the mixed micelles affected tight junctions in a composition-dependent manner. Specifically, the tight junctions were transiently opened rather than damaged by the mixed micelles with SDC of between 0.2 and 0.6mM. The mixed micelles with more lecithin also induced less apoptosis. These results demonstrate that relatively higher concentrations of mixed micelles are toxic to Caco-2 cells, while phospholipids can attenuate the toxicity of the bile salts. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

Structural changes in block copolymer micelles induced by cosolvent mixtures†

PubMed Central

Kelley, Elizabeth G.; Smart, Thomas P.; Jackson, Andrew J.; Sullivan, Millicent O.

2013-01-01

We investigated the influence of tetrahydrofuran (THF) addition on the structure of poly(1,2-butadiene-b-ethylene oxide) [PB-PEO] micelles in aqueous solution. Our studies showed that while the micelles remained starlike, the micelle core-corona interfacial tension and micelle size decreased upon THF addition. The detailed effects of the reduction in interfacial tension were probed using contrast variations in small angle neutron scattering (SANS) experiments. At low THF contents (high interfacial tensions), the SANS data were fit to a micelle form factor that incorporated a radial density distribution of corona chains to account for the starlike micelle profile. However, at higher THF contents (low interfacial tensions), the presence of free chains in solution affected the scattering at high q and required the implementation of a linear combination of micelle and Gaussian coil form factors. These SANS data fits indicated that the reduction in interfacial tension led to broadening of the core-corona interface, which increased the PB chain solvent accessibility at intermediate THF solvent fractions. We also noted that the micelle cores swelled with increasing THF addition, suggesting that previous assumptions of the micelle core solvent content in cosolvent mixtures may not be accurate. Control over the size, corona thickness, and extent of solvent accessible PB in these micelles can be a powerful tool in the development of targeting delivery vehicles. PMID:24282441

Structural changes in block copolymer micelles induced by cosolvent mixtures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kelley, Elizabeth G.; Smart, Thomas P.; Jackson, Andrew J.

2012-11-26

We investigated the influence of tetrahydrofuran (THF) addition on the structure of poly(1,2-butadiene-b-ethylene oxide) [PB-PEO] micelles in aqueous solution. Our studies showed that while the micelles remained starlike, the micelle core-corona interfacial tension and micelle size decreased upon THF addition. The detailed effects of the reduction in interfacial tension were probed using contrast variations in small angle neutron scattering (SANS) experiments. At low THF contents (high interfacial tensions), the SANS data were fit to a micelle form factor that incorporated a radial density distribution of corona chains to account for the starlike micelle profile. However, at higher THF contents (lowmore » interfacial tensions), the presence of free chains in solution affected the scattering at high q and required the implementation of a linear combination of micelle and Gaussian coil form factors. These SANS data fits indicated that the reduction in interfacial tension led to broadening of the core-corona interface, which increased the PB chain solvent accessibility at intermediate THF solvent fractions. We also noted that the micelle cores swelled with increasing THF addition, suggesting that previous assumptions of the micelle core solvent content in cosolvent mixtures may not be accurate. Control over the size, corona thickness, and extent of solvent accessible PB in these micelles can be a powerful tool in the development of targeting delivery vehicles.« less

Preparation and Characterization of Hyaluronic Acid-Polycaprolactone Copolymer Micelles for the Drug Delivery of Radioactive Iodine-131 Labeled Lipiodol.

PubMed

Chen, Shih-Cheng; Yang, Ming-Hui; Chung, Tze-Wen; Jhuang, Ting-Syuan; Yang, Jean-Dean; Chen, Ko-Chin; Chen, Wan-Jou; Huang, Ying-Fong; Jong, Shiang-Bin; Tsai, Wan-Chi; Lin, Po-Chiao; Tyan, Yu-Chang

2017-01-01

Micelles, with the structure of amphiphilic molecules including a hydrophilic head and a hydrophobic tail, are recently developed as nanocarriers for the delivery of drugs with poor solubility. In addition, micelles have shown many advantages, such as enhanced permeation and retention (EPR) effects, prolonged circulation times, and increased endocytosis through surface modification. In this study, we measured the critical micelle concentrations, diameters, stability, and cytotoxicity and the cell uptake of micelles against hepatic cells with two kinds of hydrophilic materials: PEG-PCL and HA-g-PCL. We used 131 I as a radioactive tracer to evaluate the stability, drug delivery, and cell uptake activity of the micelles. The results showed that HA-g-PCL micelles exhibited higher drug encapsulation efficiency and stability in aqueous solutions. In addition, the 131 I-lipiodol loaded HA-g-PCL micelles had better affinity and higher cytotoxicity compared to HepG2 cells.

Polymer nano-particle hybrid micelles: Encapsulation of POSS into semi-fluorinated polymer micelles

NASA Astrophysics Data System (ADS)

Ratnaweera, Dilru; Perahia, Dvora; Iacono, Scott; Mabry, Joseph; Smith, Dennis

2012-02-01

Self-assembly of block copolymers in selective solvents was used to form a nanoparticle (NP)/polymer hybrid micelles. These micelles can be used as a cargo vehicle for other substances such as drug delivery, and as building blocks for polymer-nanocomposites with controlled NP distribution. Association of NPs into specific blocks of the copolymer depends on the compatibility between the NPs and the block as well as their preference to the solvent that micellization takes place. The current work introduces a small angle neutron scattering study of association of Polyhedral Oligomeric Silsesquioxane (POSS) NPs into micelles of a highly segregating random copolymer, Biphenyl Perfluorocyclobutane (BPh-PFCB), in toluene, which is a good solvent for BPh. Incompatibility between the blocks drives copolymer into micelles with PFCB in the core and BPh in swollen corona. Modification of NPs with polymer chains drives POSS cages into the micelle core and prevents the micelle dissociation at higher temperatures.

Layer-by-Layer Motif Architectures: Programmed Electrochemical Syntheses of Multilayer Mesoporous Metallic Films with Uniformly Sized Pores.

PubMed

Jiang, Bo; Li, Cuiling; Qian, Huayu; Hossain, Md Shahriar A; Malgras, Victor; Yamauchi, Yusuke

2017-06-26

Although multilayer films have been extensively reported, most compositions have been limited to non-catalytically active materials (e.g. polymers, proteins, lipids, or nucleic acids). Herein, we report the preparation of binder-free multilayer metallic mesoporous films with sufficient accessibility for high electrocatalytic activity by using a programmed electrochemical strategy. By precisely tuning the deposition potential and duration, multilayer mesoporous architectures consisting of alternating mesoporous Pd layers and mesoporous PdPt layers with controlled layer thicknesses can be synthesized within a single electrolyte, containing polymeric micelles as soft templates. This novel architecture, combining the advantages of bimetallic alloys, multilayer architectures, and mesoporous structures, exhibits high electrocatalytic activity for both the methanol oxidation reaction (MOR) and the ethanol oxidation reaction (EOR). © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Intracellular Delivery System for Antibody–Peptide Drug Conjugates

PubMed Central

Berguig, Geoffrey Y; Convertine, Anthony J; Frayo, Shani; Kern, Hanna B; Procko, Erik; Roy, Debashish; Srinivasan, Selvi; Margineantu, Daciana H; Booth, Garrett; Palanca-Wessels, Maria Corinna; Baker, David; Hockenbery, David; Press, Oliver W; Stayton, Patrick S

2015-01-01

Antibodies armed with biologic drugs could greatly expand the therapeutic potential of antibody–drug conjugates for cancer therapy, broadening their application to disease targets currently limited by intracellular delivery barriers. Additional selectivity and new therapeutic approaches could be realized with intracellular protein drugs that more specifically target dysregulated pathways in hematologic cancers and other malignancies. A multifunctional polymeric delivery system for enhanced cytosolic delivery of protein drugs has been developed that incorporates endosomal-releasing activity, antibody targeting, and a biocompatible long-chain ethylene glycol component for optimized safety, pharmacokinetics, and tumor biodistribution. The pH-responsive polymeric micelle carrier, with an internalizing anti-CD22 monoclonal targeting antibody, effectively delivered a proapoptotic Bcl-2 interacting mediator (BIM) peptide drug that suppressed tumor growth for the duration of treatment and prolonged survival in a xenograft mouse model of human B-cell lymphoma. Antitumor drug activity was correlated with a mechanistic induction of the Bcl-2 pathway biomarker cleaved caspase-3 and a marked decrease in the Ki-67 proliferation biomarker. Broadening the intracellular target space by more effective delivery of protein/peptide drugs could expand the repertoire of antibody–drug conjugates to currently undruggable disease-specific targets and permit tailored drug strategies to stratified subpopulations and personalized medicines. PMID:25669432

Effect of diblock copolymer properties on the photophysical properties of dendrimer silicon phthalocyanine nanoconjugates

NASA Astrophysics Data System (ADS)

Chen, Kuizhi; Pan, Sujuan; Zhuang, Xuemei; Lv, Hafei; Que, Shoulin; Xie, Shusen; Yang, Hongqin; Peng, Yiru

2016-07-01

1-2 generation poly(benzyl aryl ether) dendrimer silicon phthalocyanines with axially disubstituted cyano terminal functionalities (G n -DSiPc(CN)4 n , (G n = n-generation dendrimer, n = 1-2)) were synthesized. Their structures were characterized by elemental analysis, IR, 1H NMR, and ESI-MS. Polymeric nanoparticles (G n -DSiPc(CN)4 n /m) were formed through encapsulating G n -DSiPc(CN)4 n into three monomethoxyl poly(ethylene glycol)-poly(ɛ-caprolactone) diblock copolymers (MPEG-PCL) with different hydrophilic/hydrophobic proportion, respectively. The effect of dendritic generation and the hydrophilic/hydrophobic proportion of diblock copolymers on the UV/Vis and fluorescence spectra of G n -DSiPc(CN)4 n and G n -DSiPc(CN)4 n /m were studied. The photophysical properties of polymeric nanoparticles exhibited dendritic generation and hydrophilic/hydrophobic proportion dependence. The fluorescence intensities and lifetimes of G n -DSiPc(CN)4 n /m were lower than the corresponding free dendrimer phthalocyanines. G n -DSiPc(CN)4 n encapsulated into MPEG-PCL with hydrophilic/hydrophobic molecular weight ratio 2000:4000 exhibited excellent photophysical property. The mean diameter of MPEG2000-PCL2000 micelles was about 70 nm, which decreased when loaded with G n -DSiPc(CN)4 n .

Progress in nanotechnology-based drug carrier in designing of curcumin nanomedicines for cancer therapy: current state-of-the-art.

PubMed

Ahmad, Mohammad Zaki; Alkahtani, Saad Ahmed; Akhter, Sohail; Ahmad, Farhan Jalees; Ahmad, Javed; Akhtar, Mohammad Shabib; Mohsin, Nehal; Abdel-Wahab, Basel A

2016-01-01

Comprehensive pharmacological screening of curcumin (CUR) has given the evidence that it is an excellent naturally occurring therapeutic moiety for cancer. It is very well tolerated with insignificant toxicity even after high doses of oral administration. Irrespective of its better quality as an anticancer agent, therapeutic application of CUR is hampered by its extremely low-aqueous solubility and poor bioavailability, rapid clearance and low-cellular uptake. A simple means of breaking up the restrictive factor of CUR is to perk-up its aqueous solubility, improve its bioavailability, protect it from degradation, and metabolism and potentiate its targeting capacity towards the cancer cell. The development in the field of nanomedicine has made excellent progresses toward enhancing the bioavailability of lipophilic drugs like CUR. Nanoparticles (NPs) are capable to deliver the CUR at specific area and thereby prevent it from physiological degradation and systemic clearance. In recent year, an assortment of nanomedicine-based novel drug delivery system has been designed to potentiate the bioavailability of CUR towards anticancer therapy. In this review, we discuss the recent development in the field of nanoCUR (NanoCur), including polymeric micelles, liposome, polymeric NPs, nanoemulsion, nanosuspension, solid lipid NPs (SLNPs), polymer conjugates, nanogel, etc. in anticancer application.

Targeted Drug Delivery with Polymers and Magnetic Nanoparticles: Covalent and Noncovalent Approaches, Release Control, and Clinical Studies.

PubMed

Ulbrich, Karel; Holá, Kateřina; Šubr, Vladimir; Bakandritsos, Aristides; Tuček, Jiří; Zbořil, Radek

2016-05-11

Targeted delivery combined with controlled drug release has a pivotal role in the future of personalized medicine. This review covers the principles, advantages, and drawbacks of passive and active targeting based on various polymer and magnetic iron oxide nanoparticle carriers with drug attached by both covalent and noncovalent pathways. Attention is devoted to the tailored conjugation of targeting ligands (e.g., enzymes, antibodies, peptides) to drug carrier systems. Similarly, the approaches toward controlled drug release are discussed. Various polymer-drug conjugates based, for example, on polyethylene glycol (PEG), N-(2-hydroxypropyl)methacrylamide (HPMA), polymeric micelles, and nanoparticle carriers are explored with respect to absorption, distribution, metabolism, and excretion (ADME scheme) of administrated drug. Design and structure of superparamagnetic iron oxide nanoparticles (SPION) and condensed magnetic clusters are classified according to the mechanism of noncovalent drug loading involving hydrophobic and electrostatic interactions, coordination chemistry, and encapsulation in porous materials. Principles of covalent conjugation of drugs with SPIONs including thermo- and pH-degradable bonds, amide linkage, redox-cleavable bonds, and enzymatically-cleavable bonds are also thoroughly described. Finally, results of clinical trials obtained with polymeric and magnetic carriers are analyzed highlighting the potential advantages and future directions in targeted anticancer therapy.

Redox-sensitive Pluronic F127-tocopherol micelles: synthesis, characterization, and cytotoxicity evaluation

PubMed Central

Liu, Yuling; Fu, Sai; Lin, Longfei; Cao, Yuhong; Xie, Xi; Yu, Hua; Chen, Meiwan; Li, Hui

2017-01-01

Pluronic F127 (F127), an amphiphilic triblock copolymer, has been shown to have significant potential for drug delivery, as it is able to incorporate hydrophobic drugs and self-assemble into nanosize micelles. However, it suffers from dissociation upon dilution owing to the relatively high critical micelle concentration and lack of stimuli-responsive behavior. Here, we synthesized the α-tocopherol (TOC) modified F127 polymer (F127-SS-TOC) via a redox-sensitive disulfide bond between F127 and TOC, which formed stable micelles at relatively low critical micelle concentration and was sensitive to the intracellular redox environment. The particle size and zeta potential of the F127-SS-TOC micelles were 51.87±6.39 nm and -8.43±2.27 mV, respectively, and little changes in both particle size and zeta potential were observed within 7 days at room temperature. With 10 mM dithiothreitol stimulation, the F127-SS-TOC micelles rapidly dissociated followed by a significant change in size, which demonstrated a high reduction sensitivity of the micelles. In addition, the micelles showed a high hemocompatibility even at a high micelle concentration (1,000 μg/mL). Low cytotoxicity of the F127-SS-TOC micelles at concentrations ranging from 12.5 μg/mL to 200 μg/mL was also found on both Bel 7402 and L02 cells. Overall, our results demonstrated F127-SS-TOC micelles as a stable and safe aqueous formulation with a considerable potential for drug delivery. PMID:28435248

Study on Colloid Vibration Current in Aqueous Solution of Binary Surfactant Mixtures: Effects of Counterions and Hydrophobic Chains.

PubMed

Takata, Youichi; Hyono, Atsushi; Ohshima, Hiroyuki

2016-11-01

In order to elucidate an electroacoustic phenomenon of mixed micelles in an aqueous solution, we measured the colloid vibration current (CVI) in aqueous solutions of binary surfactant mixtures. Based on the thermodynamic treatment of critical micelle concentration (cmc) values determined by conductivity measurements, it was expected that dodecyltrimethylammonium bromide (DTAB) and dodecyltrimethylammonium chloride (DTAC) molecules would mix ideally in the micelle. However, the micelle composition as evaluated from the CVI measurement, based on the linear dependence of the CVI value on the micelle composition, differed from the aforementioned ideality. Considering these observations, we concluded that the CVI measurement was more sensitive to the counterion distribution near the micelle surface, whereas the thermodynamically determined micelle composition included the counterions more loosely bound in the diffuse double layer due to the electroneutrality condition included in its assumption. On the other hand, the phase diagram illustrating micelle formation in the lithium dodecyl sulfate (LiDS) - lithium perfluorooctane sulfonate (LiFOS) mixture system showed a heteroazeotropic point arising from the stronger interactions between homologous surfactants than between heterologous ones. Although the concentration dependence of CVI values was expected to drastically change at a heteroazeotropic point due to the enormous variation in the density of the micelle core, the results showed a monotonous change, which suggests that the density of the micelle core varies continuously. By taking the partial molar volume of fluorocarbon compounds in the hydrocarbon compounds into account, the density of the micelle core was affected by the size of the micelle as well as its constituents.

Mixed micelles of 7,12-dioxolithocholic acid and selected hydrophobic bile acids: interaction parameter, partition coefficient of nitrazepam and mixed micelles haemolytic potential.

PubMed

Poša, Mihalj; Tepavčević, Vesna

2011-09-01

The formation of mixed micelles built of 7,12-dioxolithocholic and the following hydrophobic bile acids was examined by conductometric method: cholic (C), deoxycholic (D), chenodeoxycholic (CD), 12-oxolithocholic (12-oxoL), 7-oxolithocholic (7-oxoL), ursodeoxycholic (UD) and hiodeoxycholic (HD). Interaction parameter (β) in the studied binary mixed micelles had negative value, suggesting synergism between micelle building units. Based on β value, the hydrophobic bile acids formed two groups: group I (C, D and CD) and group II (12-oxoL, 7-oxoL, UD and HD). Bile acids from group II had more negative β values than bile acids from group I. Also, bile acids from group II formed intermolecular hydrogen bonds in aggregates with both smaller (2) and higher (4) aggregation numbers, according to the analysis of their stereochemical (conformational) structures and possible structures of mixed micelles built of these bile acids and 7,12-dioxolithocholic acid. Haemolytic potential and partition coefficient of nitrazepam were higher in mixed micelles built of the more hydrophobic bile acids (C, D, CD) and 7,12-dioxolithocholic acid than in micelles built only of 7,12-dioxolithocholic acid. On the other hand, these mixed micelles still had lower values of haemolytic potential than micelles built of C, D or CD. The mixed micelles that included bile acids: 12-oxoL, 7-oxoL, UD or HD did not significantly differ from the micelles of 7,12-dioxolithocholic acid, observing the values of their haemolytic potential. Copyright © 2011 Elsevier B.V. All rights reserved.

Peptide-conjugated micelles as a targeting nanocarrier for gene delivery

NASA Astrophysics Data System (ADS)

Lin, Wen Jen; Chien, Wei Hsuan

2015-09-01

The aim of this study was to develop peptide-conjugated micelles possessing epidermal growth factor receptor (EGFR) targeting ability for gene delivery. A sequence-modified dodecylpeptide, GE11(2R), with enhancing EGF receptor binding affinity, was applied in this study as a targeting ligand. The active targeting micelles were composed of poly( d,l-lactide- co-glycolide)-poly(ethylene glycol) (PLGA-PEG) copolymer conjugated with GE11(2R)-peptide. The particle sizes of peptide-free and peptide-conjugated micelles were 277.0 ± 5.1 and 308.7 ± 14.5 nm, respectively. The peptide-conjugated micelles demonstrated the cellular uptake significantly higher than peptide-free micelles in EGFR high-expressed MDA-MB-231 and MDA-MB-468 cells due to GE11(2R)-peptide specificity. Furthermore, the peptide-conjugated micelles were able to encapsulate plasmid DNA and expressed cellular transfection higher than peptide-free micelles in EGFR high-expressed cells. The EGFR-targeting delivery micelles enhanced DNA internalized into cells and achieved higher cellular transfection in EGFR high-expressed cells.

Stabilized micelles as delivery vehicles for paclitaxel.

PubMed

Yoncheva, Krassimira; Calleja, Patricia; Agüeros, Maite; Petrov, Petar; Miladinova, Ivanka; Tsvetanov, Christo; Irache, Juan M

2012-10-15

Paclitaxel is an antineoplastic drug used against a variety of tumors, but its low aqueous solubility and active removal caused by P-glycoprotein in the intestinal cells hinder its oral administration. In our study, new type of stabilized Pluronic micelles were developed and evaluated as carriers for paclitaxel delivery via oral or intravenous route. The pre-stabilized micelles were loaded with paclitaxel by simple solvent/evaporation technique achieving high encapsulation efficiency of approximately 70%. Gastrointestinal transit of the developed micelles was evaluated by oral administration of rhodamine-labeled micelles in rats. Our results showed prolonged gastrointestinal residence of the marker encapsulated into micelles, compared to a solution containing free marker. Further, the oral administration of micelles in mice showed high area under curve of micellar paclitaxel (similar to the area of i.v. Taxol(®)), longer mean residence time (9-times longer than i.v. Taxol(®)) and high distribution volume (2-fold higher than i.v. Taxol(®)) indicating an efficient oral absorption of paclitaxel delivered by micelles. Intravenous administration of micelles also showed a significant improvement of pharmacokinetic parameters of micellar paclitaxel vs. Taxol(®), in particular higher area under curve (1.2-fold), 5-times longer mean residence time and lower clearance, indicating longer systemic circulation of the micelles. Copyright © 2012 Elsevier B.V. All rights reserved.

Near-Infrared Squaraine Dye Encapsulated Micelles for in Vivo Fluorescence and Photoacoustic Bimodal Imaging.

PubMed

Sreejith, Sivaramapanicker; Joseph, James; Lin, Manjing; Menon, Nishanth Venugopal; Borah, Parijat; Ng, Hao Jun; Loong, Yun Xian; Kang, Yuejun; Yu, Sidney Wing-Kwong; Zhao, Yanli

2015-06-23

Combined near-infrared (NIR) fluorescence and photoacoustic imaging techniques present promising capabilities for noninvasive visualization of biological structures. Development of bimodal noninvasive optical imaging approaches by combining NIR fluorescence and photoacoustic tomography demands suitable NIR-active exogenous contrast agents. If the aggregation and photobleaching are prevented, squaraine dyes are ideal candidates for fluorescence and photoacoustic imaging. Herein, we report rational selection, preparation, and micelle encapsulation of an NIR-absorbing squaraine dye (D1) for in vivo fluorescence and photoacoustic bimodal imaging. D1 was encapsulated inside micelles constructed from a biocompatible nonionic surfactant (Pluoronic F-127) to obtain D1-encapsulated micelles (D1(micelle)) in aqueous conditions. The micelle encapsulation retains both the photophysical features and chemical stability of D1. D1(micelle) exhibits high photostability and low cytotoxicity in biological conditions. Unique properties of D1(micelle) in the NIR window of 800-900 nm enable the development of a squaraine-based exogenous contrast agent for fluorescence and photoacoustic bimodal imaging above 820 nm. In vivo imaging using D1(micelle), as demonstrated by fluorescence and photoacoustic tomography experiments in live mice, shows contrast-enhanced deep tissue imaging capability. The usage of D1(micelle) proven by preclinical experiments in rodents reveals its excellent applicability for NIR fluorescence and photoacoustic bimodal imaging.

Block copolymer micelles for controlled delivery of glycolytic enzyme inhibitors.

PubMed

Akter, Shanjida; Clem, Brian F; Lee, Hyun Jin; Chesney, Jason; Bae, Younsoo

2012-03-01

To develop block copolymer micelles as an aqueous dosage form for a potent glycolytic enzyme inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO). The micelles were prepared from poly(ethylene glycol)-poly(aspartate hydrazide) [PEG-p(HYD)] block copolymers to which 3PO was conjugated through an acid-labile hydrazone bond. The optimal micelle formulation was determined following the screening of block copolymer library modified with various aromatic and aliphatic pendant groups. Both physical drug entrapment and chemical drug conjugation methods were tested to maximize 3PO loading in the micelles during the screening. Particulate characterization showed that the PEG-p(HYD) block copolymers conjugated with 3PO (2.08∼2.21 wt.%) appeared the optimal polymer micelles. Block copolymer compositions greatly affected the micelle size, which was 38 nm and 259 nm when 5 kDa and 12 kDa PEG chains were used, respectively. 3PO release from the micelles was accelerated at pH 5.0, potentiating effective drug release in acidic tumor environments. The micelles retained biological activity of 3PO, inhibiting various cancer cells (Jurkat, He-La and LLC) in concentration ranges similar to free 3PO. A novel micelle formulation for controlled delivery of 3PO was successfully prepared.

Polymer Micelles with Cross-Linked Polyanion Core for Delivery of a Cationic Drug Doxorubicin

PubMed Central

Kim, Jong Oh; Kabanov, Alexander V.; Bronich, Tatiana K.

2009-01-01

Polymer micelles with cross-linked ionic cores were prepared by using block ionomer complexes of poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMA) copolymer and divalent metal cations as templates. Doxorubicin (DOX), an anthracycline anticancer drug, was successfully incorporated into the ionic cores of such micelles via electrostatic interactions. A substantial drug loading level (up to 50 w/w %) was achieved and it was strongly dependent on the structure of the cross-linked micelles and pH. The drug-loaded micelles were stable in aqueous dispersions exhibiting no aggregation or precipitation for a prolonged period of time. The DOX-loaded polymer micelles exhibited noticeable pH-sensitive behavior with accelerated release of DOX in acidic environment due to the protonation of carboxylic groups in the cores of the micelles. The attempt to protect the DOX-loaded core with the polycationic substances resulted in the decrease of loading efficacy and had a slight effect on the release characteristics of the micelles. The DOX-loaded polymer micelles exhibited a potent cytotoxicity against human A2780 ovarian carcinoma cells. These results point to a potential of novel polymer micelles with cross-linked ionic cores to be attractive carriers for the delivery of DOX. PMID:19386272

Drug-conjugated PLA-PEG-PLA copolymers: a novel approach for controlled delivery of hydrophilic drugs by micelle formation.

PubMed

Danafar, H; Rostamizadeh, K; Davaran, S; Hamidi, M

2017-12-01

A conjugate of the antihypertensive drug, lisinopril, with triblock poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (PLA-PEG-PLA) copolymer was synthesized by the reaction of PLA-PEG-PLA copolymer with lisinopril in the presence of dicyclohexylcarbodiimide and dimethylaminopyridine. The conjugated copolymer was characterized in vitro by hydrogen nuclear magnetic resonance (HNMR), Fourier transform infrared (FTIR), differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) techniques. Then, the lisinopril conjugated PLA-PEG-PLA were self-assembled into micelles in aqueous solution. The resulting micelles were characterized further by various techniques such as dynamic light scattering (DLS) and atomic force microscopy (AFM). The results revealed that the micelles formed by the lisinopril-conjugated PLA-PEG-PLA have spherical structure with the average size of 162 nm. The release behavior of conjugated copolymer, micelles and micelles physically loaded by lisinopril were compared in different media. In vitro release study showed that in contrast to physically loaded micelles, the release rate of micelles consisted of the conjugated copolymer was dependent on pH of media where it was higher at lower pH compared to the neutral medium. Another feature of the conjugated micelles was their more sustained release profile compared to the lisinopril-conjugated copolymer and physically loaded micelles.

Multidetector thermal field-flow fractionation as a unique tool for the tacticity-based separation of poly(methyl methacrylate)-polystyrene block copolymer micelles.

PubMed

Greyling, Guilaume; Pasch, Harald

2015-10-02

Poly(methyl methacrylate)-polystyrene (PMMA-PS) micelles with isotactic and syndiotactic coronas are prepared in acetonitrile and subjected to thermal field-flow fractionation (ThFFF) analysis at various conditions of increasing temperature gradients. It is shown for the first time that multidetector ThFFF provides comprehensive information on important micelle characteristics such as size (Dh), shape (Rg/Rh), aggregation number (Z), thermal diffusion (DT) and Soret coefficients (ST) as a function of temperature from a single injection. Moreover, it is found that micelles exhibit a unique decreasing trend in DT as a function of temperature which is independent of the tacticity of the corona and the micelle preparation method used. It is also demonstrated that ThFFF can monitor micelle to vesicle transitions as a function of temperature. In addition to ThFFF, it is found from DLS analysis that the tacticity of the corona influences the critical micelle concentration and the magnitude to which micelles expand/contract with temperature. The tacticity does not, however, influence the critical micelle temperature. Furthermore, the separation of micelles based on the tacticity of the corona highlight the unique capabilities of ThFFF. Copyright © 2015 Elsevier B.V. All rights reserved.

Chirality plays critical roles in enhancing the aqueous solubility of nocathiacin I by block copolymer micelles.

PubMed

Feng, Kun; Wang, Shuzhen; Ma, Hairong; Chen, Yijun

2013-01-01

Although drug solubilization by block copolymer micelles has been extensively studied, the rationale behind the choice of appropriate block copolymer micelles for various poorly water-soluble drugs has been of relatively less concern. The objective of this study was to use methoxy-poly(ethylene glycol)-polylactate micelles (MPEG-PLA) to solubilize glycosylated antibiotic nocathiacin I and to compare the effects of chirality on the enhancement of aqueous solubility. Nocathiacin I-loaded MPEG-PLA micelles with opposite optical property in PLA were synthesized and characterized. The drug release profile, micelle stability and preliminary safety properties of MPEG-PLA micelles were evaluated. Meanwhile, three other poorly water-soluble chiral compound-loaded micelles were also prepared and compared.  The aqueous solubility of nocathiacin I was greatly enhanced by both L- and D-copolymers, with the degree of enhancement appearing to depend on the chirality of the copolymers. Comparison of different chiral compounds confirmed the trend that aqueous solubility of chiral compounds can be more effectively enhanced by block copolymer micelles with specific stereochemical configuration. The present study introduced chiral concept on the selection and preparation of block copolymer micelles for the enhancement of aqueous solubility of poorly water-soluble drugs. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Polymeric Sulfated Amino Acid Surfactants: A New Class of Versatile Chiral Selectors for Micellar Electrokinetic Chromatography (MEKC) and MEKC-MS

PubMed Central

Ali Rizvi, Syed Asad; Zheng, Jie; Apkarian, Robert P.; Dublin, Steven N.; Shamsi, Shahab A.

2008-01-01

In this work, three amino acids derived (L-leucinol, L-isoleucinol and L-valinol) sulfated chiral surfactants are synthesized and polymerized. These chiral sulfated surfactants are thoroughly characterized to determine critical micelle concentration, aggregation number, polarity, optical rotation and partial specific volume. For the first time the morphological behavior of polymeric sulfated surfactants is revealed using cryogenic high-resolution electron microscopy (cryo-HRSEM). The polysodium N-undecenoyl-L-leucine sulfate (poly-L-SUCLS) shows distinct tubular structure, while polysodium N-undecenoyl-L-valine sulfate (poly-L-SUCVS) also shows tubular morphology but without any distinct order of the tubes. On the other hand, polysodium N-undecenoyl-L-isoleucine sulfate (poly-L-SUCILS) displays random distribution of coiled/curved filaments with heavy association of tightly and loosely bound water. All three polymeric sulfated surfactants are compared for enantio-separation of broad range of structurally diverse racemic compounds at very acidic, neutral and basic pH conditions in micellar electrokinetic chromatography (MEKC). A small combinatorial library of 10 structurally related phenylethylamines (PEAs) is investigated for chiral separation under acidic and moderately acidic to neutral pH conditions using an experimental design. In contrast to neutral pH conditions, at acidic pH, significantly enhanced chiral resolution is obtained for class I and class II PEAs due to the compact structure of polymeric sulfated surfactants. It is observed that the presence of hydroxy group on the benzene ring of PEAs resulted in deterioration of enantioseparation. A sensitive MEKC-mass spectrometry (MS) method is developed for one of the PEA (e.g., (±)-pseudoephedrine) in human urine. Very low limit of detection (LOD) is obtained at pH 2.0 (LOD 325 ng/mL), which is ca 16 times better compared to pH 8.0 (LOD 5.2 µg/mL). Other broad range of chiral analytes (β-blockers, phenoxypropionic acid, benzoin derivatives, PTH-amino acids, and benzodiazepinones) studied also provided improved chiral separation at low pH compared to high pH conditions. Among the three polymeric sulfated surfactants, poly-L-SUCILS with two chiral centers on the polymer head group provided overall higher enantioresolution for the investigated acidic, basic and neutral compounds. This work clearly demonstrates for the first time the superiority of chiral separation and sensitive MS detection at low pH over conventional high pH chiral separation and detection employing anionic chiral polymeric surfactants in MEKC and MEKC-MS. PMID:17263313

Synthesis of mesoporous hollow silica nanospheres using polymeric micelles as template and their application as a drug-delivery carrier.

PubMed

Sasidharan, Manickam; Zenibana, Haruna; Nandi, Mahasweta; Bhaumik, Asim; Nakashima, Kenichi

2013-10-07

Mesoporous hollow silica nanospheres with uniform particle sizes of 31-33 nm have been successfully synthesized by cocondensation of tetramethoxysilane (TMOS) and alkyltrimethoxysilanes [RSi(OR)3], where the latter also acts as a porogen. ABC triblock copolymer micelles of poly(styrene-b-2-vinyl pyridine-b-ethylene oxide) (PS-PVP-PEO) with a core-shell-corona architecture have been employed as a soft template at pH 4. The cationic shell block with 2-vinyl pyridine groups facilitates the condensation of silica precursors under the sol-gel reaction conditions. Phenyltrimethoxysilane, octyltriethoxysilane, and octadecyltriethoxysilanes were used as porogens for generating mesopores in the shell matrix of hollow silica and the octadecyl precursor produced the largest mesopore among the different porogens, of dimension ca. 4.1 nm. The mesoporous hollow particles were thoroughly characterized by small-angle X-ray diffraction (SXRD), thermal (TG/DTA) and nitrogen sorption analyses, infra-red (FTIR) and nuclear magnetic resonance ((13)C-CP MAS NMR and (29)Si MAS NMR) spectroscopies, and transmission electron microscopy (TEM). The mesoporous hollow silica nanospheres have been investigated for drug-delivery application by an in vitro method using ibuprofen as a model drug. The hollow silica nanospheres exhibited higher storage capacity than the well-known mesoporous silica MCM-41. Propylamine functionalized hollow particles show a more sustained release pattern than their unfunctionalized counterparts, suggesting a huge potential of hollow silica nanospheres in the controlled delivery of small drug molecules.

Intracellular Peptide Self-Assembly: A Biomimetic Approach for in Situ Nanodrug Preparation.

PubMed

Du, Wei; Hu, Xiaomu; Wei, Weichen; Liang, Gaolin

2018-04-18

Most nanodrugs are preprepared by encapsulating or loading the drugs with nanocarriers (e.g., dendrimers, liposomes, micelles, and polymeric nanoparticles). However, besides the low bioavailability and fast excretion of the nanodrugs in vivo, nanocarriers often exhibit in vitro and in vivo cytotoxicity, oxidative stress, and inflammation. Self-assembly is a ubiquitous process in biology where it plays important roles and underlies the formation of a wide variety of complex biological structures. Inspired by some cellular nanostructures (e.g., actin filaments, microtubules, vesicles, and micelles) in biological systems which are formed via molecular self-assembly, in recent decades, scientists have utilized self-assembly of oligomeric peptide under specific physiological or pathological environments to in situ construct nanodrugs for lesion-targeted therapies. On one hand, peptide-based nanodrugs always have some excellent intrinsic chemical (specificity, intrinsic bioactivity, biodegradability) and physical (small size, conformation) properties. On the other hand, stimuli-regulated intracellular self-assembly of nanodrugs is quite an efficient way to accumulate the drugs in lesion location and can realize an in situ slow release of the drugs. In this review article, we provided an overview on recent design principles for intracellular peptide self-assembly and illustrate how these principles have been applied for the in situ preparation of nanodrugs at the lesion location. In the last part, we list some challenges underlying this strategy and their possible solutions. Moreover, we envision the future possible theranostic applications of this strategy.

Bis-urea-based supramolecular polymer: the first self-assembled drag reducer for hydrocarbon solvents.

PubMed

Sabadini, Edvaldo; Francisco, Kelly R; Bouteiller, Laurent

2010-02-02

The hydrodynamic drag reduction phenomenon, also termed the Toms effect, is an unusual case involving macromolecules in solution in which the resistance to flow is reduced comparatively to that of the pure solvent. Although the effect is relatively well characterized, it is still unclear from the molecular viewpoint. The presence of some amount of a polymer with high molecular weight can produce large levels of drag reduction in turbulent flow as a result of the interactions of the long structures with the small vortices developed during the flow. For this reason, the effect is very attractive in the pumping process because a significant amount of energy can be saved. In aqueous systems, giant micelles can be spontaneously formed, driven by the hydrophobic effect, and are effective drag reducers. Giant micelles are interesting in promoting drag reduction because the noncovalent and reversible aggregation of the surfactant molecules avoids mechanical degradation, which typically occurs with classical polymers, due to irreversible scission of the backbone. In this letter, we present the first hydrodynamic drag reducer for hydrocarbons based on a self-assembled polymer formed from the reversible aggregation of bis-urea monomers. This system forms two competitive polymeric structures--the tube (T) and the filament (F) forms--which are in equilibrium with each other. Our rheology results in octane and toluene are fully consistent with calorimetry data and show that only the longest form, T, is able to promote the drag reduction effect.

Artificial biomembrane morphology: a dissipative particle dynamics study.

PubMed

Becton, Matthew; Averett, Rodney; Wang, Xianqiao

2017-09-18

Artificial membranes mimicking biological structures are rapidly breaking new ground in the areas of medicine and soft-matter physics. In this endeavor, we use dissipative particle dynamics simulation to investigate the morphology and behavior of lipid-based biomembranes under conditions of varied lipid density and self-interaction. Our results show that a less-than-normal initial lipid density does not create the traditional membrane; but instead results in the formation of a 'net', or at very low densities, a series of disparate 'clumps' similar to the micelles formed by lipids in nature. When the initial lipid density is high, a membrane forms, but due to the large number of lipids, the naturally formed membrane would be larger than the simulation box, leading to 'rippling' behavior as the excess repulsive force of the membrane interior overcomes the bending energy of the membrane. Once the density reaches a certain point however, 'bubbles' appear inside the membrane, reducing the rippling behavior and eventually generating a relatively flat, but thick, structure with micelles of water inside the membrane itself. Our simulations also demonstrate that the interaction parameter between individual lipids plays a significant role in the formation and behavior of lipid membrane assemblies, creating similar structures as the initial lipid density distribution. This work provides a comprehensive approach to the intricacies of lipid membranes, and offers a guideline to design biological or polymeric membranes through self-assembly processes as well as develop novel cellular manipulation and destruction techniques.

Synthesis of TiO{sub 2} nanoparticles by self-assembling reverse micelle cores of PS-b-PAA for functional textile applications

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akpolat, Leyla Budama; Çakır, Burçin Acar; Topel, Önder, E-mail: ondertopel@akdeniz.edu.tr

2015-04-15

Highlights: • TiO{sub 2} nanoparticles were synthesized within poly(styrene)-b-poly(acrylic acid) micelles. • The copolymer solution including nano TiO{sub 2} was coated onto textile fabrics. • UV-protective factor of nano TiO{sub 2} coated fabrics was estimated as 50+. • Nano TiO{sub 2} coated fabrics was found to exhibit a high photocatalytic activity. - Abstract: Titanium dioxide (i.e., titanium(IV) oxide, TiO{sub 2}) nanoparticles have been fabricated using a copolymer templating technique in micellar solution of poly(styrene)-block-poly(acrylic acid), PS(10912)-b-PAA(4842) synthesized by atom transfer radical polymerization (ATRP). The size and morphology of the synthesized TiO{sub 2} nanoparticles have been characterized via TEM and XRDmore » measurements. The average size of TiO{sub 2} nanoparticles was determined as 13 ± 3 and 13 ± 4 nm for titanium:copolymer ratios of 20:1 and 33:1, respectively. The copolymer solution including nano TiO{sub 2} particles has been coated onto textile fabrics to enhance their UV-blocking and self-cleaning properties. It has been determined that nano TiO{sub 2} coated textile fabrics have very good UV-blocking properties with 50+ of the ultraviolet protecting factor (UPF) and high photocatalytic efficiency with 69.2% of the photodegradation of methylene blue.« less

Spontaneously self-assembled micelles from poly(ethylene glycol)-b-poly(epsilon-caprolactone-co-trimethylene carbonate) for drug solubilization.

PubMed

Latere, Dwan'Isa J P; Rouxhet, L; Brewster, M E; Préat, V; Ariën, A

2008-03-01

Di-block copolymers composed of polyethylene glycol (PEG) and a second block of (co)polyesters of epsilon-caprolactone (CL) and/or trimethylene carbonate (TMC) were synthesized and characterized. Tin octoate was used as catalyst and polymerization were completed over a period of 24 h with high conversion (> 95%). Self-assembling properties in water were evaluated. All di-block copolymers behave similarly except when PCL served as the second block. Stable crew-cut micelles of about 20 nm were obtained by direct dissolution of the liquid di-block copolymers in water at room temperature. When PCL was present as the second block, no solubilization occurred. Drug encapsulation of poorly water-soluble drugs belonging to biopharmaceutics classification system (BCS) class II (ketoprofen and furosemide) was evaluated. Experimental solubility for these two drugs shows a significant enhancement such that a maximum value of 23.4 mg/ml was obtained for ketoprofen in a 10% w/v micellar solution as compared to 0.14 mg in water. In the case of furosemide, the solubility increased from 0.04 mg/ml in water to about 3.2 mg/ml in a 10% w/v micellar solution. Enzymatic degradation of diblock copolymers was also studied in the presence of Pseudomonas lipase in a phosphate buffer solution (pH 7.4). Results indicated rapid degradation of copolymers containing relatively higher amounts of CL compared to TMC suggesting the potential in vivo degradation.

Vitamin E succinate-conjugated F68 micelles for mitoxantrone delivery in enhancing anticancer activity

PubMed Central

Liu, Yuling; Xu, Yingqi; Wu, Minghui; Fan, Lijiao; He, Chengwei; Wan, Jian-Bo; Li, Peng; Chen, Meiwan; Li, Hui

2016-01-01

Mitoxantrone (MIT) is a chemotherapeutic agent with promising anticancer efficacy. In this study, Pluronic F68-vitamine E succinate (F68-VES) amphiphilic polymer micelles were developed for delivering MIT and enhancing its anticancer activity. MIT-loaded F68–VES (F68–VES/MIT) micelles were prepared via the solvent evaporation method with self-assembly under aqueous conditions. F68–VES/MIT micelles were found to be of optimal particle size with the narrow size distribution. Transmission electron microscopy images of F68–VES/MIT micelles showed homogeneous spherical shapes and smooth surfaces. F68–VES micelles had a low critical micelle concentration value of 3.311 mg/L, as well as high encapsulation efficiency and drug loading. Moreover, F68–VES/MIT micelles were stable in the presence of fetal bovine serum for 24 hours and maintained sustained drug release in vitro. Remarkably, the half maximal inhibitory concentration (IC50) value of F68–VES/MIT micelles was lower than that of free MIT in both MDA-MB-231 and MCF-7 cells (two human breast cancer cell lines). In addition, compared with free MIT, there was an increased trend of apoptosis and cellular uptake of F68–VES/MIT micelles in MDA-MB-231 cells. Taken together, these results indicated that F68–VES polymer micelles were able to effectively deliver MIT and largely improve its potency in cancer therapy. PMID:27471384

Block Copolymer Micelles as Nanocontainers for Controlled Release of Proteins from Biocompatible Oil Phases

PubMed Central

2009-01-01

Biocompatible oils are used in a variety of medical applications ranging from vaccine adjuvants to vehicles for oral drug delivery. To enable such nonpolar organic phases to serve as reservoirs for delivery of hydrophilic compounds, we explored the ability of block copolymer micelles in organic solvents to sequester proteins for sustained release across an oil−water interface. Self-assembly of the block copolymer, poly(ϵ-caprolactone)-block-poly(2-vinyl pyridine) (PCL-b-P2VP), was investigated in toluene and oleic acid, a biocompatible naturally occurring fatty acid. Micelle formation in toluene was characterized by dynamic light scattering (DLS) and atomic force microscopy (AFM) imaging of micelles cast onto silicon substrates. Cryogenic transmission electron microscopy confirmed a spherical morphology in oleic acid. Studies of homopolymer solubility implied that micelles in oleic acid consist of a P2VP corona and a PCL core, while P2VP formed the core of micelles assembled in toluene. The loading of two model proteins (ovalbumin (ova) and bovine serum albumin (BSA)) into micelles was demonstrated with loadings as high as 7.8% wt of protein per wt of P2VP in oleic acid. Characterization of block copolymer morphology in the two solvents after protein loading revealed spherical particles with similar size distributions to the as-assembled micelles. Release of ova from micelles in oleic acid was sustained for 12−30 h upon placing the oil phase in contact with an aqueous bath. Unique to the situation of micelle assembly in an oily phase, the data suggest protein is sequestered in the P2VP corona block of PCL-b-P2VP micelles in oleic acid. More conventionally, protein loading occurs in the P2VP core of micelles assembled in toluene. PMID:19235932

Structure and oil responsiveness of viscoelastic fluids based on mixed anionic/cationic wormlike surfactant micelles

NASA Astrophysics Data System (ADS)

Shibaev, A. V.; Makarov, A. V.; Aleshina, A. L.; Rogachev, A. V.; Kuklin, A. I.; Philippova, O. E.

2017-05-01

In this work, a combination of small-angle neutron scattering, dynamic light scattering and rheometry was applied in order to investigate the structure and oil responsiveness of anionic/cationic wormlike surfactant micelles formed in a mixture of potassium oleate and n-octyltrimethylammonium bromide (C8TAB). A new facile method of calculating the structure factor of charged interacting wormlike micelles was proposed. It was shown that the mean distance between the micelles decreases upon the increase of the amount of cationic co-surfactant and lowering of the net micellar charge. It was demonstrated that highly viscous fluids containing mixed anionic/cationic wormlike micelles are highly responsive to oil due to its solubilization inside the micellar cores, which leads to the disruption of micelles and formation of microemulsion droplets. Experimental data suggest that solubilization of oil proceeds differently in the case of mixed anionic/cationic micelles in the absence of salt, and anionic micelles of the same surfactant in the presence of KCl.

Reformation of casein particles from alkaline-disrupted casein micelles.

PubMed

Huppertz, Thom; Vaia, Betsy; Smiddy, Mary A

2008-02-01

In this study, the properties of casein particles reformed from alkaline disrupted casein micelles were studied. For this purpose, micelles were disrupted completely by increasing milk pH to 10.0, and subsequently reformed by decreasing milk pH to 6.6. Reformed casein particles were smaller than native micelles and had a slightly lower zeta-potential. Levels of ionic and serum calcium, as well as rennet coagulation time did not differ between milk containing native micelles or reformed casein particles. Ethanol stability and heat stability, >pH 7.0, were lower for reformed casein particles than native micelles. Differences in heat stability, ethanol stability and zeta-potential can be explained in terms of the influence of increased concentrations of sodium and chloride ions in milk containing reformed casein particles. Hence, these results indicate that, if performed in a controlled manner, casein particles with properties closely similar to those of native micelles can be reformed from alkaline disrupted casein micelles.