[Effect of free and polymer carrier encapsulated doxorubicin towards HCT116 cells of human colorectal carcinoma].

PubMed

Sen'kiv, Iu V; Heffeter, P; Riabtseva, A O; Boĭko, N M; Mitina, N Ie; Zaichenko, O S; Berger, W; Stoĭka, R S

2013-01-01

Development of novel nanoscale functionalized carriers is nowadays one of the most urgent problems in cancer treatment. The aim of our study was to compare the antineoplastic effect of free doxorubicin and its complex with a nanoscale polymeric carrier towards HTC116 colorectal carcinoma cells. It was established that application of the complex of poly(5-tret-butylperoxy)-5-methyl-1-hexene-3-in-co-glycydyl metacrylat)-graft-polyethyleneglycol (poly(VEP-GMA-PEG)-graft-PEG), where VEP--5-tret-butylperoxy)-5-methyl-1-hexene-3-in; GMA--glycydyl metacrylat; graft-PEG--graft-polyethyleneglycol accordingly, functionalized with phosphatidylcholine for doxorubicin delivery increased 10 times the efficiency of cytotoxic action of this drug, as compared wich such efficiency in case of the action of free doxorubicin. The encapsulated form of doxorubicin caused more intensive cleavage of the reparation enzyme PARP and longer delay in G2/M cell cycle arrest, compared to such effects of free doxorubicin. The developed carrier itself is non-toxic to the used mammalian cells and does not cause impairment in their cell cycle. A deletion in both alleles of p53 gene did not affect the antineoplastic action of doxorubicin that was immobilized on the nanoscale carrier. Thus, p53-dependent signaling pathways are not involved in the cytotoxic action of doxorubicin-carrier complex. It is suggested that novel nanoscale polymeric carrier poly(VEP-GMA-PEG)-graft-PEG functionalized with phosphatidylcholine could be a promising carrier for targeted delivery of anticancer drugs.

BIOCHEMICAL INDICATORS OF HEPATOTOXICITY IN BLOOD SERUM OF RATS UNDER THE EFFECT OF NOVEL 4-THIAZOLIDINONE DERIVATIVES AND DOXORUBICIN AND THEIR COMPLEXES WITH POLYETHYLENEGLYCOL-CONTAINING NANOSCALE POLYMERIC CARRIER.

PubMed

Kobylinska, L I; Havrylyuk, D Ya; Ryabtseva, A O; Mitina, N E; Zaichenko, O S; Lesyk, R B; Zimenkovsky, B S; Stoika, R S

2015-01-01

The aim of this study was to compare the effect of new synthetic 4-tiazolidinone derivatives (compounds 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethyleneglycol-containing nanoscale polymeric carrier on the biochemical indicators of hepatotoxicity in blood serum of rats. The activity of enzymes considered as the markers of hepatotoxicity, as well as. the concentration of total protein, urea and creatinine were measured in blood serum of rats. It was found that after injection of investigated compounds the activities ofalanine aminotransferase, alkaline phosphatase and α-amylase increased in comparison to control. Doxorubicin injection was accompanied by 4-fold increase in the activity of γ-glutamyltransferase, and injection ofcompound 3833 led to 2.5-fold elevation ofthe activity of this enzyme. Complexation ofthese antineoplastic derivatives with a synthetic nanocarrier lowered the activity ofthe investigated enzymes substantially if compared to the effect of these compounds infreeform. The most evident decrease was measured for α-amylase, γ-glutamyltransferase and lactate dehydrogenase activities. The normalization of concentrations of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with a polymeric carrier comparing with their introduction infreeform was also detected. Thus, the immobilization by novel polymeric carrier of anticancer drugs possessing high general toxicity in the treated organism mitigates their toxic effect, which is evident as normalization of specific biochemical indicators of the hepatodestructive effects of the anticancer drugs.

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.

Effect of fractionation on treatment outcome in local dual-frequency sonication and Dox-encapsulated nanomicelles.

PubMed

Hasanzadeh, Hadi; Mokhtari-Dizaji, Manijhe; Bathaie, S Zahra; Hassan, Zuhair M

2013-10-01

The goal of this study was to localize drug release from nanomicelles using dual-frequency sonication at low levels of acoustic intensity. In this study, the antitumor effect of simultaneous dual-frequency sonication (28 kHz and 3 MHz) at low levels of acoustic intensity in combination with doxorubicin and micellar doxorubicin injection was assessed in a spontaneous model of breast adenocarcinoma in female Balb/c mice. Sixty-three tumor-bearing mice were randomly grouped into control, sham, dual-frequency sonication, doxorubicin injection with and without dual-frequency sonication, and micellar doxorubicin injection with and without dual-frequency sonication groups. The results of volume change relative to initial volume showed that in the micellar doxorubicin injection with sonication group, this parameter was significantly different from that of the control, sham, sonication, and doxorubicin injection groups (P < 0.05). In addition, the volume began to increase on the 15th day after the start of treatment, which is a good indication to repeat treatment; therefore, another group received an extra treatment on day 15. The animal life span in the micellar doxorubicin with sonication and repeated treatment groups was significantly higher than that in all the other experimental groups except for the micellar doxorubicin injection group (P < 0.05). It was concluded that dual-frequency sonication with micellar doxorubicin injection extends the life span relative to doxorubicin injection or dual-frequency sonication alone, and that repeating this treatment on day 15 decreases the rate of tumor growth significantly.

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.

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 (�

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.

Host-guest interaction of ZnBDC-MOF + doxorubicin: A theoretical and experimental study

NASA Astrophysics Data System (ADS)

Vasconcelos, Iane B.; Wanderley, Kaline A.; Rodrigues, Nailton M.; da Costa, Nivan B.; Freire, Ricardo O.; Junior, Severino A.

2017-03-01

The incorporation of drugs in biodegradable polymeric particles is one of many processes that controllably and significantly increase their release and action. In this paper, we describe the synthesis and physicochemical characterization of ZnBDC-MOF + doxorubicin (DOXO@ZnBDC) and the system's effectiveness in the sustained release of the drug doxorubicin. An experimental and theoretical study is presented of the interaction between the [Zn(BDC)(H2O)2]n MOF and the drug doxorubicin (DOXO). The synthesis was characterized by elemental analysis and X-ray powder diffraction (XRPD). The experimental incorporation was accomplished and analyzed by Fourier transform infrared spectroscopy (FTIR), XRPD and UV-Vis (ultraviolet-visible) spectrophotometry. Based on an analysis of the doxorubicin release profile, our results suggest that the drug delivery system showed slower release than other systems under development. Studies of cytotoxicity by the MTT method showed good results for the system developed with antineoplastic doxorubicin, and together with the other results of this study, suggest the successful development of a MOF-based drug delivery system.

Matrix-assisted laser desorption/ionization mass spectrometric analysis of poly(3,4-ethylenedioxythiophene) in solid-state dye-sensitized solar cells: comparison of in situ photoelectrochemical polymerization in aqueous micellar and organic media.

PubMed

Zhang, Jinbao; Ellis, Hanna; Yang, Lei; Johansson, Erik M J; Boschloo, Gerrit; Vlachopoulos, Nick; Hagfeldt, Anders; Bergquist, Jonas; Shevchenko, Denys

2015-04-07

Solid-state dye-sensitized solar cells (sDSCs) are devoid of such issues as electrolyte evaporation or leakage and electrode corrosion, which are typical for traditional liquid electrolyte-based DSCs. Poly(3,4-ethylenedioxythiophene) (PEDOT) is one of the most popular and efficient p-type conducting polymers that are used in sDSCs as a solid-state hole-transporting material. The most convenient way to deposit this insoluble polymer into the dye-sensitized mesoporous working electrode is in situ photoelectrochemical polymerization. Apparently, the structure and the physicochemical properties of the generated conducting polymer, which determine the photovoltaic performance of the corresponding solar cell, can be significantly affected by the preparation conditions. Therefore, a simple and fast analytical method that can reveal information on polymer chain length, possible chemical modifications, and impurities is strongly required for the rapid development of efficient solar energy-converting devices. In this contribution, we applied matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) for the analysis of PEDOT directly on sDSCs. It was found that the PEDOT generated in aqueous micellar medium possesses relatively shorter polymeric chains than the PEDOT deposited from an organic medium. Furthermore, the micellar electrolyte promotes a transformation of one of the thiophene terminal units to thiophenone. The introduction of a carbonyl group into the PEDOT molecule impedes the growth of the polymer chain and reduces the conductivity of the final polymer film. Both the simplicity of sample preparation (only application of the organic matrix onto the solar cell is needed) and the rapidity of analysis hold the promise of making MALDI MS an essential tool for the physicochemical characterization of conducting polymer-based sDSCs.

Recent Progress in Functional Micellar Carriers with Intrinsic Therapeutic Activities for Anticancer Drug Delivery.

PubMed

Qu, Ying; Chu, BingYang; Shi, Kun; Peng, JinRong; Qian, ZhiYong

2017-12-01

Polymeric micelles have presented superior delivery properties for poorly water-soluble chemotherapeutic agents. However, it remains discouraging that there may be some additional short or long-term toxicities caused by the metabolites of high quantities of carriers. If carriers had simultaneous therapeutic effects with the drug, these issues would not be a concern. For this, carriers not only simply act as drug carriers, but also exert an intrinsic therapeutic effect as a therapeutic agent. The functional micellar carriers would be beneficial to maximize the anticancer effect, overcome the drug resistance and reduce the systemic toxicity. In this review, we aim to summarize the recent progress on the development of functional micellar carriers with intrinsic anticancer activities for the delivery of anticancer drugs. This review focuses on the design strategies, properties of carriers and the drug loading behavior. In addition, the combinational therapeutic effects between carriers and chemotherapeutic agents are also discussed.

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.

Microfluidic flows of wormlike micellar solutions.

PubMed

Zhao, Ya; Cheung, Perry; Shen, Amy Q

2014-09-01

The widespread use of wormlike micellar solutions is commonly found in household items such as cosmetic products, industrial fluids used in enhanced oil recovery and as drag reducing agents, and in biological applications such as drug delivery and biosensors. Despite their extensive use, there are still many details about the microscopic micellar structure and the mechanisms by which wormlike micelles form under flow that are not clearly understood. Microfluidic devices provide a versatile platform to study wormlike micellar solutions under various flow conditions and confined geometries. A review of recent investigations using microfluidics to study the flow of wormlike micelles is presented here with an emphasis on three different flow types: shear, elongation, and complex flow fields. In particular, we focus on the use of shear flows to study shear banding, elastic instabilities of wormlike micellar solutions in extensional flow (including stagnation and contraction flow field), and the use of contraction geometries to measure the elongational viscosity of wormlike micellar solutions. Finally, we showcase the use of complex flow fields in microfluidics to generate a stable and nanoporous flow-induced structured phase (FISP) from wormlike micellar solutions. This review shows that the influence of spatial confinement and moderate hydrodynamic forces present in the microfluidic device can give rise to a host of possibilities of microstructural rearrangements and interesting flow phenomena. Copyright © 2014 Elsevier B.V. All rights reserved.

Micellar systems: Novel family for drug carriers

NASA Astrophysics Data System (ADS)

Rana, Meenakshi; Chowdhury, Papia

2016-05-01

Micellar systems have attracted a great deal of interest, especially in the field of biomedical sciences. The paper deals with the encapsulation behavior of Pyrrole-2-carboxyldehyde (PCL) an anti-cancer drug in different micellar systems. The inculsion capability of PCL is verified experimentally (UV-Vis, Photoluminescence and Raman spectroscopy) in polymer matrix. Two-micellar systems sodium dodecyl sulfate (SDS) and Polysorbate 80 (TWEEN 80) have been studied with a poorly water soluble PCL. The present work provides the effects of biocompatible organic PCL molecule entrap in micellar system in polymer phase due to its vast applicability in drug industry.

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.

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.

Conductive cotton prepared by polyaniline in situ polymerization using laccase.

PubMed

Zhang, Ya; Dong, Aixue; Wang, Qiang; Fan, Xuerong; Cavaco-Paulo, Artur; Zhang, Ying

2014-09-01

The high-redox-potential catalyst laccase, isolated from Aspergillus, was first used as a biocatalyst in the oxidative polymerization of water-soluble conductive polyaniline, and then conductive cotton was prepared by in situ polymerization under the same conditions. The polymerization of aniline was performed in a water dispersion of sodium dodecylbenzenesulfonate (SDBS) micellar solution with atmospheric oxygen serving as the oxidizing agent. This method is ecologically clean and permits a greater degree of control over the kinetics of the reaction. The conditions for polyaniline synthesis were optimized. Characterizations of the conducting polyaniline and cotton were carried out using Fourier transform infrared spectroscopy, UV-vis spectroscopy, cyclic voltammetry, the fabric induction electrostatic tester, and the far-field EMC shielding effectiveness test fixture.

MRI-visual order-disorder micellar nanostructures for smart cancer theranostics.

PubMed

Patra, Hirak K; Ul Khaliq, Nisar; Romu, Thobias; Wiechec, Emilia; Borga, Magnus; Turner, Anthony P F; Tiwari, Ashutosh

2014-04-01

The development of MRI-visual order-disorder structures for cancer nanomedicine explores a pH-triggered mechanism for theragnosis of tumor hallmark functions. Superparamagnetic iron oxide nanoparticles (SPIONs) stabilized with amphiphilic poly(styrene)-b-poly(acrylic acid)-doxorubicin with folic acid (FA) surfacing are employed as a multi-functional approach to specifically target, diagnose, and deliver drugs via a single nanoscopic platform for cancer therapy. The functional aspects of the micellar nanocomposite is investigated in vitro using human breast SkBr3 and colon cancer HCT116 cell lines for the delivery, release, localization, and anticancer activity of the drug. For the first time, concentration-dependent T2 -weighted MRI contrast for a monolayer of clustered cancer cells is shown. The pH tunable order-disorder transition of the core-shell structure induces the relative changes in MRI contrast. The outcomes elucidate the potential of this material for smart cancer theranostics by delivering non-invasive real-time diagnosis, targeted therapy, and monitoring the course and response of the action before, during, and after the treatment regimen. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

High water content oil-external micellar dispersions

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

Jones, S.C.; Roszelle, W.O.; Svaldi, M.A.

1970-02-24

A high water content oil-external micellar dispersion (containing 55 percent to about 90 percent water) was developed for enhanced oil recovery. The micellar slug contained petroleum sulfonate (molecular weight averaged at about 350 to about 525), hydrocarbon, water and cosurfactant. The micellar slug was driven by a mobility buffer slug, which consisted of No. 530 Pusher, fusel oil and the residue Palestine water (420 ppm TDS) from the Palestine water reservoir in Palestine, Illinois. Fired Berea sandstone cores (porosity near 20 percent) were saturated with water (18,000 ppm sodium chloride), flooded with sweet black crude oil from Henry lease inmore » Illinois (7 cp at 72/sup 0/F), and waterflooded with water from Henry lease (18,000 ppm TDS). A maximum recovery of 11.5 percent of oil in place was recovered by 2 percent pore volume of a micellar dispersion containing petroleum sulfonate (MW 406), crude oil, 70 percent by volume distilled water, and p-hexanol.« less

Biological activity and photostability of biflorin micellar nanostructures.

PubMed

Santana, Edson R B; Ferreira-Neto, João P; Yara, Ricardo; Sena, Kêsia X F R; Fontes, Adriana; Lima, Cláudia S A

2015-05-13

Capraria biflora L. is a shrub from the Scrophulariaceae family which produces in its roots a compound named biflorin, an o-naphthoquinone that shows activity against Gram-positive bacteria and fungi and also presents antitumor and antimetastatic activities. However, biflorin is hydrophobic and photosensitive. These properties make its application difficult. In this work we prepared biflorin micellar nanostructures looking for a more effective vehiculation and better preservation of the biological activity. Biflorin was obtained, purified and characterized by UV-Vis, infrared (IR) and 1H- and 13C-NMR. Micellar nanostructures of biflorin were then assembled with Tween 80®, Tween 20® and saline (0.9%) and characterized by UV-Vis spectroscopy and dynamic light scattering (DLS). The results showed that the micellar nanostructures were stable and presented an average size of 8.3 nm. Biflorin micellar nanostructures' photodegradation was evaluated in comparison with biflorin in ethanol. Results showed that the biflorin in micellar nanostructures was better protected from light than biflorin dissolved in ethanol, and also indicated that biflorin in micelles were efficient against Gram-positive bacteria and yeast species. In conclusion, the results showed that the micellar nanostructures could ensure the maintenance of the biological activity of biflorin, conferring photoprotection. Moreover, biflorin vehiculation in aqueous media was improved, favoring its applicability in biological systems.

Folate Receptor Targeted Polymeric Micellar Nanocarriers for Delivery of Orlistat as a Repurposed Drug against Triple Negative Breast Cancer

PubMed Central

Paulmurugan, Ramasamy; Bhethanabotla, Rohith; Mishra, Kaushik; Devulapally, Rammohan; Foygel, Kira; Sekar, Thillai V; Ananta, Jeyarama S; Massoud, Tarik F; Joy, Abraham

2015-01-01

Triple negative breast cancer (TNBC) is a recalcitrant malignancy with no available targeted therapy. Off target effects and poor bioavailability of the FDA approved anti-obesity drug orlistat hinder its clinical translation as a repurposed new drug against TNBC. Here we demonstrate a newly engineered drug formulation for packaging orlistat tailored to TNBC treatment. We synthesized TNBC-specific folate receptor targeted micellar nanoparticles (NPs) carrying orlistat, which improved the solubility (70-80 μg/ml) of this water insoluble drug. The targeted NPs also improved the delivery and bioavailability of orlistat to MDA-MB-231 cells in culture and to tumor xenografts in nude mouse model. We prepared HEA-EHA copolymer micellar NPs by copolymerization of 2-hydroxyethylacrylate (HEA) and 2-ethylhexylacrylate (EHA), and functionalized them with folic acid and an imaging dye. Fluorescence activated cell sorting (FACS) analysis of TNBC cells indicated a dose dependent increase in apoptotic populations in cells treated with free orlistat, orlistat NPs, and folate-receptor targeted Fol-HEA-EHA-orlistat NPs in which Fol-HEA-EHA-orlistat NPs showed significantly higher cytotoxicity than free orlistat. In vitro analysis data demonstrated significant apoptosis at nanomolar concentrations in cells activated through caspase 3 and PARP inhibition. In vivo analysis demonstrated significant antitumor effects in living mice after targeted treatment of tumors, and confirmed by fluorescence imaging. Moreover, Folate receptor targeted Fol-DyLight747-orlistat NPs treated mice exhibited significantly higher reduction in tumor volume compared to control group. Taken together, these results indicate that orlistat packaged in HEA-b-EHA micellar NPs is a highly promising new drug formulation for TNBC therapy. PMID:26553061

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.

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.

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.

Folate-decorated hydrophilic three-arm star-block terpolymer as a novel nanovehicle for targeted co-delivery of doxorubicin and Bcl-2 siRNA in breast cancer therapy.

PubMed

Qian, Junmin; Xu, Minghui; Suo, Aili; Xu, Weijun; Liu, Ting; Liu, Xuefeng; Yao, Yu; Wang, Hongjie

2015-03-01

To minimize the side effects and enhance the efficiency of chemotherapy, a novel folate-decorated hydrophilic cationic star-block terpolymer, [poly(l-glutamic acid γ-hydrazide)-b-poly(N,N-dimethylaminopropyl methacrylamide)]3-g-poly(ethylene glycol) ((PGAH-b-PDMAPMA)3-g-PEG), with disulfide linkages between the PEG and PDMAPMA blocks, was developed for targeted co-delivery of doxorubicin and Bcl-2 small interfering RNA (siRNA) into breast cancer cells. The terpolymer was synthesized by a combination of ring-opening polymerization, reversible addition-fragmentation chain transfer polymerization, PEGylation and hydrazinolysis. The chemical structures of the polymers were confirmed by (1)H-NMR analysis. The terpolymer could conjugate doxorubicin via an acid-labile hydrazone linkage and simultaneously efficiently complex siRNA through electrostatic interaction at N/P ratios of ⩾4:1 to form "two-in-one" nanomicelleplexes, which displayed a spherical shape and had an average size of 101.3 nm. The doxorubicin loading efficiency and content were 61.0 and 13.23%, respectively. The cytotoxicity, drug release profile, targeting ability, cellular uptake and intracellular distribution of the nanomicelleplexes were evaluated in vitro. We found that the release behaviors of doxorubicin and siRNA had a pH/reduction dual dependency. They were released faster under reductive acidic conditions (pH 5.0, glutathione: 10mM) than under physiological conditions (pH 7.4). The folate-decorated nanomicelleplexes could deliver doxorubicin and Bcl-2 siRNA more efficiently into the same MCF-7 cell and exhibited a higher cytotoxicity than non-targeted nanomicelleplexes. These results indicate that the terpolymer could act as an efficient vehicle for targeted intracellular co-delivery of doxorubicin and therapeutic siRNA in cancer therapy. Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Principles of Micellar Electrokinetic Capillary Chromatography Applied in Pharmaceutical Analysis

PubMed Central

Hancu, Gabriel; Simon, Brigitta; Rusu, Aura; Mircia, Eleonora; Gyéresi, Árpád

2013-01-01

Since its introduction capillary electrophoresis has shown great potential in areas where electrophoretic techniques have rarely been used before, including here the analysis of pharmaceutical substances. The large majority of pharmaceutical substances are neutral from electrophoretic point of view, consequently separations by the classic capillary zone electrophoresis; where separation is based on the differences between the own electrophoretic mobilities of the analytes; are hard to achieve. Micellar electrokinetic capillary chromatography, a hybrid method that combines chromatographic and electrophoretic separation principles, extends the applicability of capillary electrophoretic methods to neutral analytes. In micellar electrokinetic capillary chromatography, surfactants are added to the buffer solution in concentration above their critical micellar concentrations, consequently micelles are formed; micelles that undergo electrophoretic migration like any other charged particle. The separation is based on the differential partitioning of an analyte between the two-phase system: the mobile aqueous phase and micellar pseudostationary phase. The present paper aims to summarize the basic aspects regarding separation principles and practical applications of micellar electrokinetic capillary chromatography, with particular attention to those relevant in pharmaceutical analysis. PMID:24312804

Doxorubicin Lipid Complex Injection

MedlinePlus

... has not improved or that has worsened after treatment with other medications. Doxorubicin lipid complex is also ... has not improved or that has worsened after treatment with other medications. Doxorubicin lipid complex is also ...

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.

Doxorubicin-induced second degree and complete atrioventricular block.

PubMed

Kilickap, Saadettin; Akgul, Ebru; Aksoy, Sercan; Aytemir, Kudret; Barista, Ibrahim

2005-05-01

Doxorubicin is one of the most effective chemotherapeutic agents used in the treatment of malignancies. Cardiotoxicity is the most important dose-limiting toxicity of doxorubicin. Although cardiomyopathy is the most well known side effect of doxorubicin, it usually occurs many years after the treatment and relates to cumulative doxorubicin dosage. Another form of doxorubicin cardiotoxicity is arrhythmia which may occur at any time and after any dosage. However, doxorubicin-induced arrhythmia is rarely a life-threatening side effect. In this report, we present a case in which there were doxorubicin-induced life-threatening arrhythmias.

Enzyme processing of textiles in reverse micellar solution.

PubMed

Sawada, K; Ueda, M

2001-08-23

Scouring of cotton using pectinase enzyme, bioscouring, in reverse micellar system was studied. The effectiveness of bioscouring was evaluated by measuring weight loss of cotton, analyzing pectin and cotton wax remaining and by wetness testing. Pectinase enzyme showed excellent activity even in organic media, and the effectiveness of scouring was equivalent or better than that achieved by conventional alkaline process or bioscouring in aqueous media. Enzymatic modification of wool using protease enzyme in the same system was also studied. It has found that felting property and tensile strength of wool fabrics treated by protease in reverse micellar system were superior to those in aqueous media. Possibilities of utilization of the same system for the subsequent textile dyeing process were also investigated. It was found that cotton and polyester fabrics were dyed satisfactorily by reverse micellar system compared to conventional aqueous system.

[Polymer and oligomer based doxorubicin carriers].

PubMed

Kik, Krzysztof; Lwow, Felicja; Szmigiero, Leszek

2007-01-01

Doxorubicin and other anthracycline derivatives play an important role in the treatment of many malignant diseases. Unfortunately, clinical effectiveness of this class of drugs is limited by cumulative cardiotoxicity which occurs in significant percentage of patients at cumulative dose in the range 450-600 mg/m2. Therefore, several strategies have been developed to reduce cardiotoxicity of doxorubicin and its analogues. One of the possible ways leading to the improvement of anticancer selectivity of doxorubicin is the design of polymer and olygomer carriers which may transport drug molecules more efficiently and more specifically. Synthetic polymers are of increasing interest as therapeutic agents owing to their enhanced pharmacokinetic profiles relative to small molecule drugs. Currently a new class of multifunctional polymers is being prepared that can "mask" biologically active compounds, such as cytotoxic agents, until they reach target sites, but which can then release the agent in situ to effect the therapy. The legitimacy of the development of polymer based doxorubicine carriers is supported by the growing number of clinical reports indicating that the use of hydrophilic polymers or polymer coated liposomes as a platform for delivery of the drug results in better therapeutic effects than the free drug. In this article we present the most promising strategies directed at the development of improved anthracycline drugs formulations based of polymer and olygomer carriers. We review: 1) polyethylenoglycol-coated ("pegylated") liposomal doxorubicin; 2) extracellulary tumor-activated prodrugs which are conjugates of doxorubicin with peptides; 3) doxorubicin coated by higly polymerised glycosoaminoglycans; 4) conjugates of doxorubicin with copolymer of N-(2-hydroxypropyl)methacrylamide.

Enhancement of oral bioavailability of doxorubicin through surface modified biodegradable polymeric nanoparticles.

PubMed

Ahmad, Niyaz; Ahmad, Rizwan; Alam, Md Aftab; Ahmad, Farhan Jalees

2018-05-23

Doxorubicin hydrochloride (DOX·HCl), an anthracycline glycoside antibiotic, exhibits low oral bioavailability due to active efflux from intestinal P-glycoprotein receptors. The oral administration of DOX remains a challenge hence; no oral formulation for DOX is marketed, till date. To improve the oral bioavailability of DOX through, preparation of a nanoformulation i.e. PEGylated-doxorubicin(DOX)-loaded-poly-lactic-co-glycolic acid (PLGA)-Nanoparticles (NPs) and to develop and validate an ultra-high performance liquid chromatography electrospray ionization-synapt mass spectrometric bioanalytical method (UHPLC/ESI-QTOF-MS/MS) for plasma (Wistar rats) DOX quantification. For chromatography, Waters ACQUITY UPLC™ along with a BEH C-18 column (2.1 mm × 100 mm; 1.7 μm), mobile phase conditions (acetonitrile: 0.1% formic acid::1:1 v/v) and flow rate (0.20 ml/min) was used. For analyte recovery from rat plasma, a liquid-liquid extraction method (LLE), using Acetonitrile: 5 mM ammonium acetate in a ratio of 6:4 v/v at pH 3.5, was used. Nanoformulation with a particle size (183.10 ± 7.41 nm), zeta potential (- 13.10 ± 1.04 mV), drug content (42.69 ± 1.97 µg/mg) and a spherical shape and smooth surface was developed. An elution time of 1.61 and 1.75 min along with a transition at m/z 544.42/397.27 and 528.46/321.41 were observed for DOX and internal standard (IS) Daunorubicin, respectively. In addition, a linear dynamic range with r 2  ≥ 0.9985 over a concentration range of 1.00-2500.0 ng/ml was observed for different processes and parameters used in the study. Similarly a marked improvement i.e. 6.8 fold was observed, in PEGylated-DOX-PLGA-NPs as compared to DOX-S, in pharmacokinetics studies. The promising approach of PEGylated-DOX-PLGA-NPs may provide an alternate to intravenous therapy for better patient care.

Flow-induced gelation of living (micellar) polymers

NASA Technical Reports Server (NTRS)

Bruinsma, Robijn; Gelbart, William M.; Ben-Shaul, Avinoam

1992-01-01

The effect of shear velocity gradients on the size (L) of rodlike micelles in dilute and semidilute solution is considered. A kinetic equation is introduced for the time-dependent concentration of aggregates of length L, consisting of 'bimolecular' combination processes L + L-prime yield (L + L-prime) and unimolecular fragmentations L yield L + (L - L-prime). The former are described by a generalization (from spheres to rods) of the Smoluchowski mechanism for shear-induced coalesence of emulsions, and the latter by incorporating the tension-deformation effects due to flow. Steady-state solutions to the kinetic equation are obtained, with the corresponding mean micellar size evaluated as a function of the Peclet number P (i.e., the dimensionless ratio of the flow rate and the rotational diffusion coefficient). For sufficiently dilute solutions, only a weak dependence of the micellar size on P is found. In the semidilute regime, however, an apparent divergence in the micellar size at P of about 1 suggests a flow-induced first-order gelation phenomenon.

Synthesis and characterization of smart N-isopropylacrylamide-based magnetic nanocomposites containing doxorubicin anti-cancer drug.

PubMed

Motaali, Soheila; Pashaeiasl, Maryam; Akbarzadeh, Abolfazl; Davaran, Soodabeh

2017-05-01

In the present study, magnetic and thermo/pH-sensitive (multiresponsive) nanocomposites based on N-isopropylacrylamide (NIPAAM) were synthesized and characterized. Nanocomposites were synthesized by free radical emulsion polymerization of NIPAAM as thermosensitive monomer and N,N-dimethyl-aminoethyl methacrylate (DMAEMA) as pH-sensitive monomer in the presence of methylene-bis-acrylamide as cross-linking agent. Doxorubicin, an anti-cancer drug, was loaded into these nanocomposites via equilibrium swelling method. Thermo/pH-sensitive cross-linked poly (NIPAAM-DMAEMA)-Fe 3 O 4 nanocomposites were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and vibrating sample magnetometer (VSM). The volume of the loaded drug and drug release amount was determined by UV measurements. The results showed that this thermo/pH-sensitive magnetic nanocomposite has a high drug-loading efficiency. Doxorubicin was released at 40 °C and pH 5.8 more than the 37 °C and pH 7.4.

Pyrene absorption can be a convenient method for probing critical micellar concentration (cmc) and indexing micellar polarity.

PubMed

Basu Ray, Gargi; Chakraborty, Indranil; Moulik, Satya P

2006-02-01

The critical micellar concentration (cmc) of both ionic and non-ionic surfactants can be conveniently determined from the measurements of UV absorption of pyrene in surfactant solution. The results on a number of surfactants have agreed with that realized from pyrene fluorescence measurements as well as that obtained following conductometric, tensiometric and calorimetric methods. The absorbance vs [surfactant] profiles for all the major UV spectral peaks of pyrene have been found to be sigmoidal in nature which were analyzed according to Sigmoidal-Boltzmann equation (SBE) to evaluate the cmcs of the studied surfactants. The difference between the initial and the final asymptotes (a(i) and a(f), respectively) of the sigmoidal profile, Delta a = (a(f)-a(i)) and the slope of the sigmoid, S(sig) have been observed to depend on the type of the surfactant. The Delta a has shown a linear correlation with the ratio of the fluorescence intensities of the first and the third vibronic peaks, I1/I3 of pyrene which is considered as a measure of the environmental polarity (herein micellar interior) of the probe (pyrene). Thus, Delta a values have the prospect for use as another index for the estimation of polarity of micellar interior.

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.

Oxidative mutagenesis of doxorubicin-Fe(III) complex.

PubMed

Kostoryz, E L; Yourtee, D M

2001-02-20

Doxorubicin has a high affinity for inorganic iron, Fe(III), and has potential to form doxorubicin-Fe(III) complexes in biological systems. Indirect involvement of iron has been substantiated in the oxidative mutagenicity of doxorubicin. In this study, however, direct involvement of Fe(III) was evaluated in mutagenicity studies with the doxorubicin-Fe(III) complex. The Salmonella mutagenicity assay with strain TA102 was used with a pre-incubation step. The highest mutagenicity of doxorubicin-Fe(III) complex was observed at the dose of 2.5nmol/plate of the complex. The S9-mix decreased this highest mutagenicity but increased the number of revertants at a higher dose of 10nmol/plate of the complex. On the other hand, the mutagenicity of the doxorubicin-Fe(III) complex at the doses of 0.25, 0.5, 1 and 2nmol/plate was enhanced about twice by the addition of glutathione plus H(2)O(2). This enhanced mutagenicity as well as of the complex itself, the complex plus glutathione, and the complex plus H(2)O(2) were reduced by the addition of ADR-529, an Fe(III) chelator, and potassium iodide, a hydroxyl radical scavenger. These results indicate that doxorubicin-Fe(III) complex exert the mutagenicity through oxidative DNA damage and that Fe(III) is a required element in the mutagenesis of doxorubicin.

Comparison of doxorubicin-cyclophosphamide with doxorubicin-dacarbazine for the adjuvant treatment of canine hemangiosarcoma.

PubMed

Finotello, R; Stefanello, D; Zini, E; Marconato, L

2017-03-01

Canine hemangiosarcoma (HSA) is a neoplasm of vascular endothelial origin that has an aggressive biological behaviour, with less than 10% of dogs alive at 12-months postdiagnosis. Treatment of choice consists of surgery followed by adjuvant doxorubicin-based chemotherapy. We prospectively compared adjuvant doxorubicin and dacarbazine (ADTIC) to a traditional doxorubicin and cyclophosphamide (AC) treatment, aiming at determining safety and assessing whether this regimen prolongs survival and time to metastasis (TTM). Twenty-seven dogs were enrolled; following staging work-up, 18 were treated with AC and 9 with ADTIC. Median TTM and survival time were longer for dogs treated with ADTIC compared with those receiving AC (>550 versus 112 days, P = 0.021 and >550 versus 142 days, P = 0.011, respectively). Both protocols were well tolerated, without need for dose reduction or increased interval between treatments. A protocol consisting of combined doxorubicin and dacarbazine is safe in dogs with HSA and prolongs TTM and survival time. © 2015 John Wiley & Sons Ltd.

Doxorubicin-loaded micelles based on multiarm star-shaped PLGA-PEG block copolymers: influence of arm numbers on drug delivery.

PubMed

Ma, Guilei; Zhang, Chao; Zhang, Linhua; Sun, Hongfan; Song, Cunxian; Wang, Chun; Kong, Deling

2016-01-01

Star-shaped block copolymers based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(ethylene glycol) (PEG) (st-PLGA-PEG) were synthesized with structural variation on arm numbers in order to investigate the relationship between the arm numbers of st-PLGA-PEG copolymers and their micelle properties. st-PLGA-PEG copolymers with arm numbers 3, 4 and 6 were synthesized by using different cores such as trimethylolpropane, pentaerythritol and dipentaerythritol, and were characterized by nuclear magnetic resonance and gel permeation chromatography. The critical micelle concentration decreased with increasing arm numbers in st-PLGA-PEG copolymers. The doxorubicin-loaded st-PLGA-PEG micelles were prepared by a modified nanoprecipitation method. Micellar properties such as particle size, drug loading content and in vitro drug release behavior were investigated as a function of the number of arms and compared with each other. The doxorubicin-loaded 4-arm PLGA-PEG micelles were found to have the highest cellular uptake efficiency and cytotoxicity compared with 3-arm PLGA-PEG micelles and 6-arm PLGA-PEG micelles. The results suggest that structural tailoring of arm numbers from st-PLGA-PEG copolymers could provide a new strategy for designing drug carriers of high efficiency. Structural tailoring of arm numbers from star shaped-PLGA-PEG copolymers (3-arm/4-arm/6-arm-PLGA-PEG) could provide a new strategy for designing drug carriers of high efficiency.

Ion dehydration controls adsorption at the micellar interface: hydrotropic ions.

PubMed

Lima, Filipe S; Andrade, Marcos F C; Mortara, Laura; Gustavo Dias, Luís; Cuccovia, Iolanda M; Chaimovich, Hernan

2017-11-22

The properties of ionic micelles depend on the nature of the counterion, and these effects become more evident as the ion adsorption at the interface increases. Prediction of the relative extent of ion adsorption is required for rational design of ionic micellar aggregates. Unlike the well understood adsorption of monatomic ions, the adsorption of polyatomic ions is not easily predicted. We combined experimental and computational methods to evaluate the affinity of hydrotropic ions, i.e., ions with polar and apolar regions, to the surface of positively charged micelles. We analyzed cationic micelles of dodecyltrimethylammonium and six hydrotropic counterions: methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, acetate, trifluoroacetate and benzoate. Our results demonstrated that the apolar region of hydrotropic ions had the largest influence on micellar properties. The dehydration of the apolar region of hydrotropic ions upon their adsorption at the micellar interface determined the ion adsorption extension, differently to what was expected based on Collins' law of matching affinities. These results may lead to more general models to describe the adsorption of ions, including polyatomic ions, at the micellar interface.

Chemical Endoplasmic Reticulum Chaperone Alleviates Doxorubicin-Induced Cardiac Dysfunction.

PubMed

Fu, Hai Ying; Sanada, Shoji; Matsuzaki, Takashi; Liao, Yulin; Okuda, Keiji; Yamato, Masaki; Tsuchida, Shota; Araki, Ryo; Asano, Yoshihiro; Asanuma, Hiroshi; Asakura, Masanori; French, Brent A; Sakata, Yasushi; Kitakaze, Masafumi; Minamino, Tetsuo

2016-03-04

Doxorubicin is an effective chemotherapeutic agent for cancer, but its use is often limited by cardiotoxicity. Doxorubicin causes endoplasmic reticulum (ER) dilation in cardiomyocytes, and we have demonstrated that ER stress plays important roles in the pathophysiology of heart failure. We evaluated the role of ER stress in doxorubicin-induced cardiotoxicity and examined whether the chemical ER chaperone could prevent doxorubicin-induced cardiac dysfunction. We confirmed that doxorubicin caused ER dilation in mouse hearts, indicating that doxorubicin may affect ER function. Doxorubicin activated an ER transmembrane stress sensor, activating transcription factor 6, in cultured cardiomyocytes and mouse hearts. However, doxorubicin suppressed the expression of genes downstream of activating transcription factor 6, including X-box binding protein 1. The decreased levels of X-box binding protein 1 resulted in a failure to induce the expression of the ER chaperone glucose-regulated protein 78 which plays a major role in adaptive responses to ER stress. In addition, doxorubicin activated caspase-12, an ER membrane-resident apoptotic molecule, which can lead to cardiomyocyte apoptosis and cardiac dysfunction. Cardiac-specific overexpression of glucose-regulated protein 78 by adeno-associated virus 9 or the administration of the chemical ER chaperone 4-phenylbutyrate attenuated caspase-12 cleavage, and alleviated cardiac apoptosis and dysfunction induced by doxorubicin. Doxorubicin activated the ER stress-initiated apoptotic response without inducing the ER chaperone glucose-regulated protein 78, further augmenting ER stress in mouse hearts. Cardiac-specific overexpression of glucose-regulated protein 78 or the administration of the chemical ER chaperone alleviated the cardiac dysfunction induced by doxorubicin and may facilitate the safe use of doxorubicin for cancer treatment. © 2016 American Heart Association, Inc.

Contrasting Drainage and Stratification in Horizontal Vs Vertical Micellar Foam Films

NASA Astrophysics Data System (ADS)

Wojcik, Ewelina; Yilixiati, Subinuer; Zhang, Yiran; Sharma, Vivek

Understanding and controlling the drainage kinetics of thin films is an important problem that underlies the stability, lifetime and rheology of foams and emulsions. In foam films formed with micellar solutions, the surfactant is present as interfacially-adsorbed layer at both liquid-air interfaces, as well as in bulk as self-assembled supramolecular structures called micelles. Ultrathin micellar films exhibit stratification due to confinement-induced structuring and layering of micelles. Stratification in micellar foam films is manifested as stepwise thinning over time, and it leads to the coexistence of flat domains with discretely different thicknesses. In this contribution we use Interferometry Digital Imaging Optical Microscopy (IDIOM) protocols to visualize and analyze thickness transitions and variations associated with stratification in micellar foam films made with sodium dodecyl sulfate (SDS). We contrast the drainage and stratification dynamics in horizontal and vertical foam films, and investigate the role played by gravitational, viscous, interfacial and surface forces.

Oil recovery method using high water content oil-external micellar dispersions

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

Jones, S.C.; Roszelle, W.O.; Svaldi, M.A.

1971-10-19

A high water content oil-external micellar dispersion (containing 55 percent to about 90 percent water) was developed for enhanced oil recovery. The micellar slug contained petroleum sulfonate (molecular weight averaged at about 350 to about 525), hydrocarbon, water and cosurfactant. The micellar slug was driven by a mobility buffer slug, which consisted of No. 530 Pusher, fusel oil and the residue Palestine water (420 ppm TDS) from the Palestine water reservoir in Palestine, Illinois. Fired Berea sandstone cores (porosity near 20 percent) were saturated with water (18,000 ppm sodium chloride), flooded with sweet black crude oil from Henry lease inmore » Illinois (7 cp at 72/sup 0/F), and waterflooded with water from Henry lease (18,000 ppm TDS). A maximum recovery of 11.5 percent of oil in place was recovered by 2 percent pore volume of a micellar dispersion containing petroleum sulfonate (MW 406), 70 percent by volume distilled water, and p-hexanol.« less

Phase separation in living micellar networks

NASA Astrophysics Data System (ADS)

Cristobal, G.; Rouch, J.; Curély, J.; Panizza, P.

We present a lattice model based on two n→0 spin vectors, capable of treating the thermodynamics of living networks in micellar solutions at any surfactant concentration. We establish an isomorphism between the coupling constants in the two spin vector Hamiltonian and the surfactant energies involved in the micellar situation. Solving this Hamiltonian in the mean-field approximation allows one to calculate osmotic pressure, aggregation number, free end and cross-link densities at any surfactant concentration. We derive a phase diagram, including changes in topology such as the transition between spheres and rods and between saturated and unsaturated networks. A phase separation can be found between a saturated network and a dilute solution composed of long flexible micelles or a saturated network and a solution of spherical micelles.

Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats.

PubMed

Krishnamurthy, Bhaskar; Rani, Neha; Bharti, Saurabh; Golechha, Mahaveer; Bhatia, Jagriti; Nag, Tapas Chandra; Ray, Ruma; Arava, Sudheer; Arya, Dharamvir Singh

2015-07-25

The clinical use of doxorubicin is associated with dose limiting cardiotoxicity. This is a manifestation of free radical production triggered by doxorubicin. Therefore, we evaluated the efficacy of febuxostat, a xanthine oxidase inhibitor and antioxidant, in blocking cardiotoxicity associated with doxorubicin in rats. Male albino Wistar rats were divided into four groups: control (normal saline 2.5mL/kg/dayi.p. on alternate days, a total of 6 doses); Doxorubicin (2.5mg/kg/dayi.p. on alternate days, a total of 6 doses), Doxorubicin+Febuxostat (10mg/kg/day oral) and Doxorubicin+Carvedilol (30mg/kg/day oral) for 14days. Febuxostat significantly ameliorated the doxorubicin-induced deranged cardiac functions as there was significant improvement in arterial pressures, left ventricular end diastolic pressure and inotropic and lusitropic states of the myocardium. These changes were well substantiated with biochemical findings, wherein febuxostat prevented the depletion of non-protein sulfhydryls level, with increased manganese superoxide dismutase level and reduced cardiac injury markers (creatine kinase-MB and B-type natriuretic peptide levels) and thiobarbituric acid reactive substances level. Febuxostat also exhibited significant anti-inflammatory (decreased expression of NF-κBp65, IKK-β and TNF-α) and anti-apoptotic effect (increased Bcl-2 expression and decreased Bax and caspase-3 expression and TUNEL positivity). Hematoxylin and Eosin, Masson Trichome, Picro Sirius Red and ultrastructural studies further corroborated with hemodynamic and biochemical findings showing that febuxostat mitigated doxorubicin-induced increases in inflammatory cells, edema, collagen deposition, interstitial fibrosis, perivascular fibrosis and mitochondrial damage and better preservation of myocardial architecture. In addition, all these changes were comparable to those produced by carvedilol. Thus, our results suggest that the antioxidant and anti-apoptotic effect of febuxostat

Evidence of modifications of micellar interface in sol-gel glass

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

Catuara, C.M.; Lin, C.T.

1994-12-31

A new sol-gel procedure using micellar solutions has been developed to immobilize local anesthetic drugs in optically transparent glass. Dibucaine was selected as a direct emission probe at 77 K for determining the forms of the anesthetic drug (free base, monoprotonated, and/or diprotonated) and its location (hydrophobic core, interfacial layer or hydrophilic region) in micelles. The photophysical properties of local anesthetics obtained in gels are compared to those in solutions. During the gelation stage, the predominant drug species was identified as free base dibucaine embedded in the hydrophobic core of neutral as well as charged micelles. This observation suggests thatmore » the micellar interface was modified by the large hydrophilic gel surface during the gelation stage. The modified micellar interface allows an increase in the partition of free base dibucaine into the hydrophobic region. At the xerogel stage, however, the collapse of micellar structure provides a direct interaction of dibucaine with the acidic gel surface, leading to a formation of diprotonated dibucaine. The results are discussed in terms of molecular basis of pharmacological implications such as drug delivery, release, and transport under microencapsulation conditions.« less

Use of water-external micellar dispersions in oil recovery

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

Jones, S.C.

1970-04-14

A water-external micellar dispersion followed by a mobility buffer and a water drive were used for enhanced oil recovery. Field Berea sandstone cores (19.6 percent porosity, 387 md permeability) were saturated with brine (16,500 ppM sodium chloride), flooded with crude oil from the Henry lease in Illinois (viscosity of 5.9 cp at 72/sup 0/F, specific gravity of 0.833), and waterflooded with water from Henry lease (17,210 ppM TDS). The micellar dispersion followed by the mobility buffer produced 99.6 percent of the oil in the core. The micellar slug contained ammonium petroleum sulfonate (MW 450), Henry crude oil, isopropanol, nonyl phenol,more » sodium hydroxide, and water from the Palestine water reservoir in Palestine, Illinois (412 ppM TDS). No. 530 Pusher, ammonium thiocyanate, isopropanol, and Palestine water were in the mobility buffer.« less

New doxorubicin nanocarriers based on cyclodextrins.

PubMed

Viale, Maurizio; Giglio, Valentina; Monticone, Massimiliano; Maric, Irena; Lentini, Giovanni; Rocco, Mattia; Vecchio, Graziella

2017-10-01

Polymeric nanoparticles and fibrin gels (FBGs) are attractive biomaterials for local delivery of a variety of biotherapeutic agents, from drugs to proteins. We combined these different drug delivery approaches by preparing nanoparticle-loaded FBGs characterized by their intrinsic features of drug delivery rate and antiproliferative/apoptotic activities. Inclusion complexes of doxorubicin (DOXO) with oligomeric β-cyclodextrins (oCyD) functionalized with different functional groups were studied. These nanocarriers were able to interact with FBGs as shown by a decreased release rate of DOXO. One of these complexes, oCyDNH 2 /DOXO, demonstrated good antiproliferative and apoptotic activity in vitro, reflecting a higher drug uptake by cells. As hypothesized, the nanocarrier/FBG complexes showed a lower drug release rate than similar FBGs loaded with the corresponding non-functionalized oCyD/DOXO. Taken together, our results provide experimental evidence that oCyDNH 2 /DOXO complexes may be useful components in enhanced FBGs and further build support for the great promise these complex molecules hold for clinical use in localized anticancer therapy of inoperable or surgically removable tumors of different histological origin.

Transferrin receptor-targeted pH-sensitive micellar system for diminution of drug resistance and targetable delivery in multidrug-resistant breast cancer

PubMed Central

Gao, Wei; Ye, Guihua; Duan, Xiaochuan; Yang, Xiaoying; Yang, Victor C

2017-01-01

The emergence of drug resistance is partially associated with overproduction of transferrin receptor (TfR). To overcome multidrug resistance (MDR) and achieve tumor target delivery, we designed a novel biodegradable pH-sensitive micellar system modified with HAIYPRH, a TfR ligand (7pep). First, the polymers poly(l-histidine)-coupled polyethylene glycol-2000 (PHIS-PEG2000) and 7pep-modified 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (7pep-DSPE-PEG2000) were synthesized, and the mixed micelles were prepared by blending of PHIS-PEG2000 and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (DSPE-PEG2000) or 7pep-DSPE-PEG2000 (7-pep HD micelles). The micelles exhibited good size uniformity, high encapsulation efficiency, and a low critical micelle concentration. By changing the polymer ratio in the micellar formulation, the pH response range was specially tailored to pH ~6.0. When loaded with antitumor drug doxorubicin (DOX), the micelle showed an acid pH-triggering drug release profile. The cellular uptake and cytotoxicity study demonstrated that 7-pep HD micelles could significantly enhance the intracellular level and antitumor efficacy of DOX in multidrug-resistant cells (MCF-7/Adr), which attributed to the synergistic effect of poly(l-histidine)-triggered endolysosom escape and TfR-mediated endocytosis. Most importantly, the in vivo imaging study confirmed the target-ability of 7-pep HD micelles to MDR tumor. These findings indicated that 7-pep HD micelles would be a promising drug delivery system in the treatment of drug-resistant tumors. PMID:28223798

Polyaspartic acid functionalized gold nanoparticles for tumor targeted doxorubicin delivery.

PubMed

Khandekar, Sameera V; Kulkarni, M G; Devarajan, Padma V

2014-01-01

In this paper, we present polyaspartic acid, a biodegradable polymer as a reducing and functionalizing agent for the synthesis of doxorubicin loaded gold nanoparticles by a green process. Gold nanoparticles were stable to electrolytes and pH. Secondary amino groups of polyaspartic acid enabled reduction of gold chloride to form gold nanoparticles of size 55 +/-10 nm, with face centered cubic crystalline structure as confirmed by UV, TEM, SAED and XRD studies. Cationic doxorubicin was readily loaded onto anionic polyaspartic acid gold nanoparticles by ionic complexation. Fluorescence studies confirmed doxorubicin loading while FTIR spectra confirmed ionic complexation. Doxorubicin loading onto polyaspartic acid gold nanoparticles was studied at doxorubicin/polyaspartic acid molar ratios 1:10 to 1:1. As the molar ratio tended to unity, although loading up to 60% was achieved, colloidal instability resulted and is attributed to effective covering of negative charges of polyaspartic acid. Stable doxorubicin loaded polyaspartic acid gold nanoparticles of 105 +/- 15.1 nm with doxorubicin loading of 23.85% w/w and zeta potential value of -28 +/- 0.77 mV were obtained at doxorubicin/polyaspartic acid molar ratio 1:10. Higher doxorubicin release rate from the doxorubicin loaded polyaspartic acid gold nanoparticles in an acid medium (i.e., pH 5.5) as compared to that in pH 7.4 and deionized water is a desirable characteristic for tumor targeted delivery. Enhanced cytotoxicity and 3 fold higher uptake of doxorubicin loaded polyaspartic acid gold nanoparticles as compared to doxorubicin solution were seen in MCF-7 breast cancer cells while polyaspartic acid gold nanoparticles revealed no cytotoxicity confirming safety. Prominent regression in tumor size in-vivo in fibrosarcoma tumor induced mouse model was observed upto 59 days with doxorubicin loaded polyaspartic acid gold nanoparticles while doxorubicin solution treated mice showed regrowth beyond 23rd day. Moreover, a

Quercetin attenuates doxorubicin cardiotoxicity by modulating Bmi-1 expression

PubMed Central

Dong, Qinghua; Chen, Long; Lu, Qunwei; Sharma, Sherven; Li, Lei; Morimoto, Sachio; Wang, Guanyu

2014-01-01

Background and Purpose Doxorubicin-based chemotherapy induces cardiotoxicity, which limits its clinical application. We previously reported the protective effects of quercetin against doxorubicin-induced hepatotoxicity. In this study, we tested the effects of quercetin on the expression of Bmi-1, a protein regulating mitochondrial function and ROS generation, as a mechanism underlying quercetin-mediated protection against doxorubicin-induced cardiotoxicity. Experimental Approach Effects of quercetin on doxorubicin-induced cardiotoxicity was evaluated using H9c2 cardiomyocytes and C57BL/6 mice. Changes in apoptosis, mitochondrial function, oxidative stress and related signalling were evaluated in H9c2 cells. Cardiac function, serum enzyme activity and reactive oxygen species (ROS) generation were measured in mice after a single injection of doxorubicin with or without quercetin pre-treatment. Key Results In H9c2 cells, quercetin reduced doxorubicin-induced apoptosis, mitochondrial dysfunction, ROS generation and DNA double-strand breaks. The quercetin-mediated protection against doxorubicin toxicity was characterized by decreased expression of Bid, p53 and oxidase (p47 and Nox1) and by increased expression of Bcl-2 and Bmi-1. Bmi-1 siRNA abolished the protective effect of quercetin against doxorubicin-induced toxicity in H9c2 cells. Furthermore, quercetin protected mice from doxorubicin-induced cardiac dysfunction that was accompanied by reduced ROS levels and lipid peroxidation, but enhanced the expression of Bmi-1 and anti-oxidative superoxide dismutase. Conclusions and Implications Our results demonstrate that quercetin decreased doxorubicin-induced cardiotoxicity in vitro and in vivo by reducing oxidative stress by up-regulation of Bmi-1 expression. The findings presented in this study have potential applications in preventing doxorubicin-induced cardiomyopathy. PMID:24902966

Hierarchical self-assembly: Self-organized nanostructures in a nematically ordered matrix of self-assembled polymeric chains

NASA Astrophysics Data System (ADS)

Mubeena, Shaikh; Chatterji, Apratim

2015-03-01

We report many different nanostructures which are formed when model nanoparticles of different sizes (diameter σn) are allowed to aggregate in a background matrix of semiflexible self-assembled polymeric wormlike micellar chains. The different nanostructures are formed by the dynamical arrest of phase-separating mixtures of micellar monomers and nanoparticles. The different morphologies obtained are the result of an interplay of the available free volume, the elastic energy of deformation of polymers, the density (chemical potential) of the nanoparticles in the polymer matrix, and, of course, the ratio of the size of self-assembling nanoparticles and self-avoidance diameter of polymeric chains. We have used a hybrid semi-grand-canonical Monte Carlo simulation scheme to obtain the (nonequilibrium) phase diagram of the self-assembled nanostructures. We observe rodlike structures of nanoparticles which get self-assembled in the gaps between the nematically ordered chains, as well as percolating gel-like network of conjoined nanotubes. We also find a totally unexpected interlocked crystalline phase of nanoparticles and monomers, in which each crystal plane of nanoparticles is separated by planes of perfectly organized polymer chains. We identified the condition which leads to such interlocked crystal structure. We suggest experimental possibilities of how the results presented in this paper could be used to obtain different nanostructures in the laboratory.

Au/CdS Hybrid Nanoparticles in Block Copolymer Micellar Shells.

PubMed

Koh, Haeng-Deog; Changez, Mohammad; Lee, Jae-Suk

2010-10-18

A polystyrene-block-poly(2-vinylpyridine) (PS-b-P2VP) micellar structure with a P2VP core containing 5 nm CdS nanoparticles (NPs) and a PS shell formed in toluene that is a good solvent for PS block undergoes the core-shell inversion by excess addition of methanol that is a good solvent for P2VP block. It leads to the formation of micellar shell-embedded CdS NPs in the methanol major phase. The spontaneous crystalline growth of Au NPs on the CdS surfaces positioned at micellar shells without a further reduction process is newly demonstrated. The nanostructure of Au/CdS/PS-b-P2VP hybrid NPs is confirmed by transmission electron microscopy, energy-dispersive X-ray, and UV-Vis absorption. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Synthesis, characterization and in vitro studies of doxorubicin-loaded magnetic nanoparticles grafted to smart copolymers on A549 lung cancer cell line.

PubMed

Akbarzadeh, Abolfazl; Samiei, Mohammad; Joo, Sang Woo; Anzaby, Maryam; Hanifehpour, Younes; Nasrabadi, Hamid Tayefi; Davaran, Soodabeh

2012-12-18

The aim of present study was to develop the novel methods for chemical and physical modification of superparamagnetic iron oxide nanoparticles (SPIONs) with polymers via covalent bonding entrapment. These modified SPIONs were used for encapsulation of anticancer drug doxorubicin. At first approach silane-grafted magnetic nanoparticles was prepared and used as a template for polymerization of the N-isopropylacrylamide (NIPAAm) and methacrylic acid (MAA) via radical polymerization. This temperature/pH-sensitive copolymer was used for preparation of DOX-loaded magnetic nanocomposites. At second approach Vinyltriethoxysilane-grafted magnetic nanoparticles were used as a template to polymerize PNIPAAm-MAA in 1, 4 dioxan and methylene-bis-acrylamide (BIS) was used as a cross-linking agent. Chemical composition and magnetic properties of Dox-loaded magnetic hydrogel nanocomposites were analyzed by FT-IR, XRD, and VSM. The results demonstrate the feasibility of drug encapsulation of the magnetic nanoparticles with NIPAAm-MAA copolymer via covalent bonding. The key factors for the successful prepardtion of magnetic nanocomposites were the structure of copolymer (linear or cross-linked), concentration of copolymer and concentration of drug. The influence of pH and temperature on the release profile of doxorubicin was examined. The in vitro cytotoxicity test (MTT assay) of both magnetic DOx-loaded nanoparticles was examined. The in vitro tests showed that these systems are no toxicity and are biocompatible. IC50 of DOx-loaded Fe3O4 nanoparticles on A549 lung cancer cell line showed that systems could be useful in treatment of lung cancer.

Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial.

PubMed

Tap, William D; Jones, Robin L; Van Tine, Brian A; Chmielowski, Bartosz; Elias, Anthony D; Adkins, Douglas; Agulnik, Mark; Cooney, Matthew M; Livingston, Michael B; Pennock, Gregory; Hameed, Meera R; Shah, Gaurav D; Qin, Amy; Shahir, Ashwin; Cronier, Damien M; Ilaria, Robert; Conti, Ilaria; Cosaert, Jan; Schwartz, Gary K

2016-07-30

Treatment with doxorubicin is a present standard of care for patients with metastatic soft-tissue sarcoma and median overall survival for those treated is 12-16 months, but few, if any, novel treatments or chemotherapy combinations have been able to improve these poor outcomes. Olaratumab is a human antiplatelet-derived growth factor receptor α monoclonal antibody that has antitumour activity in human sarcoma xenografts. We aimed to assess the efficacy of olaratumab plus doxorubicin in patients with advanced or metastatic soft-tissue sarcoma. We did an open-label phase 1b and randomised phase 2 study of doxorubicin plus olaratumab treatment in patients with unresectable or metastatic soft-tissue sarcoma at 16 clinical sites in the USA. For both the phase 1b and phase 2 parts of the study, eligible patients were aged 18 years or older and had a histologically confirmed diagnosis of locally advanced or metastatic soft-tissue sarcoma not previously treated with an anthracycline, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, and available tumour tissue to determine PDGFRα expression by immunohistochemistry. In the phase 2 part of the study, patients were randomly assigned in a 1:1 ratio to receive either olaratumab (15 mg/kg) intravenously on day 1 and day 8 plus doxorubicin (75 mg/m(2)) or doxorubicin alone (75 mg/m(2)) on day 1 of each 21-day cycle for up to eight cycles. Randomisation was dynamic and used the minimisation randomisation technique. The phase 1b primary endpoint was safety and the phase 2 primary endpoint was progression-free survival using a two-sided α level of 0.2 and statistical power of 0.8. This study was registered with ClinicalTrials.gov, number NCT01185964. 15 patients were enrolled and treated with olaratumab plus doxorubicin in the phase 1b study, and 133 patients were randomised (66 to olaratumab plus doxorubicin; 67 to doxorubicin alone) in the phase 2 trial, 129 (97%) of whom received at least one dose of

Hydrazone linked doxorubicin-PLA prodrug nanoparticles with high drug loading

NASA Astrophysics Data System (ADS)

Gatti, Simone; Agostini, Azzurra; Capasso Palmiero, Umberto; Colombo, Claudio; Peviani, Marco; Biffi, Alessandra; Moscatelli, Davide

2018-07-01

An optimal drug delivery system should be characterized by biocompatibility, biodegradability, high drug loading and favorable drug release profile. To achieve this goal a hydrazone linked doxorubicin-poly(lactic acid) prodrug (PLA-DOX) was synthesized by the functionalization of a short polymer chain produced by ring opening polymerization. The hydrophobic prodrug generated in this way was nanoprecipitated using a block copolymer to form polymeric nanoparticles (NPs) with a quantitative loading efficiency and a high and tunable drug loading. The effects of the concentration of the PLA-DOX prodrug and surfactant were studied by dynamic light scattering showing a range of NP size between 50 and 90 nm and monodispersed size distributions with polydispersity indexes lower then 0.27 up to a maximum DOX concentration of 27% w/w. The release profile of DOX from these NPs, tested at different pH conditions, showed a higher release rate in acidic conditions, consistent with the nature of the hydrazone bond which was used to conjugate the drug to the polymer. In vitro cytotoxicity studies performed on BV2 microglia-like cell line highlighted a specific cytotoxic effect of these NPs suggesting the maintenance of the drug efficacy and a modified release profile upon encapsulation of DOX in the NPs.

Protective effects of agmatine on doxorubicin-induced chronic cardiotoxicity in rat.

PubMed

Yarmohmmadi, Fatemeh; Rahimi, Nastaran; Faghir-Ghanesefat, Hedyeh; Javadian, Nina; Abdollahi, Alireza; Pasalar, Parvin; Jazayeri, Farahnaz; Ejtemaeemehr, Shahram; Dehpour, Ahmad Reza

2017-02-05

The detrimental cardio-toxic effect of doxorubicin, an effective chemotherapeutic agent, limited its clinical use. It has been claimed that doxorubicin cardio-toxicity occurs through calcium ions (Ca 2+ ) overload and reactive oxygen species production. Agmatine, an endogenous imidazoline receptor agonist, induce uptake of cytosolic Ca 2+ and cause an increase in activity of calcium pumps, including Ca 2+ -ATPase. Also it shows self-scavenging effect against reactive oxygen species production. Therefore, present study was designed to investigate the effects of agmatine against chronic cardio-toxicity of doxorubicin in rats. Male wistar rats were intraperitoneally injected with doxorubicin and agmatine four times a week for a month. Agmatine significantly alleviate the adverse effect of doxorubicin on left ventricular papillary muscle stimulation threshold and contractibility. Chronic co-administration of agmatine with doxorubicin blocked electrocardiographic changes induced by doxorubicin. In addition, agmatine improved body weight and decreased the mortality rate of animals by doxorubicin. Moreover, reversing the doxorubicin induced myocardial lesions was observed in animals treated by agmatine. A significant rise in the total antioxidant capacity of rat plasma was achieved in agmatine-treated animals in comparison to doxorubicin. To conclude, agmatine may improve therapeutic outcomes of doxorubicin since it exerts protective effects against doxorubicin-induced chronic cardiotoxicity in rats. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Micellar Electrolytes in Organic Electrochemical Transistors

NASA Astrophysics Data System (ADS)

Cicoira, Fabio; Giuseppe, Tarabella; Nanda, Gaurav; Iannotta, Salvatore; Santato, Clara

2012-02-01

Organic electrochemical transistors (OECTs) are promising for applications in sensing and bioelectronics. OECTs consist of a conducting polymer film (transistor channel) in contact with an electrolyte. A gate electrode immersed in the electrolyte controls the doping/dedoping level of the conducting polymer. OECTs can be operated in aqueous electrolytes, making possible the implementation of organic electronic materials at the interface with biology. The inherent signal amplification of OECTs has the potential to yield sensors with low detection limits and high sensitivity. In this talk we will present recent studies on OECTs using ionic surfactants (such as hexadecyl-trimethyl-ammonium bromide) as electrolytes. As the conducting polymer we used PEDOT:PSS, i.e. (Poly,3-4 ethylenedioxythiopene) doped with Poly(styrene sulphonate). Interestingly, ionic surfactant electrolytes result in large transistor current modulation, especially beyond the critical micellar concentration (CMC). Since micelles play a primary role in biological processes and drug-delivery systems, the use for micellar electrolytes opens new exciting opportunities for the use of OECTs in bioelectronics.

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.

Micellar electrokinetic chromatography with acid labile surfactant.

PubMed

Stanley, Bob; Lucy, Charles A

2012-02-24

We present a study of a degradable surfactant, sodium 4-[(2-methyl-2-undecyl-1,3-dioxolan-4-yl)methoxy]-1-propane sulfonate that is also known as an acid-labile surfactant (ALS). The performance of ALS as a pseudostationary phase is assessed and compared with established pseudostationary phases such as sodium dodecyl sulphate (SDS), volatile surfactants and polymeric micelles. ALS achieves separation efficiency of 100,000-145,000 theoretical plates and relative standard deviation (RSD) of electrophoretic mobility (n=5) of less than 3%. Retention factors with ALS are strongly correlated with those with SDS. This is shown by the R2=0.79 for all eleven analytes and an R2=0.992 for specifically the non-hydrogen bonding (NHB) analytes. However, ALS displays different selectivity than SDS for hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) solutes (R2 of 0.74 and 0.88, respectively). ALS is degraded to less surface active compounds in acidic solution. These less surface-active compounds are more compatible with the electrospray ionization mass spectrometry (ESI-MS). ALS has a half-life of 48 min at pH 4. ALS has the potential to couple micellar electrokinetic chromatography (MEKC) with the ESI-MS. ALS can be used as a pseudostationary phase for a high efficiency separation and later acid hydrolyzed to enable an ESI-MS analysis. Copyright © 2011 Elsevier B.V. All rights reserved.

Impact of thermooxidation of phytosteryl and phytostanyl fatty acid esters on cholesterol micellarization in vitro.

PubMed

Scholz, Birgit; Weiherer, Renate; Engel, Karl-Heinz

2017-09-01

The effects of thermooxidation of a phytosteryl/-stanyl and a phytostanyl fatty acid ester mixture on cholesterol micellarization were investigated using an in vitro digestion model simulating enzymatic hydrolysis by cholesterol esterase and subsequent competition of the liberated phytosterols/-stanols with cholesterol for incorporation into mixed micelles. As a first step, relationships between different doses of the ester mixtures and the resulting micellarized cholesterol were established. Subsequent subjection of the thermooxidized ester mixtures to the in vitro digestion model resulted in three principal observations: (i) thermal treatment of the ester mixtures led to substantial decreases of the intact esters, (ii) in vitro digestion of cholesterol in the presence of the thermooxidized ester mixtures resulted in significant increases of cholesterol micellarization, and (iii) the extents of the observed effects on cholesterol micellarization were strongly associated to the remaining contents of intact esters. The loss of efficacy to inhibit cholesterol micellarization due to thermally induced losses of intact esters corresponded to a loss of efficacy that would have been induced by an actual removal of these amounts of esters prior to the in vitro digestion. The obtained results suggest that in particular oxidative modifications of the fatty acid moieties might be responsible for the observed increases of cholesterol micellarization. Copyright © 2017 Elsevier Inc. All rights reserved.

Doxorubicin Blocks Cardiomyocyte Autophagic Flux by Inhibiting Lysosome Acidification.

PubMed

Li, Dan L; Wang, Zhao V; Ding, Guanqiao; Tan, Wei; Luo, Xiang; Criollo, Alfredo; Xie, Min; Jiang, Nan; May, Herman; Kyrychenko, Viktoriia; Schneider, Jay W; Gillette, Thomas G; Hill, Joseph A

2016-04-26

The clinical use of doxorubicin is limited by cardiotoxicity. Histopathological changes include interstitial myocardial fibrosis and the appearance of vacuolated cardiomyocytes. Whereas dysregulation of autophagy in the myocardium has been implicated in a variety of cardiovascular diseases, the role of autophagy in doxorubicin cardiomyopathy remains poorly defined. Most models of doxorubicin cardiotoxicity involve intraperitoneal injection of high-dose drug, which elicits lethargy, anorexia, weight loss, and peritoneal fibrosis, all of which confound the interpretation of autophagy. Given this, we first established a model that provokes modest and progressive cardiotoxicity without constitutional symptoms, reminiscent of the effects seen in patients. We report that doxorubicin blocks cardiomyocyte autophagic flux in vivo and in cardiomyocytes in culture. This block was accompanied by robust accumulation of undegraded autolysosomes. We go on to localize the site of block as a defect in lysosome acidification. To test the functional relevance of doxorubicin-triggered autolysosome accumulation, we studied animals with diminished autophagic activity resulting from haploinsufficiency for Beclin 1. Beclin 1(+/-) mice exposed to doxorubicin were protected in terms of structural and functional changes within the myocardium. Conversely, animals overexpressing Beclin 1 manifested an amplified cardiotoxic response. Doxorubicin blocks autophagic flux in cardiomyocytes by impairing lysosome acidification and lysosomal function. Reducing autophagy initiation protects against doxorubicin cardiotoxicity. © 2016 American Heart Association, Inc.

Polyelectrolyte-Mediated Transport of Doxorubicin Through the Bilayer Lipid Membrane

NASA Astrophysics Data System (ADS)

Yaroslavov, Alexander A.; Kitaeva, Marina V.; Melik-Nubarov, Nikolay S.; Menger, Frederic M.

A model is developed for the effect of ionic polymers on the transport of doxorubicin, an antitumor drug, through a bilayer membrane. Accordingly, a protonated (cationic) form of doxorubicin binds to an anionic polymer, poly(acrylic acid), the resulting complex being several hundred nanometers in size. Nevertheless, large complex species associate with neutral egg lecithin liposomes by means of hydrophobic attraction between the doxorubicin and the liposome bilayer. Then, the doxorubicin enters the liposome interior which has been imparted with an acidic buffer to protonate the doxorubicin. The rate of transmembrane Dox permeation decreases when elevating the polyacid-to-doxorubicin ratio. A cationic polymer, polylysine, being coupled with liposomes containing the negative lipid cardiolipin, accelerates membrane transport of doxorubicin with the maximum rate at a complete neutralization of the membrane charge by an interacting polycation. The effect of a polycation on doxorubicin transport becomes more pronounced as small negative liposomes (60-80 nm in diameter) are changed to larger ones (approx. 600 nm in diameter). An opportunity thus opens up for the manipulation of the kinetics of drug uptake by cells and, ultimately, the control of the pharmaceutical action of drugs.

Early and late arrhythmogenic effects of doxorubicin.

PubMed

Kilickap, Saadettin; Barista, Ibrahim; Akgul, Ebru; Aytemir, Kudret; Aksoy, Sercan; Tekuzman, Gulten

2007-03-01

To determine the incidence of early and late arrhythmogenic effects of doxorubicin-containing chemotherapy regimens. A prospective study including 29 patients who were treated with doxorubicin-containing regimens. Cardiac evaluation was based on 24-hour electrocardiographic monitorization (Holter), which was performed during the first cycle of doxorubicin-containing regimens, as well as after the last cycle of chemotherapy. The mean age of the patients was 45.8 +/- 15.1 (range 18-69). Holter records obtained during the first cycle of treatment revealed varying arrhythmias in 19 patients (65.5%) and in 18 (62.1%) patients after completion of therapy. One patient presented with syncope and both Mobitz Type 2 atrioventricular block and complete atrioventricular block were demonstrated. The patient subsequently underwent permanent pacemaker implantation. Doxorubicin may result in arrhythmias both in early and late periods of treatment. These arrhythmias are rarely life threatening.

Paclitaxel-loaded polymeric microparticles: Quantitative relationships between in vitro drug release rate and in vivo pharmacodynamics

PubMed Central

Tsai, Max; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

2013-01-01

Intraperitoneal therapy (IP) has demonstrated survival advantages in patients with peritoneal cancers, but has not become a widely practiced standard-of-care in part due to local toxicity and sub-optimal drug delivery. Paclitaxel-loaded, polymeric microparticles were developed to overcome these limitations. The present study evaluated the effects of microparticle properties on paclitaxel release (extent and rate) and in vivo pharmacodynamics. In vitro paclitaxel release from microparticles with varying physical characteristics (i.e., particle size, copolymer viscosity and composition) was evaluated. A method was developed to simulate the dosing rate and cumulative dose released in the peritoneal cavity based on the in vitro release data. The relationship between the simulated drug delivery and treatment outcomes of seven microparticle compositions was studied in mice bearing IP human pancreatic tumors, and compared to that of the intravenous Cremophor micellar paclitaxel solution used off-label in previous IP studies. Paclitaxel release from polymeric microparticles in vitro was multi-phasic; release was greater and more rapid from microparticles with lower polymer viscosities and smaller diameters (e.g., viscosity of 0.17 vs. 0.67 dl/g and diameter of 5–6 vs. 50–60 μm). The simulated drug release in the peritoneal cavity linearly correlated with treatment efficacy in mice (r2>0.8, p<0.001). The smaller microparticles, which distribute more evenly in the peritoneal cavity compared to the large microparticles, showed greater dose efficiency. For single treatment, the microparticles demonstrated up to 2-times longer survival extension and 4-times higher dose efficiency, relative to the paclitaxel/Cremophor micellar solution. Upon repeated dosing, the paclitaxel/Cremophor micellar solution showed cumulative toxicity whereas the microparticle that yielded 2-times longer survival did not display cumulative toxicity. The efficacy of IP therapy depended on both

MICELLAR ELECTROKINETIC CHROMATOGRAPHY-MASS SPECTROMETRY (R823292)

EPA Science Inventory

The combination of micellar electrokinetic chromatography (MEKC) with mass spectrometry (MS) is very attractive for the direct identification of analyte molecules, for the possibility of selectivity enhancement, and for the structure confirmation and analysis in a MS-MS mode. The...

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

Doxorubicin Delivery into Tumor Cells by Stable Cavitation without Contrast Agents.

PubMed

Chettab, Kamel; Mestas, Jean-Louis; Lafond, Maxime; Saadna, Djamel Eddine; Lafon, Cyril; Dumontet, Charles

2017-02-06

Doxorubicin, alone or in combination with other anticancer agents, is one of the most widely used chemotherapeutic agents and is administered in a wide range of cancers. However, the use of doxorubicin is limited due to its potential serious adverse reactions. Previous studies have established the ability of high intensity focused ultrasound (HIFU) in combination with various contrast agents to increase intracellular doxorubicin delivery in a targeted and noninvasive manner. In this study, we developed a new sonoporation device generating and monitoring acoustic cavitation bubbles without any addition of contrast agents. The device was used to potentiate the delivery of active doxorubicin into both adherent and suspended cell lines. Combining doxorubicin with ultrasound resulted in a significant enhancement of doxorubicin intracellular delivery and a decrease in cell viability at 48 and 72 h, in comparison to doxorubicin alone. More importantly and unlike previous investigations, our procedure does not require the addition of contrast agents to generate acoustic cavitation and to achieve high levels of doxorubicin delivery. The successful translation of this approach for an in vivo application may allow a significant reduction in the dosage and the adverse effects of doxorubicin therapy in patients.

Anaphylaxis to pegylated liposomal Doxorubicin: a case report.

PubMed

Sharma, L R; Subedi, A; Shah, B K

2014-08-01

Liposomal doxorubicin is used for the treatment of various cancers like epithelial ovarian cancers, multiple myeloma and sarcomas. We report the first case of anaphylaxis to pegylated liposomal doxorubicin.

Effective solubilization of chalcones in micellar phase: Conductivity and voltammetric study

NASA Astrophysics Data System (ADS)

Ahmed, Safeer; Khan, Gul Tiaz; Shah, Syed Sakhawat

2013-12-01

The solubilization of four chalcones, between aqueous and micellar phases of ionic surfactants (SDS and CTAB), was investigated by conductivity and cyclic voltammetry (CV) techniques. From conductivity data, a decrease in the critical micellar concentration (CMC) of the surfactants, in presence of the chalcones was ascribed to the decreased charge density over the surfactants. The results were seconded by thermodynamic parameters including degree of ionization (α), counter ion binding (β), and standard Gibbs free energy of micellization (Δ G {m/○}). The added surfactant decreased the peak current of the oxidized chalcone and shifted the peak potential either positively (in presence of SDS) or negatively (in presence of CTAB). The effect is rationalized as chalcone-surfactant interaction and quantitated as binding constant ( K b) assorting values from 8.78 to 552.97 M-1. The preferred solubilization of the chalcones in the micellar phase has been inferred.

Stepwise dynamics of an anionic micellar film - Formation of crown lenses.

PubMed

Lee, Jongju; Nikolov, Alex; Wasan, Darsh

2017-06-15

We studied the stepwise thinning of a microscopic circular foam film formed from an anionic micellar solution of sodium dodecyl sulfate (SDS). The foam film formed from the SDS micellar solution thins in a stepwise manner by the formation and expansion of a dark spot(s) of one layer less than the film thickness. During the last stages of film thinning (e.g., a film with one micellar layer), the dark spot expansion occurs via two steps. Initially, a small dark circular spot inside a film of several microns in size is formed, which expands at a constant rate. Then, a ridge along the expanding spot is formed. As the ridge grows, it becomes unstable and breaks into regular crown lenses, which are seen as white spots in the reflected light at the border of the dark spot with the surrounding thicker film. The Rayleigh type of instability contributes to the formation of the lenses, which results in the increase of the dark spot expansion rate with time. We applied the two-dimensional micellar-vacancy diffusion model and took into consideration the effects of the micellar layering and film volume on the rate of the dark spot expansion [Lee et al., 2016] to predict the rate of the dark spot expansion for a 0.06M SDS film in the presence of lenses. We briefly discuss the Rayleigh type of instability in the case of a 0.06M SDS foam film. The goals of this study are to reveal why the crown lenses are formed during the foam film stratification and to elucidate their effect on the rate of spot expansion. Copyright © 2017 Elsevier Inc. All rights reserved.

Selection of reservoirs amenable to micellar flooding. First annual report, October 1978-December 1979

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

Goldburg, A.; Price, H.

The overall project objective is to build a solid engineering base upon which the Department of Energy (DOE) can improve and accelerate the application of micellar-polymer recovery technology to Mid-Continent and California sandstone reservoirs. The purpose of the work carried out under these two contracts is to significantly aid, both DOE and the private sector, in gaining the following Project Objectives: to select the better micellar-polymer prospects in the Mid-Continent and California regions; to assess all of the available field and laboratory data which has a bearing on recovering oil by micellar-polymer projects in order to help identify and resolvemore » both the technical and economic constraints relating thereto; and to design and analyze improved field pilots and tests and to develop a micellar-polymer applications matrix for use by the potential technology users; i.e., owner/operators. The report includes the following: executive summary and project objectives; development of a predictive model for economic evaluation of reservoirs; reservoir data bank for micellar-polymer recovery evaluation; PECON program for preliminary economic evaluation; ordering of candidate reservoirs for additional data acquisition; validation of predictive model by numerical simulation; and work forecast. Tables, figures and references are included.« less

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.

Anaphylaxis to Pegylated Liposomal Doxorubicin: A Case Report

PubMed Central

Sharma, LR; Subedi, A; Shah, BK

2014-01-01

Liposomal doxorubicin is used for the treatment of various cancers like epithelial ovarian cancers, multiple myeloma and sarcomas. We report the first case of anaphylaxis to pegylated liposomal doxorubicin. PMID:25429486

Micellar liquid chromatography

NASA Astrophysics Data System (ADS)

Basova, Elena M.; Ivanov, Vadim M.; Shpigun, Oleg A.

1999-12-01

Background and possibilities of practical applications of micellar liquid chromatography (MLC) are considered. Various retention models in MLC, the effects of the nature and concentration of surfactants and organic modifiers, pH, temperature and ionic strength on the MLC efficiency and selectivity are discussed. The advantages and limitations of MLC are demonstrated. The performance of MLC is critically evaluated in relationship to the reversed-phase HPLC and ion-pair chromatography. The potential of application of MLC for the analysis of pharmaceuticals including that in biological fluids and separation of inorganic anions, transition metal cations, metal chelates and heteropoly compounds is described. The bibliography includes 146 references.

Micellar and Structural Stability of Nanoscale Amphiphilic Polymers: Implications for Anti-atherosclerotic Bioactivity

PubMed Central

Zhang, Yingyue; Li, Qi; Welsh, William J.; Moghe, Prabhas V.; Uhrich, Kathryn E.

2016-01-01

Atherosclerosis, a leading cause of mortality in developed countries, is characterized by the buildup of oxidized low-density lipoprotein (oxLDL) within the vascular intima, unregulated oxLDL uptake by macrophages, and ensuing formation of arterial plaque. Amphiphilic polymers (AMPs) comprised of a branched hydrophobic domain and a hydrophilic poly(ethylene glycol) (PEG) tail have shown promising anti-atherogenic effects through direct inhibition of oxLDL uptake by macrophages. In this study, five AMPs with controlled variations were evaluated for their micellar and structural stability in the presence of serum and lipase, respectively, to develop underlying structure-atheroprotective activity relations. In parallel, molecular dynamics simulations were performed to explore the AMP conformational preferences within an aqueous environment. Notably, AMPs with ether linkages between the hydrophobic arms and sugar backbones demonstrated enhanced degradation stability and storage stability, and also elicited enhanced anti-atherogenic bioactivity. Additionally, AMPs with increased hydrophobicity elicited increased atheroprotective bioactivity in the presence of serum. These studies provide key insights for designing more serum-stable polymeric micelles as prospective cardiovascular nanotherapies. PMID:26828687

Micellar and structural stability of nanoscale amphiphilic polymers: Implications for anti-atherosclerotic bioactivity.

PubMed

Zhang, Yingyue; Li, Qi; Welsh, William J; Moghe, Prabhas V; Uhrich, Kathryn E

2016-04-01

Atherosclerosis, a leading cause of mortality in developed countries, is characterized by the buildup of oxidized low-density lipoprotein (oxLDL) within the vascular intima, unregulated oxLDL uptake by macrophages, and ensuing formation of arterial plaque. Amphiphilic polymers (AMPs) comprised of a branched hydrophobic domain and a hydrophilic poly(ethylene glycol) (PEG) tail have shown promising anti-atherogenic effects through direct inhibition of oxLDL uptake by macrophages. In this study, five AMPs with controlled variations were evaluated for their micellar and structural stability in the presence of serum and lipase, respectively, to develop underlying structure-atheroprotective activity relations. In parallel, molecular dynamics simulations were performed to explore the AMP conformational preferences within an aqueous environment. Notably, AMPs with ether linkages between the hydrophobic arms and sugar backbones demonstrated enhanced degradation stability and storage stability, and also elicited enhanced anti-atherogenic bioactivity. Additionally, AMPs with increased hydrophobicity elicited increased atheroprotective bioactivity in the presence of serum. These studies provide key insights for designing more serum-stable polymeric micelles as prospective cardiovascular nanotherapies. Copyright © 2015 Elsevier Ltd. All rights reserved.

The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

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

Henninger, Christian; Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf; Huelsenbeck, Johannes

2012-05-15

Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by anmore » attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer.

PubMed

Cheng, Menglin; Rizwan, Asif; Jiang, Lu; Bhujwalla, Zaver M; Glunde, Kristine

2017-08-01

Abnormal choline phospholipid metabolism is a hallmark of cancer. The magnetic resonance spectroscopy (MRS) detected total choline (tCho) signal can serve as an early noninvasive imaging biomarker of chemotherapy response in breast cancer. We have quantified the individual components of the tCho signal, glycerophosphocholine (GPC), phosphocholine (PC) and free choline (Cho), before and after treatment with the commonly used chemotherapeutic drug doxorubicin in weakly metastatic human MCF7 and triple-negative human MDA-MB-231 breast cancer cells. While the tCho concentration did not change following doxorubicin treatment, GPC significantly increased and PC decreased. Of the two phosphatidylcholine-specific PLD enzymes, only PLD1, but not PLD2, mRNA was down-regulated by doxorubicin treatment. For the two reported genes encoding GPC phosphodiesterase, the mRNA of GDPD6, but not GDPD5, decreased following doxorubicin treatment. mRNA levels of choline kinase α (ChKα), which converts Cho to PC, were reduced following doxorubicin treatment. PLD1 and ChKα protein levels decreased following doxorubicin treatment in a concentration dependent manner. Treatment with the PLD1 specific inhibitor VU0155069 sensitized MCF7 and MDA-MB-231 breast cancer cells to doxorubicin-induced cytotoxicity. Low concentrations of 100 nM of doxorubicin increased MDA-MB-231 cell migration. GDPD6, but not PLD1 or ChKα, silencing by siRNA abolished doxorubicin-induced breast cancer cell migration. Doxorubicin induced GPC increase and PC decrease are caused by reductions in PLD1, GDPD6, and ChKα mRNA and protein expression. We have shown that silencing or inhibiting these genes/proteins can promote drug effectiveness and reduce adverse drug effects. Our findings emphasize the importance of detecting PC and GPC individually. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Biochemical characterization of the interactions between doxorubicin and lipidic GM1 micelles with or without paclitaxel loading

PubMed Central

Leonhard, Victoria; Alasino, Roxana V; Bianco, Ismael D; Garro, Ariel G; Heredia, Valeria; Beltramo, Dante M

2015-01-01

Doxorubicin (Dox) is an anthracycline anticancer drug with high water solubility, whose use is limited primarily due to significant side effects. In this study it is shown that Dox interacts with monosialoglycosphingolipid (GM1) ganglioside micelles primarily through hydrophobic interactions independent of pH and ionic strength. In addition, Dox can be incorporated even into GM1 micelles already containing highly hydrophobic paclitaxel (Ptx). However, it was not possible to incorporate Ptx into Dox-containing GM1 micelles, suggesting that Dox could be occupying a more external position in the micelles. This result is in agreement with a higher hydrolysis of Dox than of Ptx when micelles were incubated at alkaline pH. The loading of Dox into GM1 micelles was observed over a broad range of temperature (4°C–55°C). Furthermore, Dox-loaded micelles were stable in aqueous solutions exhibiting no aggregation or precipitation for up to 2 months when kept at 4°C–25°C and even after freeze–thawing cycles. Upon exposure to blood components, Dox-containing micelles were observed to interact with human serum albumin. However, the amount of human serum albumin that ended up being associated to the micelles was inversely related to the amount of Dox, suggesting that both could share their binding sites. In vitro studies on Hep2 cells showed that the cellular uptake and cytotoxic activity of Dox and Ptx from the micellar complexes were similar to those of the free form of these drugs, even when the micelle was covered with albumin. These results support the idea of the existence of different nano-domains in a single micelle and the fact that this micellar model could be used as a platform for loading and delivering hydrophobic and hydrophilic active pharmaceutical ingredients. PMID:26005348

Identification of yeast DNA topoisomerase II mutants resistant to the antitumor drug doxorubicin: implications for the mechanisms of doxorubicin action and cytotoxicity.

PubMed

Patel, S; Sprung, A U; Keller, B A; Heaton, V J; Fisher, L M

1997-10-01

Doxorubicin is a therapeutically useful anticancer drug that exerts multiple biological effects. Its antitumor and cardiotoxic properties have been ascribed to anthracycline-mediated free radical damage to DNA and membranes. Evidence for this idea comes in part from the selection by doxorubicin from stationary phase yeast cells of mutants (petites) deficient in mitochondrial respiration and therefore defective in free radical generation. However, doxorubicin also binds to DNA topoisomerase II, converting the enzyme into a DNA damaging agent through the trapping of a covalent enzyme-DNA complex termed the 'cleavable complex.' We have used yeast to determine whether stabilization of cleavable complexes plays a role in doxorubicin action and cytotoxicity. A plasmid-borne yeast TOP2 gene was mutagenized with hydroxylamine and used to transform drug-permeable yeast strain JN394t2-4, which carries a temperature-sensitive top2-4 mutation in its chromosomal TOP2 gene. Selection in growth medium at the nonpermissive temperature of 35 degrees in the presence of doxorubicin resulted in the isolation of plasmid-borne top2 mutants specifying functional doxorubicin-resistant DNA topoisomerase II. Single-point changes of Gly748 to Glu or Ala642 to Ser in yeast topoisomerase II, which lie in and adjacent to the CAP-like DNA binding domain, respectively, were identified as responsible for resistance to doxorubicin, implicating these regions in drug action. None of the mutants selected in JN394t2-4, which has a rad52 defect in double-strand DNA break repair, was respiration-deficient. We conclude that topoisomerase II is an intracellular target for doxorubicin and that the genetic background and/or cell proliferation status can determine the relative importance of topoisomerase II- versus free radical-killing.

Tailoring magnetic PLGA nanoparticles suitable for doxorubicin delivery

NASA Astrophysics Data System (ADS)

Tansık, Gülistan; Yakar, Arzu; Gündüz, Ufuk

2014-01-01

One of the main problems of current cancer chemotherapy is the lack of selectivity of anti-cancer drugs to tumor cells, which leads to systemic toxicity and adverse side effects. In order to overcome these limitations, researches on controlled drug delivery systems have gained much attention. Nanoscale-based drug delivery systems provide tumor targeting. Among many types of nanocarriers, superparamagnetic nanoparticles with their biocompatible polymer coatings can be targeted to an intented site by an external magnetic field. Thus, the drug can be carried to the targeted site safely. The aim of this study is to prepare poly( dl-lactic- co-glycolic acid) (PLGA)-coated magnetic nanoparticles and load anti-cancer drug, doxorubicin to them. For this purpose, magnetite (Fe3O4) iron oxide nanoparticles were synthesized as a magnetic core material (MNP) and then coated with oleic acid. Oleic acid-coated MNP (OA-MNP) was encapsulated into PLGA. Effects of different OA-MNP/PLGA ratios on magnetite entrapment efficiency were investigated. Doxorubicin-loaded magnetic polymeric nanoparticles (DOX-PLGA-MNP) were prepared. After the characterization of prepared nanoparticles, their cytotoxic effects on MCF-7 cell line were studied. PLGA-coated magnetic nanoparticles (PLGA-MNP) had a proper size and superparamagnetic character. The highest magnetite entrapment efficiency of PLGA-MNP was estimated as 63 % at 1:8 ratio. Cytotoxicity studies of PLGA-MNP did not indicate any notable cell death between the concentration ranges of 2 and 125 μg/ml. Drug loading efficiency was estimated as 32 %, and it was observed that DOX-PLGA-MNP showed significant cytotoxicity on MCF-7 cells compared to PLGA-MNP. The results showed that prepared nanoparticles have desired size and superparamagnetic characteristics without serious toxic effects on cells. These nanoparticles may be suitable for targeted drug delivery applications.

miR-137 regulates the constitutive androstane receptor and modulates doxorubicin sensitivity in parental and doxorubicin-resistant neuroblastoma cells

PubMed Central

Takwi, Apana A; Wang, Yue-Ming; Wu, Jing; Michaelis, Martin; Cinatl, Jindrich; Chen, Taosheng

2013-01-01

Chemotherapy is the most common treatment for cancer. However, multidrug resistance (MDR) remains a major obstacle to effective chemotherapy, limiting the efficacy of both conventional chemotherapeutic and novel biologic agents. The constitutive androstane receptor (CAR), a xenosensor, is a key regulator of MDR. It functions in xenobiotic detoxification by regulating the expression of phase I drug metabolizing enzymes and ATP-binding cassette (ABC) transporters, whose overexpression in cancers and whose role in drug resistance make them potential therapeutic targets for reducing MDR. MicroRNAs (miRNAs) are endogenous negative regulators of gene expression and have been implicated in most cellular processes, including drug resistance. Here we report the inversely related expression of miR-137 and CAR in parental and doxorubicin-resistant neuroblastoma cells, wherein miR-137 is down-regulated in resistant cells. miR-137 over-expression resulted in down-regulation of CAR protein and mRNA (via mRNA degradation); it sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and increased G2-phase cell cycle arrest) and reduced the in vivo growth rate of neuroblastoma xenografts. We observed similar results in cellular models of hepatocellular and colon cancers, indicating that the doxorubicin-sensitizing effect of miR-137 is not tumor type-specific. Finally, we show for the first time a negative feedback loop whereby miR-137 down-regulates CAR expression and CAR down-regulates miR-137 expression. Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells. These findings demonstrate that miR-137 is a crucial regulator of cancer response to doxorubicin treatment, and they identify miR-137 as a highly promising target to reduce CAR-driven doxorubicin resistance. PMID

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.

Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy.

PubMed

Moruno-Manchon, Jose F; Uzor, Ndidi-Ese; Kesler, Shelli R; Wefel, Jeffrey S; Townley, Debra M; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S; Sood, Anil K; Tsvetkov, Andrey S

2018-01-01

Doxorubicin, a commonly used anti-neoplastic agent, causes severe neurotoxicity. Doxorubicin promotes thinning of the brain cortex and accelerates brain aging, leading to cognitive impairment. Oxidative stress induced by doxorubicin contributes to cellular damage. In addition to mitochondria, peroxisomes also generate reactive oxygen species (ROS) and promote cell senescence. Here, we investigated if doxorubicin affects peroxisomal homeostasis in neurons. We demonstrate that the number of peroxisomes is increased in doxorubicin-treated neurons and in the brains of mice which underwent doxorubicin-based chemotherapy. Pexophagy, the specific autophagy of peroxisomes, is downregulated in neurons, and peroxisomes produce more ROS. 2-hydroxypropyl-β-cyclodextrin (HPβCD), an activator of the transcription factor TFEB, which regulates expression of genes involved in autophagy and lysosome function, mitigates damage of pexophagy and decreases ROS production induced by doxorubicin. We conclude that peroxisome-associated oxidative stress induced by doxorubicin may contribute to neurotoxicity, cognitive dysfunction, and accelerated brain aging in cancer patients and survivors. Peroxisomes might be a valuable new target for mitigating neuronal damage caused by chemotherapy drugs and for slowing down brain aging in general. Copyright © 2017 Elsevier Inc. All rights reserved.

Phosphatidylcholine embedded micellar systems: enhanced permeability through rat skin.

PubMed

Spernath, Aviram; Aserin, Abraham; Sintov, Amnon C; Garti, Nissim

2008-02-15

Micellar and microemulsion systems are excellent potential vehicles for delivery of drugs because of their high solubilization capacity and improved transmembrane bioavailability. Mixtures of propylene glycol (PG) and nonionic surfactants with sodium diclofenac (DFC) were prepared in the presence of phosphatidylcholine (PC) as transmembrane transport enhancers. Fully dilutable systems with maximum DFC solubilization capacity (SC) at pH 7 are presented. It was demonstrated that the concentrates underwent phase transitions from reverse micelles to swollen reverse micelles and, via the bicontinuous transitional mesophase, into inverted O/W microstructures. The SC decreases as a function of dilution. DFC transdermal penetration using rat skin in vitro correlated with SC, water content, effect of phospholipid content, presence of an oil phase, and ethanol. Skin penetration from the inverted bicontinuous mesophase and the skin penetration from the O/W-like microstructure were higher than that measured from the W/O-like droplets, especially when the micellar system containing the nonionic surfactant, sugar ester L-1695, and hexaglycerol laurate. PC embedded within the micelle interface significantly increased the penetration flux across the skin compared to micellar systems without the embedded PC at their interface. Moreover, the combination of PC with HECO40 improved the permeation rate (P) and shortened the lag-time (T(L)).

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.

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.

Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes.

PubMed

Karagiannis, Tom C; Lin, Ann J E; Ververis, Katherine; Chang, Lisa; Tang, Michelle M; Okabe, Jun; El-Osta, Assam

2010-10-01

Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by γH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer.

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

Pharmacokinetics of Doxorubicin in Pregnant Women

PubMed Central

Ryu, Rachel J.; Eyal, Sara; Kaplan, Henry G.; Akbarzadeh, Arezoo; Hays, Karen; Puhl, Kristin; Easterling, Thomas R.; Berg, Stacey L.; Scorsone, Kathleen A.; Feldman, Eric M.; Umans, Jason G.; Miodovnik, Menachem; Hebert, Mary F.

2014-01-01

Purpose Our objective was to evaluate the pharmacokinetics (PK) of doxorubicin during pregnancy compared to previously published data from non-pregnant subjects. Methods During mid- to late-pregnancy, serial blood and urine samples were collected over 72 hours from 7 women treated with doxorubicin for malignancies. PK parameters were estimated using noncompartmental techniques. Pregnancy parameters were compared to those previously reported non-pregnant subjects. Results During pregnancy, mean (± SD) doxorubicin PK parameters utilizing 72 hour sampling were: clearance (CL), 412 ± 80 mL/min/m2; steady-state volume of distribution (Vss), 1132 ± 476 L/m2; and terminal half-life (T1/2), 40.3 ± 8.9 hr. The BSA-adjusted CL was significantly decreased (p < 0.01) and T1/2 was not different compared to non-pregnant women. Truncating our data to 48 hours, PK parameters were: CL, 499 ± 116 ml/min/m2; Vss, 843 ± 391 L/m2; and T1/2, 24.8 ± 5.9 hr. The BSA-adjusted CL in pregnancy compared to non-pregnant data was significantly decreased in 2 of 3 non-pregnant studies (p < 0.05, < 0.05, NS). Vss and T1/2 were not significantly different. Conclusions In pregnant subjects, we observed significantly lower doxorubicin CL in our 72 hour and most of our 48 hour sampling comparisons with previously reported non-pregnant subjects. However, the parameters were within the range previously reported in smaller studies. At this time, we cannot recommend alternate dosage strategies for pregnant women. Further research is needed to understand the mechanism of doxorubicin pharmacokinetic changes during pregnancy and optimize care for pregnant women. PMID:24531558

Synthesis of Well-defined Amphiphilic Block Copolymers by Organotellurium-Mediated Living Radical Polymerization (TERP).

PubMed

Kumar, Santosh; Changez, Mohammad; Murthy, C N; Yamago, Shigeru; Lee, Jae-Suk

2011-10-04

Low-molecular weight amphiphilic diblock copolymers, polystyrene-block-poly (2-vinylpyridine) (PS-b-P2VP), and (P2VP-b-PS) with different block ratios were synthesized for the first time via organotellurium-mediated living radical polymerization (TERP). For both the homo- and block copolymerizations, good agreement between the theoretical, and experimental molecular weights was found with nearly 100% yield in every case. The molecular weight distribution for all the samples ranged between 1.10 and 1.24, which is well below the theoretical lower limit of 1.50 for a conventional free radical polymerization. Furthermore, a very simple approach to producing highly dense arrays of titania nanoparticles (TiO2 ) is presented using a site-selective reaction of titanium tetraisopropoxide within the P2VP domains of micellar film of P2VP-b-PS in toluene through the sol-gel method. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Visible-light system for detecting doxorubicin contamination on skin and surfaces.

PubMed

Van Raalte, J; Rice, C; Moss, C E

1990-05-01

A portable system that uses fluorescence stimulated by visible light to identify doxorubicin contamination on skin and surfaces was studied. When activated by violet-blue light in the 465-nm range, doxorubicin fluoresces, emitting orange-red light in the 580-nm range. The light source to stimulate fluorescence was a slide projector with a filter to selectively pass short-wave (blue) visible light. Fluorescence was both observed visually with viewing spectacles and photographed. Solutions of doxorubicin in sterile 0.9% sodium chloride injection were prepared in nine standard concentrations ranging from 2 to 0.001 mg/mL. Droplets of each admixture were placed on stainless steel, laboratory coat cloth, pieces of latex examination glove, bench-top absorbent padding, and other materials on which antineoplastics might spill or leak. These materials then were stored for up to eight weeks and photographed weekly. The relative ability of water, household bleach, hydrogen peroxide solution, and soap solution to deactivate doxorubicin was also measured. Finally, this system was used to inspect the antineoplastic-drug preparation and administration areas of three outpatient cancer clinics for doxorubicin contamination. Doxorubicin fluorescence was easily detectable with viewing spectacles when a slide projector was used as the light source. The photographic method was sensitive for doxorubicin concentrations from 2.0 to 0.001 mg/mL. Immersion of study materials in bleach for one minute eliminated detectable fluorescence. Doxorubicin contamination is detectable for at least eight weeks in the ambient environment. Probable doxorubicin contamination was detected in two of the three clinics surveyed. A safe, portable system that uses fluorescence stimulated by visible light is a sensitive method for detecting doxorubicin on skin and surfaces.

Doxorubicin coupled to lactosaminated albumin: Effects on rats with liver fibrosis and cirrhosis.

PubMed

Di Stefano, G; Fiume, L; Domenicali, M; Busi, C; Chieco, P; Kratz, F; Lanza, M; Mattioli, A; Pariali, M; Bernardi, M

2006-06-01

The conjugate of doxorubicin with lactosaminated human albumin has the potential of increasing the doxorubicin efficacy in the treatment of hepatocellular carcinomas expressing the asialoglycoprotein receptor. However, coupled doxorubicin also accumulates in the liver, which might damage hepatocytes. To verify whether coupled doxorubicin impairs liver function in rats with liver fibrosis and cirrhosis. Coupled doxorubicin was administered using the same schedule which exerted an antineoplastic effect on rat hepatocellular carcinomas (4-weekly injections of doxorubicin at 1 microg/g). Liver fibrosis/cirrhosis was produced by carbon tetrachloride (CCl4) poisoning. Liver samples were studied histologically. Serum parameters of liver function and viability were determined. In normal rats, administration of coupled doxorubicin neither caused microscopic changes of hepatocytes nor modified serum liver parameters. In rats with fibrosis/cirrhosis, although a selective doxorubicin accumulation within the liver followed coupled doxorubicin administration, the drug did not have a detrimental effect on the histology of the liver and, among serum liver tests, only alanine aminotransferase and aspartate aminotransferase levels were moderately modified. Coupled doxorubicin can be administered to rats with liver fibrosis/cirrhosis without inducing a severe liver damage. If further studies will confirm the efficacy and safety of this compound, coupled doxorubicin therapy may open a new perspective in the treatment of hepatocellular carcinoma.

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.

Cross-Linked Micellar Spherical Nucleic Acids from Thermoresponsive Templates

PubMed Central

2017-01-01

A one-pot synthesis of micellar spherical nucleic acid (SNA) nanostructures using Pluronic F127 as a thermoresponsive template is reported. These novel constructs are synthesized in a chemically straightforward process that involves intercalation of the lipid tails of DNA amphiphiles (CpG motifs for TLR-9 stimulation) into the hydrophobic regions of Pluronic F127 micelles, followed by chemical cross-linking and subsequent removal of non-cross-linked structures. The dense nucleic acid shell of the resulting cross-linked micellar SNA enhances their stability in physiological media and facilitates their rapid cellular internalization, making them effective TLR-9 immunomodulatory agents. These constructs underscore the potential of SNAs in regulating immune response and address the relative lack of stability of noncovalent constructs. PMID:28207251

Effect of ripening, heat processing, and fat type on the micellarization of pigments from jalapeño peppers.

PubMed

Victoria-Campos, Claudia I; Ornelas-Paz, José de Jesús; Yahia, Elhadi M; Jiménez-Castro, Jorge A; Cervantes-Paz, Braulio; Ibarra-Junquera, Vrani; Pérez-Martínez, Jaime David; Zamudio-Flores, Paul B; Escalante-Minakata, Pilar

2013-10-16

Raw and heat-processed (boiled and grilled) jalapeño peppers at three intermediate ripening stages (brown, 50% red, and 75% red) were digested in vitro without fat and in the presence of soybean oil (SO) or beef tallow (BT), and the micellarization of their lipid soluble pigments (LSP) was measured. The micelles from digestions with brown, 50% red, and 75% red peppers contained up to 27, 35, and 29 different LSP, respectively. Boiling and grilling decreased the micellarization of LSP from brown peppers, whereas the opposite was observed with 75% red peppers. Heat processing did not clearly affect the micellarization of LSP from 50% red fruits. The impact of fat on LSP micellarization was ripening-dependent, but the micellarization of the less polar carotenoids was always increased by SO or BT. This positive effect of fat was higher with SO than with BT.

The influence of bile acids on the oral bioavailability of vitamin K encapsulated in polymeric micelles.

PubMed

van Hasselt, P M; Janssens, G E P J; Slot, T K; van der Ham, M; Minderhoud, T C; Talelli, M; Akkermans, L M; Rijcken, C J F; van Nostrum, C F

2009-01-19

The purpose of this study was to assess the ability of polymeric micelles to enable gastrointestinal absorption of the extremely hydrophobic compound vitamin K, by comparison of its absorption in bile duct ligated and sham operated rats. Hereto, vitamin K was encapsulated in micelles composed of mPEG(5000)-b-p(HPMAm-lac(2)), a thermosensitive block copolymer. Vitamin K plasma levels rose significantly upon gastric administration of 1 mg vitamin K encapsulated in polymeric micelles in sham operated rats, but not after bile duct ligation (AUC 4543 and 1.64 ng/mL/h respectively, p<0.01). Duodenal administration of polymeric micelles together with bile acids in bile duct ligated rats fully restored absorption. Dynamic light scattering time series showed a significant and dose dependent rise in micellar size in the presence of bile acids in vitro, indicating the gradual formation of mixed micelles during the first 3 h of incubation. The highest bile acid amounts (11 mM deoxycholic acid and 41 mM taurocholic acid) eventually caused aggregation of the loaded micelles after the formation of mixed micelles. These data suggest that the gastrointestinal absorption of encapsulated vitamin K from polymeric micelles is mediated by free bile and that uptake of intact micelles through pinocytosis is insignificant.

Albumin as a "Trojan Horse" for polymeric nanoconjugate transendothelial transport across tumor vasculatures for improved cancer targeting.

PubMed

Yin, Qian; Tang, Li; Cai, Kaimin; Yang, Xujuan; Yin, Lichen; Zhang, Yanfeng; Dobrucki, Lawrence W; Helferich, William G; Fan, Timothy M; Cheng, Jianjun

2018-05-01

Although polymeric nanoconjugates (NCs) hold great promise for the treatment of cancer patients, their clinical utility has been hindered by the lack of efficient delivery of therapeutics to targeted tumor sites. Here, we describe an albumin-functionalized polymeric NC (Alb-NC) capable of crossing the endothelium barrier through a caveolae-mediated transcytosis pathway to better target cancer. The Alb-NC is prepared by nanoprecipitation of doxorubicin (Doxo) conjugates of poly(phenyl O-carboxyanhydrides) bearing aromatic albumin-binding domains followed by subsequent surface decoration of albumin. The administration of Alb-NCs into mice bearing MCF-7 human breast cancer xenografts with limited tumor vascular permeability resulted in markedly increased tumor accumulation and anti-tumor efficacy compared to their conventional counterpart PEGylated NCs (PEG-NCs). The Alb-NC provides a simple, low-cost and broadly applicable strategy to improve the cancer targeting efficiency and therapeutic effectiveness of polymeric nanomedicine.

Grape seed and skin extract protects kidney from doxorubicin-induced oxidative injury.

PubMed

Mokni, Meherzia; Hamlaoui, Sonia; Kadri, Safwen; Limam, Ferid; Amri, Mohamed; Marzouki, Lamjed; Aouani, Ezzedine

2016-05-01

The study investigated the protective effect of grape seed and skin extract (GSSE) against doxorubicin-induced renal toxicity in healthy rats. Animals were treated with GSSE or not (control), for 8 days, administered with doxorubicin (20mg/kg) in the 4th day, and renal function as well as oxidative stress parameters were evaluated. Data showed that doxorubicin induced renal toxicity by affecting renal architecture and plasma creatinine. Doxorubicin also induced an oxidative stress characterized by an increase in malondialdehyde (MDA), calcium and H(2)O(2) and a decrease in catalase (CAT) and superoxide dismutase (SOD). Unexpectedly doxorubicin increased peroxidase (POD) and decreased carbonyl protein and plasma urea. Treatment with GSSE counteracted almost all adverse effects induced by doxorubicin. Data suggest that doxorubicin induced an oxidative stress into rat kidney and GSSE exerted antioxidant properties, which seem to be mediated by the modulation of intracellular calcium.

Engineering cocrystal solubility, stability, and pH(max) by micellar solubilization.

PubMed

Huang, Neal; Rodríguez-Hornedo, Naír

2011-12-01

Cocrystals offer great promise in enhancing drug aqueous solubilities, but face the challenge of conversion to a less soluble drug when in contact with solvent. This manuscript shows that differential solubilization of cocrystal components by micelles can impart thermodynamic stability to otherwise unstable cocrystals. The theoretical foundation for controlling cocrystal solubility and stability is presented by considering the contributions of micellar solubilization and ionization of cocrystal components. A surfactant critical stabilization concentration (CSC) and a solution pH (pH(max)) where cocrystal and drug are thermodynamically stable are shown to characterize cocrystal stability in micellar solutions. The solubility, CSC, and pH(max) of carbamazepine cocrystals in micellar solutions of sodium lauryl sulfate predicted by the models are in very good agreement with experimental measurements. The findings from this work demonstrate that cocrystal CSC and pH(max) can be tailored from the selection of coformer and solubilizing additives such as surfactants, thus providing an unprecedented level of control over cocrystal stability and solubility via solution phase chemistry. Copyright © 2011 Wiley-Liss, Inc.

Fabrication of size-controlled nanoring arrays by selective incorporation of ionic liquids in diblock copolymer micellar cores

NASA Astrophysics Data System (ADS)

Kim, Sung-Soo; Kang, Donghwi; Sohn, Byeong-Hyeok

2017-06-01

We report the synthesis of arrayed nanorings with tunable physical dimensions from thin films of polystyrene-block-poly(4-vinylpyridine) (PS-P4VP) micelles. For accurate control of the inner and outer diameters of the nanorings, we added imidazolium-based ionic liquids (ILs) into the micellar solution, which were eventually incorporated into the micellar cores. We observed the structural changes of the micellar cores coated on a substrate due to the presence of ILs. The spin-coated micellar cores were treated with an acidic precursor solution and generated toroid nanostructures, of which size depended on the amount of IL loaded into the micelles. We then treated the transformed micellar films with oxygen plasma to produce arrays of various metal and oxide nanorings on a substrate. The spacings and diameters of nanorings were governed by the molecular weight of the PS-P4VP and the amount of IL used. We also demonstrated that arrayed Pt nanorings enabled the fabrication of reduced graphene oxide anti-nanoring arrays via a catalytic tailoring process.

Trichostatin A accentuates doxorubicin-induced hypertrophy in cardiac myocytes

PubMed Central

Karagiannis, Tom C; Lin, Ann JE; Ververis, Katherine; Chang, Lisa; Tang, Michelle M; Okabe, Jun; El-Osta, Assam

2010-01-01

Histone deacetylase inhibitors represent a new class of anticancer therapeutics and the expectation is that they will be most effective when used in combination with conventional cancer therapies, such as the anthracycline, doxorubicin. The dose-limiting side effect of doxorubicin is severe cardiotoxicity and evaluation of the effects of combinations of the anthracycline with histone deacetylase inhibitors in relevant models is important. We used a well-established in vitro model of doxorubicin-induced hypertrophy to examine the effects of the prototypical histone deacetylase inhibitor, Trichostatin A. Our findings indicate that doxorubicin modulates the expression of the hypertrophy-associated genes, ventricular myosin light chain-2, the alpha isoform of myosin heavy chain and atrial natriuretic peptide, an effect which is augmented by Trichostatin A. Furthermore, we show that Trichostatin A amplifies doxorubicin-induced DNA double strand breaks, as assessed by γH2AX formation. More generally, our findings highlight the importance of investigating potential side effects that may be associated with emerging combination therapies for cancer. PMID:20930262

Self-Assembled Polymeric Micelles Based on Hyaluronic Acid-g-Poly(d,l-lactide-co-glycolide) Copolymer for Tumor Targeting

PubMed Central

Son, Gyung Mo; Kim, Hyun Yul; Ryu, Je Ho; Chu, Chong Woo; Kang, Dae Hwan; Park, Su Bum; Jeong, Young-IL

2014-01-01

Graft copolymer composed hyaluronic acid (HA) and poly(d,l-lactide-co-glycolide) (PLGA) (HAgLG) was synthesized for antitumor targeting via CD44 receptor of tumor cells. The carboxylic end of PLGA was conjugated with hexamethylenediamine (HMDA) to have amine end group in the end of chain (PLGA-amine). PLGA-amine was coupled with carboxylic acid of HA. Self-assembled polymeric micelles of HAgLG have spherical morphologies and their sizes were around 50–200 nm. Doxorubicin (DOX)-incorporated polymeric micelles were prepared by dialysis procedure. DOX was released over 4 days and its release rate was accelerated by the tumoric enzyme hyaluronidase. To assess targetability of polymeric micelles, CD44-positive HepG2 cells were employed treated with fluorescein isothiocyanate (FITC)-labeled polymeric micelles. HepG2 cells strongly expressed green fluorescence at the cell membrane and cytosol. However, internalization of polymeric micelles were significantly decreased when free HA was pretreated to block the CD44 receptor. Furthermore, the CD44-specific anticancer activity of HAgLG polymeric micelles was confirmed using CD44-negative CT26 cells and CD44-positive HepG2 cells. These results indicated that polymeric micelles of HaLG polymeric micelles have targetability against CD44 receptor of tumor cells. We suggest HAgLG polymeric micelles as a promising candidate for specific drug targeting. PMID:25216338

Doxorubicin Action on Mitochondria: Relevance to Osteosarcoma Therapy?

PubMed

Armstrong, Jo; Dass, Crispin R

2018-01-01

The mitochondria may very well determine the final commitment of the cell to death, particularly in times of energy stress. Cancer chemotherapeutics such as the anthracycline doxorubicin perturb mitochondrial structure and function in tumour cells, as evidenced in osteosarcoma, for which doxorubicin is used clinically as frontline therapy. This same mechanism of cell inhibition is also pertinent to doxorubicin's primary cause of side-effects, that to the cardiac tissue, culminating in such dire events as congestive heart failure. Reactive oxygen species are partly to blame for this effect on the mitochondria, which impact the electron transport chain. As this review highlights that, there is much more to be learnt about the mitochondria and how it is affected by such effective but toxic drugs as doxorubicin. Such information will aid researchers who search for cancer treatment able to preserve mitochondrial number and function in normal cells. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Fundamental Characterization of the Micellar Self-Assembly of Sophorolipid Esters.

PubMed

Koh, Amanda; Todd, Katherine; Sherbourne, Ezekiel; Gross, Richard A

2017-06-13

Surfactants are ubiquitous constituents of commercial and biological systems that function based on complex structure-dependent interactions. Sophorolipid (SL) n-alkyl esters (SL-esters) comprise a group of modified naturally derived glycolipids from Candida bombicola. Herein, micellar self-assembly behavior as a function of SL-ester chain length was studied. Surface tensions as low as 31.2 mN/m and critical micelle concentrations (CMCs) as low as 1.1 μM were attained for diacetylated SL-decyl ester (dASL-DE) and SL-octyl ester, respectively. For deacetylated SL-esters, CMC values reach a lower limit at SL-ester chains above n-butyl (SL-BE, 1-3 μM). This behavior of SL-esters with increasing hydrophobic tail length is unlike other known surfactants. Diffusion-ordered spectroscopy (DOSY) and T 1 relaxation NMR experiments indicate this behavior is due to a change in intramolecular interactions, which impedes the self-assembly of SL-esters with chain lengths above SL-BE. This hypothesis is supported by micellar thermodynamics where a disruption in trends occurs at n-alkyl ester chain lengths above those of SL-BE and SL-hexyl ester (SL-HE). Diacetylated (dA) SL-esters exhibit an even more unusual trend in that CMC increases from 1.75 to 815 μM for SL-ester chain lengths of dASL-BE and dASL-DE, respectively. Foaming studies, performed to reveal the macroscopic implications of SL-ester micellar behavior, show that the observed instability in foams formed using SL-esters are due to coalescence, which highlights the importance of understanding intermicellar interactions. This work reveals that SL-esters are an important new family of green high-performing surfactants with unique structure-property relationships that can be tuned to optimize micellar characteristics.

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

PubMed Central

Shimauchi, Tsukasa; Numaga-Tomita, Takuro; Ito, Tomoya; Nishimura, Akiyuki; Matsukane, Ryosuke; Oda, Sayaka; Hoka, Sumio; Ide, Tomomi; Koitabashi, Norimichi; Uchida, Koji; Sumimoto, Hideki; Mori, Yasuo

2017-01-01

Myocardial atrophy is a wasting of cardiac muscle due to hemodynamic unloading. Doxorubicin is a highly effective anticancer agent but also induces myocardial atrophy through a largely unknown mechanism. Here, we demonstrate that inhibiting transient receptor potential canonical 3 (TRPC3) channels abolishes doxorubicin-induced myocardial atrophy in mice. Doxorubicin increased production of ROS in rodent cardiomyocytes through hypoxic stress–mediated upregulation of NADPH oxidase 2 (Nox2), which formed a stable complex with TRPC3. Cardiomyocyte-specific expression of TRPC3 C-terminal minipeptide inhibited TRPC3-Nox2 coupling and suppressed doxorubicin-induced reduction of myocardial cell size and left ventricular (LV) dysfunction, along with its upregulation of Nox2 and oxidative stress, without reducing hypoxic stress. Voluntary exercise, an effective treatment to prevent doxorubicin-induced cardiotoxicity, also downregulated the TRPC3-Nox2 complex and promoted volume load–induced LV compliance, as demonstrated in TRPC3-deficient hearts. These results illustrate the impact of TRPC3 on LV compliance and flexibility and, focusing on the TRPC3-Nox2 complex, provide a strategy for prevention of doxorubicin-induced cardiomyopathy. PMID:28768915

Solubilization of Therapeutic Agents in Micellar Nanomedicines

PubMed Central

Vuković, Lela; Madriaga, Antonett; Kuzmis, Antonina; Banerjee, Amrita; Tang, Alan; Tao, Kevin; Shah, Neil; Král, Petr; Onyuksel, Hayat

2014-01-01

We use atomistic molecular dynamics simulations to reveal the binding mechanisms of therapeutic agents in PEG-ylated micellar nanocarriers (SSM). In our experiments, SSM in buffer solutions can solubilize either ≈ 11 small bexarotene molecules or ≈ 6 (2 in low ionic strength buffer) human vasoactive intestinal peptide (VIP) molecules. Free energy calculations reveal that molecules of the poorly water soluble drug bexarotene can reside at the micellar ionic interface of the PEG corona, with their polar ends pointing out. Alternatively, they can reside in the alkane core center, where several bexarotene molecules can self-stabilize by forming a cluster held together by a network of hydrogen bonds. We also show that highly charged molecules, such as VIP, can be stabilized at the SSM ionic interface by Coulombic coupling between their positively charged residues and the negatively charged phosphate head-groups of the lipids. The obtained results illustrate that atomistic simulations can reveal drug solubilization character in nanocarriers and be used in efficient optimization of novel nanomedicines. PMID:24283508

Modulation of Induced Cytotoxicity of Doxorubicin by Using Apoferritin and Liposomal Cages

PubMed Central

Gumulec, Jaromir; Fojtu, Michaela; Raudenska, Martina; Sztalmachova, Marketa; Skotakova, Anna; Vlachova, Jana; Skalickova, Sylvie; Nejdl, Lukas; Kopel, Pavel; Knopfova, Lucia; Adam, Vojtech; Kizek, Rene; Stiborova, Marie; Babula, Petr; Masarik, Michal

2014-01-01

Doxorubicin is an effective chemotherapeutic drug, however, its toxicity is a significant limitation in therapy. Encapsulation of doxorubicin inside liposomes or ferritin cages decreases cardiotoxicity while maintaining anticancer potency. We synthesized novel apoferritin- and liposome-encapsulated forms of doxorubicin (“Apodox” and “lip-8-dox”) and compared its toxicity with doxorubicin and Myocet on prostate cell lines. Three different prostatic cell lines PNT1A, 22Rv1, and LNCaP were chosen. The toxicity of the modified doxorubicin forms was compared to conventional doxorubicin using the MTT assay, real-time cell impedance-based cell growth method (RTCA), and flow cytometry. The efficiency of doxorubicin entrapment was 56% in apoferritin cages and 42% in the liposome carrier. The accuracy of the RTCA system was verified by flow-cytometric analysis of cell viability. The doxorubicin half maximal inhibition concentrations (IC50) were determined as 170.5, 234.0, and 169.0 nM for PNT1A, 22Rv1, and LNCaP, respectively by RTCA. Lip8-dox is less toxic on the non-tumor cell line PNT1A compared to doxorubicin, while still maintaining the toxicity to tumorous cell lines similar to doxorubicin or epirubicin (IC50 = 2076.7 nM for PNT1A vs. 935.3 and 729.0 nM for 22Rv1 and LNCaP). Apodox IC50 was determined as follows: 603.1, 1344.2, and 931.2 nM for PNT1A, 22Rv1, and LNCaP. PMID:25514405

Micellar-shape anisometry near isotropic-liquid-crystal phase transitions

NASA Astrophysics Data System (ADS)

Itri, R.; Amaral, L. Q.

1993-04-01

Micellar phases of the sodium dodecyl (lauryl) sulfate (SLS)-water-decanol system have been studied by x-ray scattering in the isotropic (I) phase, with emphasis on the I-->hexagonal (Hα) and I-->nematic-cylindrical (Nc) lyotropic liquid-crystal phase transitions. Analysis of the scattering curves is made through modeling of the product P(q)S(q), where P(q) is the micellar form factor and S(q) is the intermicellar interference function, calculated from screened Coulombic repulsion in a mean spherical approximation. Results show that micelles grow more by decanol addition near the I-->Nc transition (anisometry ν~=3) than by increased amphiphile concentration in the binary system near the I-->Hα phase transition (ν~=2.4). These results compare well with recent theories for isotropic-liquid-crystal phase transitions.

Propofol ameliorates doxorubicin-induced oxidative stress and cellular apoptosis in rat cardiomyocytes

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

Lai, H.C.; Department of Medicine and Cardiovascular Research Center, National Yang-Ming University School of Medicine, Taipei, Taiwan; Yeh, Y.C.

2011-12-15

Background: Propofol is an anesthetic with pluripotent cytoprotective properties against various extrinsic insults. This study was designed to examine whether this agent could also ameliorate the infamous toxicity of doxorubicin, a widely-used chemotherapeutic agent against a variety of cancer diseases, on myocardial cells. Methods: Cultured neonatal rat cardiomyocytes were administrated with vehicle, doxorubicin (1 {mu}M), propofol (1 {mu}M), or propofol plus doxorubicin (given 1 h post propofol). After 24 h, cells were harvested and specific analyses regarding oxidative/nitrative stress and cellular apoptosis were conducted. Results: Trypan blue exclusion and MTT assays disclosed that viability of cardiomyocytes was significantly reduced bymore » doxorubicin. Contents of reactive oxygen and nitrogen species were increased and antioxidant enzymes SOD1, SOD2, and GPx were decreased in these doxorubicin-treated cells. Mitochondrial dehydrogenase activity and membrane potential were also depressed, along with activation of key effectors downstream of mitochondrion-dependent apoptotic signaling. Besides, abundance of p53 was elevated and cleavage of PKC-{delta} was induced in these myocardial cells. In contrast, all of the above oxidative, nitrative and pro-apoptotic events could be suppressed by propofol pretreatment. Conclusions: Propofol could extensively counteract oxidative/nitrative and multiple apoptotic effects of doxorubicin in the heart; hence, this anesthetic may serve as an adjuvant agent to assuage the untoward cardiac effects of doxorubicin in clinical application. -- Highlights: Black-Right-Pointing-Pointer We evaluate how propofol prevents doxorubicin-induced toxicity in cardiomyocytes. Black-Right-Pointing-Pointer Propofol reduces doxorubicin-imposed nitrative and oxidative stress. Black-Right-Pointing-Pointer Propofol suppresses mitochondrion-, p53- and PKC-related apoptotic signaling. Black-Right-Pointing-Pointer Propofol ameliorates apoptosis and

Nanoengineered mesoporous silica nanoparticles for smart delivery of doxorubicin

NASA Astrophysics Data System (ADS)

Mishra, Akhilesh Kumar; Pandey, Himanshu; Agarwal, Vishnu; Ramteke, Pramod W.; Pandey, Avinash C.

2014-08-01

The motive of the at hand exploration was to contrive a proficient innovative pH-responsive nanocarrier designed for an anti-neoplastic agent that not only owns competent loading capacity but also talented to liberate the drug at the specific site. pH sensitive hollow mesoporous silica nanoparticles ( MSN) have been synthesized by sequence of chemical reconstruction with an average particle size of 120 nm. MSN reveal noteworthy biocompatibility and efficient drug loading magnitude. Active molecules such as Doxorubicin (DOX) can be stocked and set free from the pore vacuities of MSN by tuning the pH of the medium. The loading extent of MSN was found up to 81.4 wt% at pH 7.8. At mild acidic pH, DOX is steadily released from the pores of MSN. Both, the nitrogen adsorption-desorption isotherms and X-ray diffraction patterns reflects that this system holds remarkable stable mesostructure. Additionally, the outcomes of cytotoxicity assessment further establish the potential of MSN as a relevant drug transporter which can be thought over an appealing choice to a polymeric delivery system.

Spin label studies of micellar and pre-micellar aggregates.

PubMed

Ernades, J R; Schreier, S; Chaimovich, H

1976-02-01

Micelles of hexadecyl trimethyl ammonium bromide (CTABr) have been investigated with the use of a faty acid spin label and its methyl ester derivative. The esr * spectra provided information about the degree of motion of the probes in the micelles as evaluated from calculation of rotational correlation times. Evidence is presented for the formation of pre-micellar aggregates at concentrations below the cmc. The effect of addition of thiophenoxide on the structure of CTABr micelles was to decrease the rate of motion of the spin probes, probably due to a tighter packing of the hydrophobic core as a consequence of charge neutralization at the micelle surface by the substrate. Decreasing values of the isotropic hyperfine splitting of the spin probe with increasing concentration of thiophenoxide were taken as indicating that the latter causes a decrease of the degree of hydration of the polar head region of the detergent.

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.

Genotoxic and cytotoxic effects of doxorubicin and silymarin on human hepatocellular carcinoma cells.

PubMed

Yurtcu, E; İşeri, Öd; Sahin, Fi

2014-12-01

The aim of this study was to investigate genotoxic and cytotoxic effects of doxorubicin, silymarin, or in combination on HepG2 cells for 24 and 48 h. Both doxorubicin and silymarin caused dose-dependent inhibition of cell proliferation. After 48 h of treatment, doxorubicin application caused dramatically increased ratio of apoptotic cells. Both 24 and 48 h of silymarin and doxorubicin-silymarin combination caused significant increases in the rate of apoptotic cells. Applications of doxorubicin and silymarin separately for 24 h led to deoxyribonucleic acid (DNA) damages. After 48 h of incubation, doxorubicin-induced genotoxic damage was 2-fold higher than the silymarin-induced damage. After 24 and 48 h, DNA damage in response to combined applications of doxorubicin and silymarin was indifferent from silymarin- and doxorubicin-induced damage respectively. There was not any difference in genotoxicity levels between incubation periods in combined applications of doxorubicin and silymarin. Lipid peroxidation levels increased in all applications. Biopharmacotherapy with chemotherapeutic agents are of interest in the issue of adjuvant therapy. Here, we demonstrate in vitro potential genotoxic and cytotoxic antitumor effect of silymarin on HepG2 cells at achievable plasma level concentrations. © The Author(s) 2014.

Antioxidant activities of celery and parsley juices in rats treated with doxorubicin.

PubMed

Kolarovic, Jovanka; Popovic, Mira; Zlinská, Janka; Trivic, Svetlana; Vojnovic, Matilda

2010-09-03

We have examined the influence of diluted pure celery and parsley leaf and root juices and their combinations with doxorubicin on the antioxidant status [as measured by the content of reduced glutathione (GSH) and ferric reducing antioxidant power (FRAP)] in liver homogenate and hemolysate and on the contents of cytochrome P450 in liver homogenate. It was found that doxorubicin significantly decreased the content of reduced glutathione and the total antioxidative status (FRAP) in liver homogenate and hemolysate, while celery and parsley juices alone and in combination with doxorubicin had different actions. Doxorubicin and celery juice had no effect on content of cytochrome P450. However, in combination with doxorubicin, parsley root juice significant increased, and parsley leaves juice decreased the cytochrome P450 content (compared to doxorubicin treated animals). Only parsley root juice significantly increased the content of cytochrome P450.

Anisotropy Changes of a Fluorescent Probe during the Micellar Growth and Clouding of a Nonionic Detergent.

PubMed

Komaromy-Hiller; von Wandruszka R

1996-01-15

The effects of temperature and Triton X-114 (TX-114) concentration on the fluorescence anisotropy of perylene were investigated before and after detergent clouding. The measured anisotropy values were used to estimate the microviscosity of the micellar interior. In the lower detergent concentration range, an anisotropy maximum was observed at the critical micelle concentration (CMC), while the values decreased in the range immediately above the CMC. This was ascribed to the micellar volume increase, which, in the case of TX-114, was not accompanied by a more ordered internal environment. A gradual decrease of anisotropy and microviscosity with increasing temperature below the cloud point was observed. At the cloud point, no abrupt changes were found to occur. Compared to detergents with more flexible hydrophobic moieties, TX-114 micelles have a relatively ordered micellar interior indicated by the microviscosity and calculated fusion energy values. In the separated micellar phase formed after clouding, the probe anisotropy increased as water was eliminated at higher temperatures.

Wetting properties and critical micellar concentration of benzalkonium chloride mixed in sodium hypochlorite.

PubMed

Bukiet, Frédéric; Couderc, Guillaume; Camps, Jean; Tassery, Hervé; Cuisinier, Frederic; About, Imad; Charrier, Anne; Candoni, Nadine

2012-11-01

The purposes of the present study were to (1) assess the effect of the addition of benzalkonium chloride to sodium hypochlorite on its wetting properties, contact angle, and surface energy; (2) determine the critical micellar concentration of benzalkonium chloride in sodium hypochlorite; and (3) investigate the influence of addition of benzalkonium chloride on the free chlorine level, cytotoxicity, and antiseptic properties of the mixture. Solutions of benzalkonium chloride, with concentrations ranging from 0%-1%, were mixed in 2.4% sodium hypochlorite and tested as follows. The wetting properties were investigated by measuring the contact angle of the solutions on a nondehydrated dentin surface by using the static sessile drop method. The pending drop technique was subsequently used to determine the surface energy of the solutions. The critical micellar concentration of benzalkonium chloride mixed in sodium hypochlorite was calculated from the data. When 2.4% NaOCl was mixed with benzalkonium chloride at the critical micellar concentration, 3 parameters were tested: free chloride content, cytotoxicity, and antibacterial effects against Enterococcus faecalis. The contact angle (P < .001) as well as the surface energy (P < .001) significantly decreased with increasing benzalkonium chloride concentrations. The critical micellar concentration of benzalkonium chloride in sodium hypochlorite was 0.008%. At this concentration, the addition of benzalkonium chloride had no effect on the free chlorine content, cytotoxicity, or antibacterial efficiency of the mixture. The addition of benzalkonium chloride to sodium hypochlorite at the critical micellar concentration reduced the contact angle by 51.2% and the surface energy by 53.4%, without affecting the free chloride content, cytotoxicity, or antibacterial properties of the mixture. Copyright © 2012 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Effect of the interaction of heat-processing style and fat type on the micellarization of lipid-soluble pigments from green and red pungent peppers (Capsicum annuum).

PubMed

Victoria-Campos, Claudia I; Ornelas-Paz, José de Jesús; Yahia, Elhadi M; Failla, Mark L

2013-04-17

The high diversity of carotenoids and chlorophylls in foods contrasts with the reduced number of pigments that typically are investigated in micellarization studies. In this study, pepper samples (raw and heat-treated) contained 68 individual pigments, but only 38 of them were micellarized after in vitro digestion. The micellarization of pigments was majorly determined by the interaction effect of processing style (food matrix effect) and fat type (saturated and unsaturated). The highest micellarization was observed with raw peppers. Unsaturated fat increased the micellarization of carotenoid esters, while the impact of fat on the micellarization of free carotenoids seemed to be dependent on pigment structure. The micellarization efficiency was diminished as the esterification level of carotenoids increased. The type of fatty acid moiety and the polarity of the carotenoids modulated their micellarization. Chlorophylls were transformed into pheophytins by heat-processing and digestion, with the pheophytins being stable under gastrointestinal conditions. Micellarization of pheophytins was improved by fat.

MSAll strategy for comprehensive quantitative analysis of PEGylated-doxorubicin, PEG and doxorubicin by LC-high resolution q-q-TOF mass spectrometry coupled with all window acquisition of all fragment ion spectra.

PubMed

Yin, Lei; Su, Chong; Ren, Tianming; Meng, Xiangjun; Shi, Meiyun; Paul Fawcett, J; Zhang, Mengliang; Hu, Wei; Gu, Jingkai

2017-11-06

2K), and mPEG2K-doxorubicin in rats after a single intravenous injection of mPEG2K-doxorubicin. To the best of our knowledge, this is the first assay that simultaneously determines mPEG, Dox, and mPEG2K-Dox in a biological matrix. We believe the MS All technique as applied in this study can be potentially extended to the determination of other PEGylated small molecules or polymeric compounds.

TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin

PubMed Central

Moruno Manchon, Jose Felix; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Townley, Debra M.; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S.; Sood, Anil K.; Tsvetkov, Andrey S.

2016-01-01

Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin. PMID:27992857

TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin.

PubMed

Moruno-Manchon, Jose Felix; Uzor, Ndidi-Ese; Kesler, Shelli R; Wefel, Jeffrey S; Townley, Debra M; Nagaraja, Archana Sidalaghatta; Pradeep, Sunila; Mangala, Lingegowda S; Sood, Anil K; Tsvetkov, Andrey S

2016-12-16

Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin.

The same drug but a different mechanism of action: comparison of free doxorubicin with two different N-(2-hydroxypropyl)methacrylamide copolymer-bound doxorubicin conjugates in EL-4 cancer cell line.

PubMed

Kovár, Lubomír; Strohalm, Jirí; Chytil, Petr; Mrkvan, Tomás; Kovár, Marek; Hovorka, Ondrej; Ulbrich, Karel; Ríhová, Blanka

2007-01-01

Doxorubicin is one of the most potent anti-tumor drugs with a broad spectrum of use. To reduce its toxic effect and improve its pharmacokinetics, we conjugated it to an HPMA copolymer carrier that enhances its passive accumulation within solid tumors via the EPR effect and decreases its cytotoxicity to normal, noncancer cells. In this study, we compared the antiproliferative, pro-survival, and death signals triggered in EL-4 cancer cells exposed to free doxorubicin and doxorubicin conjugated to a HPMA copolymer carrier via either enzymatically (PK1) or hydrolytically (HYD) degradable bonds. We have previously shown that the intracellular distribution of free doxorubicin, HYD, and PK1 is markedly different. Here, we demonstrated that these three agents greatly differ also in the antiproliferative effect and cell death signals they trigger. JNK phosphorylation sharply increased in cells treated with HYD, while treatment with free doxorubicin moderately decreased and treatment with PK1 even strongly decreased it. On the other hand, treatment with free doxorubicin greatly increased p38 phosphorylation, while PK1 and HYD increased it slightly. PK1 also significantly increased ERK phosphorylation, while both the free doxorubicin and HYD conjugate slightly decreased it. Long-term inhibition of JNK significantly increased both proliferation and viability of EL-4 cells treated with free doxorubicin, showing that the JNK signaling pathway could be critical for mediating cell death in EL-4 cells exposed to free doxorubicin. Both activation of caspase 3 and decreased binding activity of the p50 subunit of NFkappaB were observed in cells treated with free doxorubicin and HYD, while no such effects were seen in cells incubated with PK1. Analysis of the expression of genes involved in apoptosis and regulation of the cell cycle demonstrated that free doxorubicin and HYD have very similar mechanisms of action, while PK1 has very different characteristics.

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

Development and characterization of morin hydrate-loaded micellar nanocarriers for the effective management of Alzheimer's disease.

PubMed

Singh, Manpreet; Thakur, Vandana; Deshmukh, Rahul; Sharma, Amit; Rathore, M S; Kumar, Ajay; Mishra, Neeraj

2018-03-01

The aim of this study was to prepare and characterise oral delivery of morin hydrate-loaded micellar nanocarriers using Pluronic P127 and Pluronic F123 for the effective management of Alzheimer's disease. After administration of formulation brain and blood drug concentration were found to be highest for optimised morin hydrate-loaded micellar nanocarriers as compared to plain morin hydrate. Significant (p < 0.05) reduction in assessed pharmacodynamic parameters was observed after administration of morin hydrate-loaded micellar nanocarriers as compared to disease control group. Chronic treatment with morin-loaded micelles significantly increased the memory in AlCl 3 induced Alzheimer's disease in Wistar rats.

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.

Identification of involved tissue during surgical treatment of doxorubicin-induced extravasation necrosis.

PubMed

Cohen, F J; Manganaro, J; Bezozo, R C

1983-01-01

The extravascular escape of intravenously administered doxorubicin (Adriamycin) leads to a painful, slowly enlarging subcutaneous lesion which, if not diagnosed, will progress to a chronic severe cellulitis with inflammatory reaction, ulceration of the skin, and possible further involvement. Past attempts at immediate treatment have failed because of, or have been complicated by, incomplete removal of the doxorubicin with continuing tissue necrosis. Three patients who underwent antineoplastic therapy with doxorubicin suffered extravasation leading to deep tissue necrosis requiring skin grafts. In all cases identification of doxorubicin-containing tissue was accomplished by injection of fluorescein. The residual necrotic tissue that did not fluoresce was removed. A protocol is presented to detect doxorubicin extravasation and distinguish the viable from the nonviable components.

A polymeric nanoparticle consisting of mPEG-PLA-Toco and PLMA-COONa as a drug carrier: improvements in cellular uptake and biodistribution.

PubMed

Yi, Yilwoong; Kim, Jae Hong; Kang, Hye-Won; Oh, Hun Seung; Kim, Sung Wan; Seo, Min Hyo

2005-02-01

To evaluate a new polymeric nanoparticulate drug delivery formulation that consists of two components: i) an amphiphilic diblock copolymer having tocopherol moiety at the end of the hydrophobic block in which the hydrophobic tocopherol moiety increases stability of hydrophobic core of the nanoparticle in aqueous medium; and ii) a biodegradable copolyester having carboxylate end group that is capable of forming ionic complex with positively charged compounds such as doxorubicin. A doxourubicin-loaded polymeric nanoparticle (Dox-PNP) was prepared by solvent evaporation method. The entrapment efficiency, size distribution, and in vitro release profile at various pH conditions were characterized. In vitro cellular uptake was investigated by confocal microscopy, flow cytometry, and MTT assay using drug-sensitive and drug-resistant cell lines. Pharmacokinetics and biodistribution were evaluated in rats and tumor-bearing mice. Doxorubicin (Dox) was efficiently loaded into the PNP (higher than 95% of entrapment efficiency), and the diameter of Dox-PNP was in the range 20-25 nm with a narrow size distribution. In Vitro study showed that Dox-PNP exhibited higher cellular uptake into both human breast cancer cell (MCF-7) and human uterine cancer cell (MES-SA) than free doxorubicin solution (Free-Dox), especially into drug-resistant cells (MCF-7/ADR and MES-SA/Dx-5). In pharmacokinetics and tissue distribution study, the bioavailability of Dox-PNP calculated from the area under the blood concentration-time curve (AUC) was 69.8 times higher than that of Free-Dox in rats, and Dox-PNP exhibited 2 times higher bioavailability in tumor tissue of tumor-bearing mice. Dox-PNP exhibited enhanced cellular uptake of the drug. In the cytotoxic activity study, this improved cellular uptake was proved to be more advantageous in drug-resistant cell. Dox-PNP exhibited much higher bioavailability in blood plasma and more drug accumulation in tumor tissue than conventional doxorubicin

Self assembled linear polymeric chains with tuneable semiflexibility using isotropic interactions.

PubMed

Abraham, Alex; Chatterji, Apratim

2018-04-21

We propose a two-body spherically symmetric (isotropic) potential such that particles interacting by the potential self-assemble into linear semiflexible polymeric chains without branching. By suitable control of the potential parameters, we can control the persistence length of the polymer and can even introduce a controlled number of branches. Thus we show how to achieve effective directional interactions starting from spherically symmetric potentials. The self-assembled polymers have an exponential distribution of chain lengths akin to what is observed for worm-like micellar systems. On increasing particle density, the polymeric chains self-organize to an ordered line-hexagonal phase where every chain is surrounded by six parallel chains, the transition is first order. On further increase in monomer density, the order is destroyed and we get a branched gel-like phase. This potential can be used to model semi-flexible equilibrium polymers with tunable semiflexibility and excluded volume. The use of the potential is computationally cheap and hence can be used to simulate and probe equilibrium polymer dynamics with long chains. The potential also gives a plausible method of tuning colloidal interactions in experiments such that one can obtain self-assembling polymeric chains made up of colloids and probe polymer dynamics using an optical microscope. Furthermore, we show how a modified potential leads to the observation of an intermediate nematic phase of self-assembled chains in between the low density disordered phase and the line-ordered hexagonal phase.

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

Self assembled linear polymeric chains with tuneable semiflexibility using isotropic interactions

NASA Astrophysics Data System (ADS)

Abraham, Alex; Chatterji, Apratim

2018-04-01

We propose a two-body spherically symmetric (isotropic) potential such that particles interacting by the potential self-assemble into linear semiflexible polymeric chains without branching. By suitable control of the potential parameters, we can control the persistence length of the polymer and can even introduce a controlled number of branches. Thus we show how to achieve effective directional interactions starting from spherically symmetric potentials. The self-assembled polymers have an exponential distribution of chain lengths akin to what is observed for worm-like micellar systems. On increasing particle density, the polymeric chains self-organize to an ordered line-hexagonal phase where every chain is surrounded by six parallel chains, the transition is first order. On further increase in monomer density, the order is destroyed and we get a branched gel-like phase. This potential can be used to model semi-flexible equilibrium polymers with tunable semiflexibility and excluded volume. The use of the potential is computationally cheap and hence can be used to simulate and probe equilibrium polymer dynamics with long chains. The potential also gives a plausible method of tuning colloidal interactions in experiments such that one can obtain self-assembling polymeric chains made up of colloids and probe polymer dynamics using an optical microscope. Furthermore, we show how a modified potential leads to the observation of an intermediate nematic phase of self-assembled chains in between the low density disordered phase and the line-ordered hexagonal phase.

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

Stabilization of mitochondrial membrane potential prevents doxorubicin-induced cardiotoxicity in isolated rat heart

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

Montaigne, David; Marechal, Xavier; Baccouch, Riadh

2010-05-01

The present study was undertaken to examine the effects of doxorubicin on left ventricular function and cellular energy state in intact isolated hearts, and, to test whether inhibition of mitochondrial membrane potential dissipation would prevent doxorubicin-induced mitochondrial and myocardial dysfunction. Myocardial contractile performance and mitochondrial respiration were evaluated by left ventricular tension and its first derivatives and cardiac fiber respirometry, respectively. NADH levels, mitochondrial membrane potential and glucose uptake were monitored non-invasively via epicardial imaging of the left ventricular wall of Langendorff-perfused rat hearts. Heart performance was reduced in a time-dependent manner in isolated rat hearts perfused with Krebs-Henseleit solutionmore » containing 1 muM doxorubicin. Compared with controls, doxorubicin induced acute myocardial dysfunction (dF/dt{sub max} of 105 +- 8 mN/s in control hearts vs. 49 +- 7 mN/s in doxorubicin-treated hearts; *p < 0.05). In cardiac fibers prepared from perfused hearts, doxorubicin induced depression of mitochondrial respiration (respiratory control ratio of 4.0 +- 0.2 in control hearts vs. 2.2 +- 0.2 in doxorubicin-treated hearts; *p < 0.05) and cytochrome c oxidase kinetic activity (24 +- 1 muM cytochrome c/min/mg in control hearts vs. 14 +- 3 muM cytochrome c/min/mg in doxorubicin-treated hearts; *p < 0.05). Acute cardiotoxicity induced by doxorubicin was accompanied by NADH redox state, mitochondrial membrane potential, and glucose uptake reduction. Inhibition of mitochondrial permeability transition pore opening by cyclosporine A largely prevented mitochondrial membrane potential dissipation, cardiac energy state and dysfunction. These results suggest that in intact hearts an impairment of mitochondrial metabolism is involved in the development of doxorubicin cardiotoxicity.« less

Poly-L-arginine: Enhancing Cytotoxicity and Cellular Uptake of Doxorubicin and Necrotic Cell Death.

PubMed

Movafegh, Bahareh; Jalal, Razieh; Mohammadi, Zobeideh; Aldaghi, Seyyede Araste

2018-04-11

Cell resistance to doxorubicin and its toxicity to healthy tissue reduce its efficiency. The use of cell penetrating peptides as drug delivery system along with doxorubicin is a strategy to reduce its side effects. In this study, the influence of poly-L-arginine on doxorubicin cytotoxicity, its cellular uptake and doxorubicin-induced apoptosis on human prostate cancer DU145 cells are assessed. The cytotoxicity of doxorubicin and poly-L-arginine, alone and in combination, in DU145 cells was evaluated at different exposure times using MTT assay. The influence of poly-L-arginine on doxorubicin delivery into cells was evaluated by fluorescence microscopy and ultraviolet spectroscopy. DAPI and ethidium bromide-acridine orange stainings, flow cytometry using annexin V/propidium iodide, western blot analysis with anti-p21 antibody and caspase-3 activity were used to examine the influence of poly-L-arginine on doxorubicin-induced cell death. Poly-L-arginine had no cytotoxicity at low concentrations and short exposure times. Poly-L-arginine increased the cytotoxic effect of doxorubicin in DU145 cells in a time-dependent manner. But no significant reduction was found in HFF cell viability. Poly-L-arginine seems to facilitate doxorubicin uptake and increase its intracellular concentration. 24 h combined treatment of cells with doxorubicin (0.5 μM) and poly-L-arginine (1 μg ml-1) caused a small increase in doxorubicin-induced apoptosis and significant elevated necrosis in DU145 cells as compared to each agent alone. Conlusion: Our results indicate that poly-L-arginine at lowest and highest concentrations act as proliferation-inducing and antiproliferative agents, respectively. Between these concentrations, poly-L-arginine increases the cellular uptake of doxorubicin and its cytotoxicity through induction of necrosis. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Doxorubicin, mesenchymal stem cell toxicity and antitumour activity: implications for clinical use.

PubMed

Baxter-Holland, Mia; Dass, Crispin R

2018-03-01

The use of doxorubicin, an antineoplastic medication used for the treatment of cancers via mechanisms that prevent replication of cells or lead to their death, can result in damage to healthy cells as well as malignant. Among the affected cells are mesenchymal stem cells (MSCs), which are involved in the maintenance and repair of tissues in the body. This review explores the mechanisms of biological effects and damage attributed to doxorubicin on MSCs. The PubMed database was used as a source of literature for this review. Doxorubicin has the potential to lead to significant and irreversible damage to the human bone marrow environment, including MSCs. The primary known mechanism of these changes is through free radical damage and activation of apoptotic pathways. The presence of MSCs in culture or in vivo appears to either suppress or promote tumour growth. Interactions between doxorubicin and MSCs have the potential to increase chemotherapy resistance. Doxorubicin-induced damage to MSCs is of concern clinically. However, MSCs also have been associated with resistance of tumour cells to drugs including doxorubicin. Further studies, particularly in vivo, are needed to provide consistent results of how the doxorubicin-induced changes to MSCs affect treatment and patient health. © 2018 Royal Pharmaceutical Society.

A simplified radiometabolite analysis procedure for PET radioligands using a solid phase extraction with micellar medium.

PubMed

Nakao, Ryuji; Halldin, Christer

2013-07-01

A solid phase extraction method has been developed for simple and high-speed direct determination of PET radioligands in plasma. This methodology makes use of a micellar medium and a solid-phase extraction cartridge for displacement of plasma protein bound radioligand and separation of PET radioligands from their radiometabolites without significant preparation. The plasma samples taken from monkey or human during PET measurements were mixed with a micellar eluent containing an anionic surfactant sodium dodecyl sulphate and loaded onto SPE cartridges. The amount of radioactivity corresponding to parent radioligand (retained on the cartridge) and its radioactive metabolites (eluted with micellar eluent) was measured. Under the optimized conditions, excellent separation of target PET radioligands from their radiometabolites was achieved with a single elution and short run-time of 1 min. This method was successfully applied to study the metabolism for (11)C-labelled radioligands in human or monkey plasma. The amount of parent PET radioligands estimated by micellar solid phase extraction strongly corresponded with that determined by radio-LC. The improved throughput permitted the analysis of a large number of plasma samples (up to 13 samples per one PET study) for accurate estimation of metabolite-corrected input function during quantitative PET imaging studies. Solid phase extraction together with micellar medium is fast, sensitive and easy to use, and therefore it is an attractive alternative method to determine relative composition of PET radioligands in plasma. Copyright © 2013 Elsevier Inc. All rights reserved.

Micellar Electrokinetic Chromatography of Aminoglycosides.

PubMed

Holzgrabe, Ulrike; Schmitt, Stefanie; Wienen, Frank

2016-01-01

The components of the aminoglycosides, e.g., gentamicin, sisomicin, netilmicin, kanamycin, amikacin, and tobramycin, and related impurities of these antibiotics can be separated by means of micellar electrokinetic chromatography (MEKC). Derivatization with o-phthaldialdehyde and thioglycolic acid is found to be appropriate for these antibiotics. The background electrolyte was composed of sodium tetraborate (100 mM), sodium deoxycholate (20 mM), and β-cyclodextrin (15 mM) having a pH value of 10.0. This method is valid for evaluation of gentamicin, kanamycin, and tobramycin. It has to be adopted for amikacin, paromomycin, neomycin, and netilmicin.

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy.

PubMed

Jo, Chor Ho; Kim, Sua; Park, Joon-Sung; Kim, Gheun-Ho

2018-06-15

Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91phox, p47phox, and p67phox in rat kidneys with doxorubicin nephropathy. NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress. © 2018 The Author(s). Published by S. Karger AG, Basel.

Doxorubicin-mediated radiosensitivity in multicellular spheroids from a lung cancer cell line is enhanced by composite micelle encapsulation

PubMed Central

Xu, Wen-Hong; Han, Min; Dong, Qi; Fu, Zhi-Xuan; Diao, Yuan-Yuan; Liu, Hai; Xu, Jing; Jiang, Hong-Liang; Zhang, Su-Zhan; Zheng, Shu; Gao, Jian-Qing; Wei, Qi-Chun

2012-01-01

Background The purpose of this study is to evaluate the efficacy of composite doxorubicinloaded micelles for enhancing doxorubicin radiosensitivity in multicellular spheroids from a non-small cell lung cancer cell line. Methods A novel composite doxorubicin-loaded micelle consisting of polyethylene glycolpolycaprolactone/Pluronic P105 was developed, and carrier-mediated doxorubicin accumulation and release from multicellular spheroids was evaluated. We used confocal laser scanning microscopy and flow cytometry to study the accumulation and efflux of doxorubicin from A549 multicellular spheroids. Doxorubicin radiosensitization and the combined effects of irradiation and doxorubicin on cell migration and proliferation were compared for the different doxorubicin delivery systems. Results Confocal laser scanning microscopy and quantitative flow cytometry studies both verified that, for equivalent doxorubicin concentrations, composite doxorubicin-loaded micelles significantly enhanced cellular doxorubicin accumulation and inhibited doxorubicin release. Colony-forming assays demonstrated that composite doxorubicin-loaded micelles are radiosensitive, as shown by significantly reduced survival of cells treated by radiation + composite micelles compared with those treated with radiation + free doxorubicin or radiation alone. The multicellular spheroid migration area and growth ability verified higher radiosensitivity for the composite micelles loaded with doxorubicin than for free doxorubicin. Conclusion Our composite doxorubicin-loaded micelle was demonstrated to have radiosensitization. Doxorubicin loading in the composite micelles significantly increased its cellular uptake, improved drug retention, and enhanced its antitumor effect relative to free doxorubicin, thereby providing a novel approach for treatment of cancer. PMID:22679376

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.

Impact of Doxorubicin Treatment on the Physiological Functions of White Adipose Tissue

PubMed Central

Cruz, Maysa Mariana; Cunha, Roberta D. C.; Alonso-Vale, Maria Isabel; Oyama, Lila Missae; Nascimento, Claudia M. Oller; Pimentel, Gustavo Duarte; dos Santos, Ronaldo V. T.; Lira, Fabio Santos

2016-01-01

White adipose tissue (WAT) plays a fundamental role in maintaining energy balance and important endocrine functions. The loss of WAT modifies adipokine secretion and disrupts homeostasis, potentially leading to severe metabolic effects and a reduced quality of life. Doxorubicin is a chemotherapeutic agent used clinically because of its good effectiveness against various types of cancer. However, doxorubicin has deleterious effects in many healthy tissues, including WAT, liver, and skeletal and cardiac muscles. Our objective was to investigate the effects of doxorubicin on white adipocytes through in vivo and in vitro experiments. Doxorubicin reduced the uptake of glucose by retroperitoneal adipocytes and 3T3-L1 cells via the inhibition of AMP-activated protein kinase Thr172 phosphorylation and glucose transporter 4 content. Doxorubicin also reduced the serum level of adiponectin and, to a greater extent, the expression of genes encoding lipogenic (Fas and Acc) and adipogenic factors (Pparg, C/ebpa, and Srebp1c) in retroperitoneal adipose tissue. In addition, doxorubicin inhibited both lipogenesis and lipolysis and reduced the hormone-sensitive lipase and adipose tissue triacylglycerol lipase protein levels. Therefore, our results demonstrate the impact of doxorubicin on WAT. These results are important to understand some side effects observed in patients receiving chemotherapy and should encourage new adjuvant treatments that aim to inhibit these side effects. PMID:27015538

Simulating the injection of micellar solutions to recover diesel in a sand column.

PubMed

Bernardez, Letícia A; Therrien, René; Lefebvre, René; Martel, Richard

2009-01-26

This paper presents numerical simulations of laboratory experiments where diesel, initially present at 18% residual saturation in a sand column, was recovered by injecting a micellar solution containing the surfactant Hostapur SAS-60 (SAS), and two alcohols, n-butanol (n-BuOH), and n-pentanol (n-PeOH). The micellar solution was developed and optimized for diesel recovery using phase diagrams and soil column experiments. Numerical simulations with the compositional simulator UTCHEM agree with the experimental results and show that the entire residual diesel in the sand column was recovered after the downward injection of 5 pore volumes of the micellar solution. Recovery of diesel occurs by enhanced solubility in the microemulsion phase and by mobilization. An additional series of simulations investigated the effects of phase transfer, alcohol partitioning, and component segregation on diesel recovery. These simulations indicate that diesel can be accurately represented in the model by a single component, but that the pseudo-component approach for active matter and the assumption of local phase equilibrium leads to an underestimation of diesel mobilization.

Simulating the injection of micellar solutions to recover diesel in a sand column

NASA Astrophysics Data System (ADS)

Bernardez, Letícia A.; Therrien, René; Lefebvre, René; Martel, Richard

2009-01-01

This paper presents numerical simulations of laboratory experiments where diesel, initially present at 18% residual saturation in a sand column, was recovered by injecting a micellar solution containing the surfactant Hostapur SAS-60 (SAS), and two alcohols, n-butanol ( n-BuOH), and n-pentanol ( n-PeOH). The micellar solution was developed and optimized for diesel recovery using phase diagrams and soil column experiments. Numerical simulations with the compositional simulator UTCHEM agree with the experimental results and show that the entire residual diesel in the sand column was recovered after the downward injection of 5 pore volumes of the micellar solution. Recovery of diesel occurs by enhanced solubility in the microemulsion phase and by mobilization. An additional series of simulations investigated the effects of phase transfer, alcohol partitioning, and component segregation on diesel recovery. These simulations indicate that diesel can be accurately represented in the model by a single component, but that the pseudo-component approach for active matter and the assumption of local phase equilibrium leads to an underestimation of diesel mobilization.

Multiscale Modeling of the Effects of Salt and Perfume Raw Materials on the Rheological Properties of Commercial Threadlike Micellar Solutions.

PubMed

Tang, Xueming; Zou, Weizhong; Koenig, Peter H; McConaughy, Shawn D; Weaver, Mike R; Eike, David M; Schmidt, Michael J; Larson, Ronald G

2017-03-23

We link micellar structures to their rheological properties for two surfactant body-wash formulations at various concentrations of salts and perfume raw materials (PRMs) using molecular simulations and micellar-scale modeling, as well as traditional surfactant packing arguments. The two body washes, namely, BW-1EO and BW-3EO, are composed of sodium lauryl ethylene glycol ether sulfate (SLEnS, where n is the average number of ethylene glycol repeat units), cocamidopropyl betaine (CAPB), ACCORD (which is a mixture of six PRMs), and NaCl salt. BW-3EO is an SLE3S-based body wash, whereas BW-1EO is an SLE1S-based body wash. Additional PRMs are also added into the body washes. The effects of temperature, salt, and added PRMs on micellar lengths, breakage times, end-cap free energies, and other properties are obtained from fits of the rheological data to predictions of the "Pointer Algorithm" [ Zou , W. ; Larson , R.G. J. Rheol. 2014 , 58 , 1 - 41 ], which is a simulation method based on the Cates model of micellar dynamics. Changes in these micellar properties are interpreted using the Israelachvili surfactant packing argument. From coarse-grained molecular simulations, we infer how salt modifies the micellar properties by changing the packing between the surfactant head groups, with the micellar radius remaining nearly constant. PRMs do so by partitioning to different locations within the micelles according to their octanol/water partition coefficient P OW and chemical structures, adjusting the packing of the head and/or tail groups, and by changing the micelle radius, in the case of a large hydrophobic PRM. We find that relatively hydrophilic PRMs with log P OW < 2 partition primarily to the head group region and shrink micellar length, decreasing viscosity substantially, whereas more hydrophobic PRMs, with log P OW between 2 and 4, mix with the hydrophobic surfactant tails within the micellar core and slightly enhance the viscosity and micelle length, which is

Complementary experimental-simulational study of surfactant micellar phase in the extraction process of metallic ions: Effects of temperature and salt concentration

NASA Astrophysics Data System (ADS)

Soto-Ángeles, Alan Gustavo; Rodríguez-Hidalgo, María del Rosario; Soto-Figueroa, César; Vicente, Luis

2018-02-01

The thermoresponsive micellar phase behaviour that exhibits the Triton-X-100 micelles by temperature effect and addition of salt in the extraction process of metallic ions was explored from mesoscopic and experimental points. In the theoretical study, we analyse the formation of Triton-X-100 micelles, load and stabilization of dithizone molecules and metallic ions extraction inside the micellar core at room temperature; finally, a thermal analysis is presented. In the experimental study, the spectrophotometric outcomes confirm the solubility of the copper-dithizone complex in the micellar core, as well as the extraction of metallic ions of aqueous environment via a cloud-point at 332.2 K. The micellar solutions with salt present a low absorbance value compared with the micellar solutions without salt. The decrease in the absorbance value is attributed to a change in the size of hydrophobic region of colloidal micelles. All transitory stages of extraction process are discussed and analysed in this document.

Multifunctional polymeric nanoconstructs for biomedical applications (Conference Presentation)

NASA Astrophysics Data System (ADS)

Decuzzi, Paolo

2016-09-01

Multifunctional nanoconstructs are particle-based nano-scale systems designed for the `smart' delivery of therapeutic and imaging agents. The Laboratory of Nanotechnology for Precision Medicine at the Italian Institute of Technology synthesizes polymeric nanoconstructs with different sizes, ranging from a few tens of nanometers to a few microns; shapes, including spherical, cubical and discoidal; surface properties, with positive, negative, neutral coatings; and mechanical stiffness, varying from that of cells to rigid, inorganic materials, such as iron oxide. These are the 4S parameters - size, shape, surface, stiffness - which can be precisely tuned in the synthesis process enabling disease- and patient-specific designs of multifunctional nanoconstructs. In this lecture, the application of these nanoconstructs to the detection and treatment of cancer lesions and cardiovascular diseases, such as thrombosis and atherosclerosis, is discussed. The contribution of the 4S parameters in modulating nanoconstruct sequestration by the mononuclear phagocyte system, organ specific accumulation, and blood longevity is also critically presented. These polymeric nanoconstructs can be loaded with a variety of therapeutic payloads - anti-cancer molecules (docetaxel, paclitaxel, doxorubicin), anti-inflammatory molecules (curcumin, diclofenac, celecoxib) and small biologicals (peptides, siRNAs, miRNAs); and imaging agents - optical probes; Gd and iron oxide nanoparticles for MR imaging; and radio-isotopes for Nuclear Imaging.

Ameliorative effects of sildenafil and/or febuxostat on doxorubicin-induced nephrotoxicity in rats.

PubMed

Khames, Ali; Khalaf, Marwa M; Gad, Amany M; Abd El-Raouf, Ola M

2017-06-15

Sildenafil and febuxostat protect against doxorubicin-induced nephrotoxicity; however the exact mechanism remains to be elucidated. The effect of sildenafil and febuxostat on doxorubicin-induced nephrotoxicity in rats was studied. Male rats were subdivided into nine groups. The 1st group served as normal control, the 2nd group received dimethylsulfoxide 50% (DMSO), the 3rd group received doxorubicin (3.5mg/kg, i.p.), twice weekly for 3 weeks. The next 3 groups received sildenafil (5mg/kg; p.o.), febuxostat (10mg/kg; p.o.) and their combination, respectively daily for 21 days. The last 3 groups received doxorubicin in combination with sildenafil, febuxostat or their combination. Nephrotoxicity was evaluated histopathologically by light microscopy and biochemically through measuring the following parameters, Kidney function biomarkers [serum levels of urea, creatinine and uric acid], oxidative stress biomarkers [kidney contents of glutathione reduced (GSH) and malondialdehyde (MDA)], The apoptotic marker namely; caspase-3 in kidney tissue and the inflammatory mediator tumor necrosis factor alpha (TNF-α). doxorubicin-induced a significant elevation in nephrotoxicity markers, expression of caspase-3 and caused induction of inflammation and oxidative stress. Histological changes in the kidney was tubular necrosis. Sildenafil and/or febuxostat administration with doxorubicin caused a significant decrease in nephrotoxicity markers and inflammatory mediators, restoration of normal values of oxidative stress biomarkers and hampering the expression of renal caspase-3. They also ameliorate histological changes induced by doxorubicin. sildenafil and febuxostat are promising protective agents against doxorubicin-nephrotoxicity through improving biochemical, inflammatory, histopathological and immunohistochemical alterations induced by doxorubicin. Copyright © 2017 Elsevier B.V. All rights reserved.

Facile fabrication of core cross-linked micelles by RAFT polymerization and enzyme-mediated reaction.

PubMed

Wu, Yukun; Lai, Quanyong; Lai, Shuqi; Wu, Jing; Wang, Wei; Yuan, Zhi

2014-06-01

Polymeric micelles formed in aqueous solution by assembly of amphiphilic block copolymers have been extensively investigated due to their great potential as drug carriers. However, the stability of polymeric assembly is still one of the major challenges in delivering drugs to tissues and cells. Here, we report a facile route to fabricate core cross-linked (CCL) micelles using an enzymatic polymerization as the cross-linking method. We present synthesis of poly(ethylene glycol)-block-poly(N-isopropyl acrylamide-co-N-(4-hydroxyphenethyl) acrylamide) diblock copolymer PEG-b-P(NIPAAm-co-NHPAAm) via reversible addition-fragmentation chain transfer (RAFT) polymerization. The diblock copolymer was then self-assembled into non-cross-linked (NCL) micelles upon heating above the lower critical solution temperature (LCST), and subsequently cross-linked using horseradish peroxidase (HRP) and hydrogen peroxide (H2O2) as enzyme and oxidant. The characterization of the diblock copolymer and micelles were studied by NMR, DLS, UV-vis, and fluorescence spectroscopy. The fluorescence study reveals that the cross-linking process endows the micelles with much lower critical micelle concentration (CMC). In addition, the drug release study shows that the CCL micelles have lower release amount of doxorubicin (DOX) than the NCL micelles due to the enhanced stability of the CCL micelles by core cross-linking process. Copyright © 2014 Elsevier B.V. All rights reserved.

Histone deacetylase inhibitors augment doxorubicin-induced DNA damage in cardiomyocytes.

PubMed

Ververis, Katherine; Rodd, Annabelle L; Tang, Michelle M; El-Osta, Assam; Karagiannis, Tom C

2011-12-01

Histone deacetylase inhibitors have emerged as a new class of anticancer therapeutics with suberoylanilide hydroxamic acid (Vorinostat) and depsipeptide (Romidepsin) already being approved for clinical use. Numerous studies have identified that histone deacetylase inhibitors will be most effective in the clinic when used in combination with conventional cancer therapies such as ionizing radiation and chemotherapeutic agents. One promising combination, particularly for hematologic malignancies, involves the use of histone deacetylase inhibitors with the anthracycline, doxorubicin. However, we previously identified that trichostatin A can potentiate doxorubicin-induced hypertrophy, the dose-limiting side-effect of the anthracycline, in cardiac myocytes. Here we have the extended the earlier studies and evaluated the effects of combinations of the histone deacetylase inhibitors, trichostatin A, valproic acid and sodium butyrate on doxorubicin-induced DNA double-strand breaks in cardiomyocytes. Using γH2AX as a molecular marker for the DNA lesions, we identified that all of the broad-spectrum histone deacetylase inhibitors tested augment doxorubicin-induced DNA damage. Furthermore, it is evident from the fluorescence photomicrographs of stained nuclei that the histone deacetylase inhibitors also augment doxorubicin-induced hypertrophy. These observations highlight the importance of investigating potential side-effects, in relevant model systems, which may be associated with emerging combination therapies for cancer.

Optimization of doxorubicin loading for superabsorbent polymer microspheres: in vitro analysis.

PubMed

Liu, David M; Kos, Sebastian; Buczkowski, Andrzej; Kee, Stephen; Munk, Peter L; Klass, Darren; Wasan, Ellen

2012-04-01

This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP's ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics. Phase I: 50-100 μm SAP subject to various prehydration methods (normal saline 10 cc, hypertonic saline 4 cc, iodinated contrast 10 cc) or left in their dry state, and combined with 50 mg of clinical grade lyophilized doxorubicin reconstituted with various methods (normal saline 10 cc and 25 cc, sterile water 4 cc, iodinated contrast 5 cc) were placed in buffer and assessed based on loading, handling, and elution utilizing high-performance liquid chromatography (HPLC). Phase II: top two performing methods were subject to loading of doxorubicin (50, 75, 100 mg) in a single bolus (group A) or as a serial loading method (group B) followed by measurement of loading vs. time and elution vs. time. Phase I revealed the most effective loading mechanisms and easiest handling to be dry (group A) vs. normal saline prehydrated (group B) SAP with normal saline reconstituted doxorubicin (10 mg/mL) with loading efficiencies of 83.1% and 88.4%. Phase II results revealed unstable behavior of SAP with 100 mg of doxorubicin and similar loading/elution profiles of dry and prehydrated SAP, with superior handling characteristics of group B SAP at 50 and 75 mg. SAP demonstrates the ability to load and bulk phase transfer doxorubicin at 50 and 75 mg with ease of handling and optimal efficiency through dry loading of SAP.

Cryomilling for the fabrication of doxorubicin-containing silica-nanoparticle/polycaprolactone nanocomposite films

NASA Astrophysics Data System (ADS)

Gao, Yu; Lim, Jing; Han, Yiyuan; Wang, Lifeng; Chong, Mark Seow Khoon; Teoh, Swee-Hin; Xu, Chenjie

2016-01-01

Bionanocomposites need to have a homogeneous distribution of nanomaterials in the polymeric matrix to achieve consistent mechanical and biological functions. However, a significant challenge lies in achieving the homogeneous distribution of nanomaterials, particularly through a solvent-free approach. This report introduces a technology to address this need. Specifically, cryomilling, a solvent-free, low-temperature processing method, was applied to generate a bionanocomposite film with well-dispersed nanoparticles. As a proof-of-concept, polycaprolactone (PCL) and doxorubicin-containing silica nanoparticles (Si-Dox) were processed through cryomilling and subsequently heat pressed to form the PCL/Si-Dox (cPCL/Si-Dox) film. Homogeneous distribution of Si-Dox was observed under both confocal imaging and atomic force microscopy imaging. The mechanical properties of cPCL/Si-Dox were comparable to those of the pure PCL film. Subsequent in vitro release profiles suggested that sustained release of Dox from the cPCL/Si-Dox film was achievable over 50 days. When human cervical cancer cells were seeded directly on these films, uptake of Dox was observed as early as day 1 and significant inhibition of cell growth was recorded on day 5.Bionanocomposites need to have a homogeneous distribution of nanomaterials in the polymeric matrix to achieve consistent mechanical and biological functions. However, a significant challenge lies in achieving the homogeneous distribution of nanomaterials, particularly through a solvent-free approach. This report introduces a technology to address this need. Specifically, cryomilling, a solvent-free, low-temperature processing method, was applied to generate a bionanocomposite film with well-dispersed nanoparticles. As a proof-of-concept, polycaprolactone (PCL) and doxorubicin-containing silica nanoparticles (Si-Dox) were processed through cryomilling and subsequently heat pressed to form the PCL/Si-Dox (cPCL/Si-Dox) film. Homogeneous

[Preparation and release exam of magnetic chitosan nano-spheres of doxorubicin].

PubMed

Han, Tao; Xiao, Qingping; Zhang, Yuanming

2010-02-01

Magnetic chitosan (CS) nano-spheres were prepared by the modified suspension cross-linking technique. The results demonstrated that the magnetic drug nano-spheres are mainly spherical in form with a size of 200 to 800 nm, and show good magnetic responsivity. Here, Doxorubicin was used as exam drug. Glutaraldehyde connects Doxorubicin to CS by the chemical bond (-N = C-), and the drug content is in range of 1% to 15% (w/w). The chemical bond is broken depending on pH, so pH is the important factor for the release of doxorubicin. The doxorubicin release was 22.0%, 13.4%, and 4.1% in the space of 7d, when pH was 1, 2, 4. So the nano-spheres are pH-sensitive magnetic targeting drug micro-spheres.

Inhibition of hyaluronic acid formation sensitizes chronic myelogenous leukemia to treatment with doxorubicin.

PubMed

Uchakina, Olga N; Ban, Hao; Hostetler, Bryan J; McKallip, Robert J

2016-11-01

In the current study we examined the ability of 4-methylumbelliferone (4-MU), which can inhibit hyaluronic acid synthesis, to sensitize K562 chronic myelogenous leukemia (CML) cells to doxorubicin therapy. Exposure of K562 cells to doxorubicin led to increased hyaluronic acid synthase (HAS) gene expression and increased levels of cell surface hyaluronic acid. Furthermore, exposure of K562 cells to exogenous HA caused resistance to doxorubicin-induced cell death. The combination of low dose 4-MU and doxorubicin led to increased apoptosis when compared to higher doses of any agent alone. Additionally, treatment with 4-MU led to a significant reduction in doxorubicin-induced increase in HA cell surface expression. Mechanistically, 4-MU treatment led to an increase in p38 activation and PARP cleavage. The role of p38 in 4-MU/doxorubicin-treated K562 cells was confirmed when p38 inhibitors led to protection from 4-MU/doxorubicin-induced apoptosis. Together, results from this study suggest that treatment with 4-MU increases the sensitivity of CML to chemotherapeutics by decreasing their HA-mediated resistance to apoptosis. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Effects of ranolazine in a model of doxorubicin-induced left ventricle diastolic dysfunction.

PubMed

Cappetta, Donato; Esposito, Grazia; Coppini, Raffaele; Piegari, Elena; Russo, Rosa; Ciuffreda, Loreta Pia; Rivellino, Alessia; Santini, Lorenzo; Rafaniello, Concetta; Scavone, Cristina; Rossi, Francesco; Berrino, Liberato; Urbanek, Konrad; De Angelis, Antonella

2017-11-01

Doxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin-dependent ROS may explain, in part, Ca 2+ and Na + overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na + current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline. Fischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg -1 over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg -1 , daily) for the following 4 weeks. While diastolic and systolic function progressively deteriorated in doxorubicin-treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative/nitrative stress. Expression of the Na + /Ca 2+ exchanger 1 and Na v 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca 2+ /calmodulin-dependent protein kinase II, and decreased myocardial fibrosis. Ranolazine, by the increased Na + influx, induced by doxorubicin, altered cardiac Ca 2+ and Na + handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy. This article is part of a themed section on New Insights into Cardiotoxicity Caused by Chemotherapeutic Agents

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.

Formation of DNA adducts by ellipticine and its micellar form in rats - a comparative study.

PubMed

Stiborova, Marie; Manhartova, Zuzana; Hodek, Petr; Adam, Vojtech; Kizek, Rene; Frei, Eva

2014-12-03

The requirements for early diagnostics as well as effective treatment of cancer diseases have increased the pressure on development of efficient methods for targeted drug delivery as well as imaging of the treatment success. One of the most recent approaches covering the drug delivery aspects is benefitting from the unique properties of nanomaterials. Ellipticine and its derivatives are efficient anticancer compounds that function through multiple mechanisms. Formation of covalent DNA adducts after ellipticine enzymatic activation is one of the most important mechanisms of its pharmacological action. In this study, we investigated whether ellipticine might be released from its micellar (encapsulated) form to generate covalent adducts analogous to those formed by free ellipticine. The (32)P-postlabeling technique was used as a useful imaging method to detect and quantify covalent ellipticine-derived DNA adducts. We compared the efficiencies of free ellipticine and its micellar form (the poly(ethylene oxide)-block-poly(allyl glycidyl ether) (PAGE-PEO) block copolymer, P 119 nanoparticles) to form ellipticine-DNA adducts in rats in vivo. Here, we demonstrate for the first time that treatment of rats with ellipticine in micelles resulted in formation of ellipticine-derived DNA adducts in vivo and suggest that a gradual release of ellipticine from its micellar form might produce the enhanced permeation and retention effect of this ellipticine-micellar delivery system.

Impact of doxorubicin on survival in advanced ovarian cancer.

PubMed

A'Hern, R P; Gore, M E

1995-03-01

Our study examined the impact of the addition of doxorubicin to ovarian cancer regimens in general, while removing the confounding influence of other drugs. We performed an overview using the data from two large analyses, the Advanced Ovarian Cancer Trialists Group (AOCTG [Br Med J 303:884-893, 1991] and Williams et al [Seminars in Oncol 19:120-128, 1992 (suppl 2)]) and the Ovarian Cancer Meta-Analysis Project (OCMP [J Clin Oncol 9:1668-1674, 1991]). Our data suggest that the addition of doxorubicin significantly improves survival (hazards ratio, 0.85; 95% confidence interval [CI], 0.76 to 0.95; P = .003) and that the size of this benefit is of a similar magnitude to that of platinum. The implication of our results is that the basic drugs for the standard treatment of advanced ovarian should be a combination of platinum and doxorubicin. The addition of an alkylating agent may add toxicity and lead to a dose reduction of these two drugs. In view of recent data on combination therapy with paclitaxel and platinum, it would be appropriate to compare this regimen with a combination of doxorubicin and platinum.

Flow of viscoelastic fluids around a sharp microfluidic bend: Role of wormlike micellar structure

NASA Astrophysics Data System (ADS)

Hwang, Margaret Y.; Mohammadigoushki, Hadi; Muller, Susan J.

2017-04-01

We examine the flow and instabilities of three viscoelastic fluids—a semidilute aqueous solution of polyethylene oxide (PEO) and two wormlike micellar solutions of cetylpyridinium chloride and sodium salicylate—around a microfluidic 90∘ bend, in which shear deformation and streamline curvature dominate. Similar to results reported by Gulati et al. [S. Gulati et al., Phys. Rev. E 78, 036314 (2008), 10.1103/PhysRevE.78.036314; S. Gulati et al., J. Rheol. 54, 375 (2010), 10.1122/1.3308643] for PEO solutions, we report a critical Weissenberg number (Wi) for the onset of lip vortex formation upstream of the corner. However, the decreased aspect ratio (channel depth to width) results in a slightly higher critical Wi and a vortex that grows more slowly. We consider wormlike micellar solutions of two salt to surfactant concentration ratios R =0.55 and R =0.79 . At R =0.55 , the wormlike micelles are linear and exhibit strong viscoelastic behavior, but at R =0.79 , the wormlike micelles become branched and exhibit shear-banding behavior. Microfluidic experiments on the R =0.55 solution reveal two flow transitions. The first transition, at Wi =6 , is characterized by the formation of a stationary lip vortex upstream of the bend; at the second transition, at Wi =20 , the vortex fluctuates in time and changes size. The R =0.79 solution also exhibits two transitions. The first transition at Wi =4 is characterized by the appearance of two intermittent vortices, one at the lip and one at the far outside corner. Increasing the flow rate to Wi >160 results in a transition to a second unstable regime, where there is only a lip vortex that fluctuates in size. The difference in flow transitions in PEO and wormlike micellar solutions presumably arises from the additional contribution of wormlike micellar breakage and reformation under shear. The flow transitions in wormlike micellar solutions are also significantly affected by chain branching.

Optimization of Doxorubicin Loading for Superabsorbent Polymer Microspheres: in vitro Analysis

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

Liu, David M., E-mail: dave.liu@vch.ca; Kos, Sebastian; Buczkowski, Andrzej

2012-04-15

Purpose: This study was designed to establish the ability of super-absorbent polymer microspheres (SAP) to actively uptake doxorubicin and to establish the proof of principle of SAP's ability to phase transfer doxorubicin onto the polymer matrix and to elute into buffer with a loading method that optimizes physical handling and elution characteristics. Methods: Phase I: 50-100 {mu}m SAP subject to various prehydration methods (normal saline 10 cc, hypertonic saline 4 cc, iodinated contrast 10 cc) or left in their dry state, and combined with 50 mg of clinical grade lyophilized doxorubicin reconstituted with various methods (normal saline 10 cc andmore » 25 cc, sterile water 4 cc, iodinated contrast 5 cc) were placed in buffer and assessed based on loading, handling, and elution utilizing high-performance liquid chromatography (HPLC). Phase II: top two performing methods were subject to loading of doxorubicin (50, 75, 100 mg) in a single bolus (group A) or as a serial loading method (group B) followed by measurement of loading vs. time and elution vs. time. Results: Phase I revealed the most effective loading mechanisms and easiest handling to be dry (group A) vs. normal saline prehydrated (group B) SAP with normal saline reconstituted doxorubicin (10 mg/mL) with loading efficiencies of 83.1% and 88.4%. Phase II results revealed unstable behavior of SAP with 100 mg of doxorubicin and similar loading/elution profiles of dry and prehydrated SAP, with superior handling characteristics of group B SAP at 50 and 75 mg. Conclusions: SAP demonstrates the ability to load and bulk phase transfer doxorubicin at 50 and 75 mg with ease of handling and optimal efficiency through dry loading of SAP.« less

Response of cultured normal canine mammary epithelial cells to deracoxib-doxorubicin combination.

PubMed

Bakirel, Tulay; Ustun Alkan, Fulya; Ustuner, Oya; Çinar, Suzan; Anlas, Ceren; Bilge Sari, Ataman

2017-09-01

Currently, there is a growing interest in combining anticancer drugs with the aim to improve outcome in patients suffering from tumours and reduce the long-term toxicity associated with the current standard of treatment. In this study, we evaluated the possible role of deracoxib against the toxicity of doxorubicin on normal canine mammary epithelial cells. The effect of deracoxib and doxorubicin combination on cell viability was determined by MTT assay. Apoptosis was characterised by flow cytometry. Cell nitrite concentrations were measured with the Griess reaction. Deracoxib (50 and 100 μM) treatment decreased the cytotoxic action of doxorubicin at 0.9 μM in the cells, from 33.63% to 13.4% and 25.82%, respectively. Our results also showed that the reverse effect of deracoxib on doxorubicin-induced cytotoxic activity in the cells was associated with a marked (3.04- to 3.57-fold) decrease in apoptosis. In additional studies identifying the mechanism of the observed effect, deracoxib exhibited an activity to prevent doxorubicin-mediated overproduction of nitric oxide in the cells. Our in vitro study results indicate that deracoxib (50 and 100 μM) can be beneficial in protecting normal cells from the toxic effect of doxorubicin in conjunction with apoptosis by the modulation of nitric oxide production.

Vertical structures in vibrated wormlike micellar solutions

NASA Astrophysics Data System (ADS)

Epstein, Tamir; Deegan, Robert

2008-11-01

Vertically vibrated shear thickening particulate suspensions can support a free-standing interfaces oriented parallel to gravity. We find that shear thickening worm-like micellar solutions also support such vertical interfaces. Above a threshold in acceleration, the solution spontaneously accumulates into a labyrinthine pattern characterized by a well-defined vertical edge. The formation of vertical structures is of interest because they are unique to shear-thickening fluids, and they indicate the existence of an unknown stress bearing mechanism.

Formulation and optimization of doxorubicin loaded polymeric nanoparticles using Box-Behnken design: ex-vivo stability and in-vitro activity.

PubMed

Shaikh, Muhammad Vaseem; Kala, Manika; Nivsarkar, Manish

2017-03-30

Biodegradable nanoparticles (NPs) have gained tremendous interest for targeting chemotherapeutic drugs to the tumor environment. Inspite of several advances sufficient encapsulation along with the controlled release and desired size range have remained as considerable challenges. Hence, the present study examines the formulation optimization of doxorubicin loaded PLGA NPs (DOX-PLGA-NPs), prepared by single emulsion method for cancer targeting. Critical process parameters (CPP) were selected by initial screening. Later, Box-Behnken design (BBD) was used for analyzing the effect of the selected CPP on critical quality attributes (CQA) and to generate a design space. The optimized formulation was stabilized by lyophilization and was used for in-vitro drug release and in-vitro activity on A549 cell line. Moreover, colloidal stability of the NPs in the biological milieu was assessed. Amount of PLGA and PVA, oil:water ratio and sonication time were the selected independent factors for BBD. The statistical data showed that a quadratic model was fitted to the data obtained. Additionally, the lack of fit values for the models was not significant. The delivery system showed sustained release behavior over a period of 120h and was governed by Fickian diffusion. The multipoint analysis at 24, 48 and 72h showed gradual reduction in IC50 value of DOX-PLGA-NPs (p<0.05, Fig. 9). DOX-PLGA-NPs were found to be stable in the biological fluids indicating their in-vivo applicability. In conclusion, optimization of the DOX-PLGA-NPs by BBD yielded in a promising drug carrier for doxorubicin that could provide a novel treatment modality for cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Structural and phase transition changes of sodium dodecyl sulfate micellar solution in alcohols probed by small-angle neutron scattering (SANS)

NASA Astrophysics Data System (ADS)

Putra, Edy Giri Rachman; Patriati, Arum

2015-04-01

Small-angle neutron scattering (SANS) measurements on 0.3M sodium dodecyl sulfate (SDS) micellar solutions have been performed in the presence of n-alcohols, from ethanol to decanol at different alcohol concentrations, 2-10 wt%. The ellipsoid micellar structure which occurred in the 0.3M SDS in aqueous solution with the size range of 30-50 Å has different behavior at various hydrocarbon chain length and concentration of alcohols. At low concentration and short chain-length of alcohols, such as ethanol, propanol, and butanol, the size of micelles reduced and had a spherical-like structure. The opposite effect occurred as medium to long chain alcohols, such as hexanol, octanol and decanol was added into the 0.3M SDS micellar solutions. The micelles structure changed to be more elongated in major axis and then crossed the critical phase transition from micellar solution into liquid crystal phase as lamellar structure emerged by further addition of alcohols. The inter-lamellar distances were also depending on the hydrocarbon chain length and concentration of alcohols. In the meantime, the persistent micellar structures occurred in addition of medium chain of n-alcohol, pentanol at all concentrations.

Micellar Packing in Aqueous Solutions of As-Received and Pure Pluronic Block Copolymers

NASA Astrophysics Data System (ADS)

Ryu, Chang; Park, Han Jin

2013-03-01

Pluronic block copolymers (Pluronics) are produced on a commercial scale to enable wide range of novel applications from emulsification and colloidal stabilization as nonionic surfactants. While the Pluronic block copolymers offer the advantages of being readily available for such applications, it contains non-micellizable low molecular weight (MW) impurities that would interfere with the self-assembly and micellar packing of PEO-PPO-PEO triblock copolymers in aqueous solutions. The impacts of the low MW impurities will be discussed on the micellar packing of Pluronics F108 and F127 solutions, which form BCC and FCC. While as-received Pluronic samples typically contain about 20 wt.% low MW impurities, we were able to reduce the impurity level to less than 2 wt.% using our large scale purification technique. Comparative studies on small angle x-ray scattering (SAXS) experiments on as-received and purified Pluronics solutions revealed that the contents of triblock copolymers in solutions essentially governs the inter-micellar distance of Pluronic cubic structures. A universal relationship between triblock copolymer concentration and SAXS-based domain spacing has been finally discussed. Funding from Agency for Defense Development, Korea.

Construction of Hierarchical Polymer Brushes on Upconversion Nanoparticles via NIR-Light-Initiated RAFT Polymerization.

PubMed

Xie, Zhongxi; Deng, Xiaoran; Liu, Bei; Huang, Shanshan; Ma, Pingan; Hou, Zhiyao; Cheng, Ziyong; Lin, Jun; Luan, Shifang

2017-09-13

Photoinduced reversible addition-fragmentation chain transfer (RAFT) polymerization generally adopts high-energy ultraviolet (UV) or blue light. In combination with photoredox catalyst, the excitation light wavelength was extended to the visible and even near-infrared (NIR) region for photoinduced electron transfer RAFT polymerization. In this report, we introduce for the first time a surface NIR-light-initiated RAFT polymerization on upconversion nanoparticles (UCNPs) without adding any photocatalyst and construct a functional inorganic core/polymer shell nanohybrid for application in cancer theranostics. The multilayer core-shell UCNPs (NaYF 4 :Yb/Tm@NaYbF 4 :Gd@NaNdF 4 :Yb@NaYF 4 ), with surface anchorings of chain transfer agents, can serve as efficient NIR-to-UV light transducers for initiating the RAFT polymerization. A hierarchical double block copolymer brush, consisting of poly(acrylic acid) (PAA) and poly(oligo(ethylene oxide)methacrylate-co-2-(2-methoxy-ethoxy)ethyl methacrylate) (PEG for short), was grafted from the surface in sequence. The targeting arginine-glycine-aspartic (RGD) peptide was modified at the end of the copolymer through the trithiolcarbonate end group. After loading of doxorubicin, the UCNPs@PAA-b-PEG-RGD exhibited an enhanced U87MG cancer cell uptake efficiency and cytotoxicity. Besides, the unique upconversion luminescence of the nanohybrids was used for the autofluoresence-free cell imaging and labeling. Therefore, our strategy verified that UCNPs could efficiently activate RAFT polymerization by NIR photoirradiation and construct the complex nanohybrids, exhibiting prospective biomedical applications due to the low phototoxicity and deep penetration of NIR light.

Strip waves in vibrated shear-thickening wormlike micellar solutions

NASA Astrophysics Data System (ADS)

Epstein, T.; Deegan, R. D.

2010-06-01

We present an instability in vertically vibrated dilute wormlike micellar solutions. Above a critical driving acceleration the fluid forms elongated solitary domains of high amplitude waves. We model this instability using a Mathieu equation modified to account for the non-Newtonian character of the fluid. We find that our model successfully reproduces the observed transitions.

Protective effect of saponins from Panax notoginseng against doxorubicin-induced cardiotoxicity in mice.

PubMed

Liu, Li; Shi, Run; Shi, Qiang; Cheng, Yiyu; Huo, Yang

2008-02-01

The dried rhizome of Panax notoginseng is a traditional Chinese herb extensively used for treatment of cardiovascular diseases and other ailments. Panax notoginseng saponins (PNS) are known as the major pharmacologically active constituents. The purpose of this study was to investigate the cardioprotective effects of PNS against doxorubicin-induced cardiotoxicity and its possible influence on the anti-tumor activity of doxorubicin. Five groups of ICR mice were treated with saline (control group), doxorubicin alone (20 mg/kg I. P.), PNS alone, doxorubicin pretreated with PNS (100 mg/kg I. G. for 5 consecutive days) or amifostine (single dose of 200 mg/kg I. V., used as positive control). After 72 h of doxorubicin treatment, cardiac function, serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and creatine kinase isoenzyme (CK-MB) and activities of antioxidant enzymes in heart tissue were measured. Pretreatment with PNS significantly protected the mice from DOX-induced cardiotoxicity as evidenced from improved ventricular contractile function, lower levels of serum LDH, CK and CK-MB, minimal morphological changes in hearts, and normalization of myocardial superoxide dismutase, glutathione peroxidase and catalase activities. Additionally, IN VITRO cytotoxic studies demonstrated that PNS did not compromise the inhibitory effect of doxorubicin on the proliferation of cancer cells. These results imply the potentially clinical application of PNS to overcome the negative side effects of doxorubicin.

Local injections of corticotropin releasing factor reduce doxorubicin-induced acute inflammation in the eyelid.

PubMed

McLoon, L K; Wirtschafter, J

1997-04-01

Doxorubicin chemomyectomy is an effective alternative treatment option for patients with blepharospasm and hemifacial spasm. One side effect of the use of doxorubicin in localized injections is the development of acute inflammation and skin injury at the injection site. Corticotropin releasing factor (CRF) was reported to reduce inflammation after acute inflammatory injuries due to other causes and at other sites. This study was performed to assess the potential of CRF to prevent the development of skin injury and eyelid soreness after local doxorubicin injection. Rabbits received lower eyelid injections of either 75 or 150 micrograms CRF followed by injection of either 0.5, 1, or 2 mg doxorubicin or doxorubicin alone. Eyelids were assessed for changes in acute inflammation by immunohistochemical localization of macrophages and monocytes using anti-CD11, an antibody specific for these cell types. Short-term alterations in vascular permeability were assessed using an Evans blue assay. Additional eyelids were followed daily for changes in the skin over the injection site to determine day of onset of skin injury and the total duration of skin injury. After 1 month, the eyelids were processed histologically for morphometric analysis of muscle fiber loss. Monkey eyelids also were examined for the effect of CRF and doxorubicin injections. Doxorubicin alone produced an acute inflammatory reaction in the treated eyelids, with a large influx of macrophages and monocytes throughout the connective tissue at 1 and 2 days. Corticotropin releasing factor pretreatment significantly reduced this influx of inflammatory cells into the connective tissue. Doxorubicin produced a large increase in vascular permeability in the treated eyelids, with resultant edema. Corticotropin releasing factor did not alter this change in vascular permeability, indicating that CRF appears to have a specific effect on migration of inflammatory cells rather than just a generalized effect on vascular

Identification of the active protein in rice bran protein having an inhibitory activity of cholesterol micellar solubility.

PubMed

Wang, Jilite; Shimada, Masaya; Nagaoka, Satoshi

2017-06-01

In our previous study, rice bran protein (RBP) inhibited cholesterol micellar solubility in vitro and decreased serum cholesterol level in rats. In the present study, RBP was separated and purified by size-exclusion chromatography and reversed-phase chromatography. The active protein of RBP related to cholesterol micellar solubility was identified as lectin and non-specific lipid-transfer protein 1 using MALDI-TOF mass spectrometry analysis.

HER2-targeted liposomal doxorubicin displays enhanced anti-tumorigenic effects without associated cardiotoxicity

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

Reynolds, Joseph G.; Geretti, Elena; Hendriks, Bart S.

2012-07-01

Anthracycline-based regimens are a mainstay of early breast cancer therapy, however their use is limited by cardiac toxicity. The potential for cardiotoxicity is a major consideration in the design and development of combinatorial therapies incorporating anthracyclines and agents that target the HER2-mediated signaling pathway, such as trastuzumab. In this regard, HER2-targeted liposomal doxorubicin was developed to provide clinical benefit by both reducing the cardiotoxicity observed with anthracyclines and enhancing the therapeutic potential of HER2-based therapies that are currently available for HER2-overexpressing cancers. While documenting the enhanced therapeutic potential of HER2-targeted liposomal doxorubicin can be done with existing models, there hasmore » been no validated human cardiac cell-based assay system to rigorously assess the cardiotoxicity of anthracyclines. To understand if HER2-targeting of liposomal doxorubicin is possible with a favorable cardiac safety profile, we applied a human stem cell-derived cardiomyocyte platform to evaluate the doxorubicin exposure of human cardiac cells to HER2-targeted liposomal doxorubicin. To the best of our knowledge, this is the first known application of a stem cell-derived system for evaluating preclinical cardiotoxicity of an investigational agent. We demonstrate that HER2-targeted liposomal doxorubicin has little or no uptake into human cardiomyocytes, does not inhibit HER2-mediated signaling, results in little or no evidence of cardiomyocyte cell death or dysfunction, and retains the low penetration into heart tissue of liposomal doxorubicin. Taken together, this data ultimately led to the clinical decision to advance this drug to Phase I clinical testing, which is now ongoing as a single agent in HER2-expressing cancers. -- Highlights: ► Novel approach using stem cell-derived cardiomyocytes to assess preclinical safety. ► HER2-targeted liposomal doxorubicin has improved safety profile vs free

Transepithelial Transport of Curcumin in Caco-2 Cells Is significantly Enhanced by Micellar Solubilisation.

PubMed

Frank, Jan; Schiborr, Christina; Kocher, Alexa; Meins, Jürgen; Behnam, Dariush; Schubert-Zsilavecz, Manfred; Abdel-Tawab, Mona

2017-03-01

Curcumin, the active constituent of Curcuma longa L. (family Zingiberaceae), has gained increasing interest because of its anti-cancer, anti-inflammatory, anti-diabetic, and anti-rheumatic properties associated with good tolerability and safety up to very high doses of 12 g. Nanoscaled micellar formulations on the base of Tween 80 represent a promising strategy to overcome its low oral bioavailability. We therefore aimed to investigate the uptake and transepithelial transport of native curcumin (CUR) vs. a nanoscaled micellar formulation (Sol-CUR) in a Caco-2 cell model. Sol-CUR afforded a higher flux than CUR (39.23 vs. 4.98 μg min -1  cm -2 , respectively). This resulted in a higher P app value of 2.11 × 10 -6  cm/s for Sol-CUR compared to a P app value of 0.56 × 10 -6  cm/s for CUR. Accordingly a nearly 9.5 fold higher amount of curcumin was detected on the basolateral side at the end of the transport experiments after 180 min with Sol-CUR compared to CUR. The determined 3.8-fold improvement in the permeability of curcumin is in agreement with an up to 185-fold increase in the AUC of curcumin observed in humans following the oral administration of the nanoscaled micellar formulation compared to native curcumin. The present study demonstrates that the enhanced oral bioavailability of micellar curcumin formulations is likely a result of enhanced absorption into and increased transport through small intestinal epithelial cells.

Worming Their Way into Shape: Toroidal Formations in Micellar Solutions

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

Cardiel Rivera, Joshua J.; Tonggu, Lige; Dohnalkova, Alice

2013-11-01

We report the formation of nanostructured toroidal micellar bundles (nTMB) from a semidilute wormlike micellar solution, evidenced by both cryogenicelectron microscopy and transmission electron microscopy images. Our strategy for creating nTMB involves a two-step protocol consisting of a simple prestraining process followed by flow through a microfluidic device containing an array of microposts, producing strain rates in the wormlike micelles on the order of 105 s^1. In combination with microfluidic confinement, these unusually large strain rates allow for the formation of stable nTMB. Electron microscopy images reveal a variety of nTMB morphologies and provide the size distribution of the nTMB.more » Small-angle neutron scattering indicates the underlying microstructural transition from wormlike micelles to nTMB. We also show that other flow-induced approaches such as sonication can induce and control the emergence of onion-like and nTMB structures, which may provide a useful tool for nanotemplating.« less

Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells

PubMed Central

Holmgren, Gustav; Synnergren, Jane; Bogestål, Yalda; Améen, Caroline; Åkesson, Karolina; Holmgren, Sandra; Lindahl, Anders; Sartipy, Peter

2015-01-01

Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days’ exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the

Identification of novel biomarkers for doxorubicin-induced toxicity in human cardiomyocytes derived from pluripotent stem cells.

PubMed

Holmgren, Gustav; Synnergren, Jane; Bogestål, Yalda; Améen, Caroline; Åkesson, Karolina; Holmgren, Sandra; Lindahl, Anders; Sartipy, Peter

2015-02-03

Doxorubicin is a chemotherapeutic agent indicated for the treatment of a variety of cancer types, including leukaemia, lymphomas, and many solid tumours. The use of doxorubicin is, however, associated with severe cardiotoxicity, often resulting in early discontinuation of the treatment. Importantly, the toxic symptoms can occur several years after the termination of the doxorubicin administration. In this study, the toxic effects of doxorubicin exposure have been investigated in cardiomyocytes derived from human embryonic stem cells (hESC). The cells were exposed to different concentrations of doxorubicin for up to 2 days, followed by a 12 day recovery period. Notably, the cell morphology was altered during drug treatment and the cells showed a reduced contractile ability, most prominent at the highest concentration of doxorubicin at the later time points. A general cytotoxic response measured as Lactate dehydrogenase leakage was observed after 2 days' exposure compared to the vehicle control, but this response was absent during the recovery period. A similar dose-dependant pattern was observed for the release of cardiac specific troponin T (cTnT) after 1 day and 2 days of treatment with doxorubicin. Global transcriptional profiles in the cells revealed clusters of genes that were differentially expressed during doxorubicin exposure, a pattern that in some cases was sustained even throughout the recovery period, suggesting that these genes could be used as sensitive biomarkers for doxorubicin-induced toxicity in human cardiomyocytes. The results from this study show that cTnT release can be used as a measurement of acute cardiotoxicity due to doxorubicin. However, for the late onset of doxorubicin-induced cardiomyopathy, cTnT release might not be the most optimal biomarker. As an alternative, some of the genes that we identified as differentially expressed after doxorubicin exposure could serve as more relevant biomarkers, and may also help to explain the cellular

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

Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

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

Wang, Feng; Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030; Yang, Yong, E-mail: yyang@houstonmethodist.org

2014-11-21

Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy.more » Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.« less

Protective role of Osthole on myocardial cell apoptosis induced by doxorubicin in rats.

PubMed

Xu, Hongdang; Han, Yu; Zhang, Mengwei; Yan, Min; Gao, Chuanyu

2015-01-01

To explore the effect of Osthole on protecting myocardial cell apoptosis induced by doxorubicin during cardiac failure in rats. Myocardial cells isolated from the newborn SD rats were separated into three groups: cells treated with 1 μmol doxorubicin, cells treated with Osthole at three concentrations of 10, 20, and 40 μmol, cells treated neither with Osthole nor with doxorubicin were the control groups. Consequently, cell apoptosis of myocardial cells in each group was analyzed using TUNEL assay. Also, expressions of oxidase, NADPH, and ROS in myocardial cells were analyzed using different biological methods. Moreover, expressions of cell apoptosis associated proteins were analyzed using Western blotting. Compared with the controls, the results showed that cells received Osthole and doxorubicin treatments performed high percentage of cell apoptosis, suggesting that Osthole could anesis myocardial cell apoptosis induced by doxorubicin (P<0.05). Osthole of 10 μmol depressed the expressions of cell apoptosis associated proteins including Caspase-3 and Cytc, and enhancing expression of Bcl-XL expression (P<0.05). Osthole of 20 μmol significantly decreased the generation of intracellar superoxidase, NADPH, and NADPH activity in myocardial cells treated with doxorubicin (P<0.05). Moreover, Osthole of 20 μmol could significantly increase phosphorylated elF2α level in cells. Our study suggested that Osthole may play a protective role in suppressing myocardial apoptosis induced by doxorubicin through inhibiting NADPH and superoxidase production and downstream phosphorylated elF2α.

Protective role of Osthole on myocardial cell apoptosis induced by doxorubicin in rats

PubMed Central

Xu, Hongdang; Han, Yu; Zhang, Mengwei; Yan, Min; Gao, Chuanyu

2015-01-01

Objective: To explore the effect of Osthole on protecting myocardial cell apoptosis induced by doxorubicin during cardiac failure in rats. Methods: Myocardial cells isolated from the newborn SD rats were separated into three groups: cells treated with 1 μmol doxorubicin, cells treated with Osthole at three concentrations of 10, 20, and 40 μmol, cells treated neither with Osthole nor with doxorubicin were the control groups. Consequently, cell apoptosis of myocardial cells in each group was analyzed using TUNEL assay. Also, expressions of oxidase, NADPH, and ROS in myocardial cells were analyzed using different biological methods. Moreover, expressions of cell apoptosis associated proteins were analyzed using Western blotting. Results: Compared with the controls, the results showed that cells received Osthole and doxorubicin treatments performed high percentage of cell apoptosis, suggesting that Osthole could anesis myocardial cell apoptosis induced by doxorubicin (P<0.05). Osthole of 10 μmol depressed the expressions of cell apoptosis associated proteins including Caspase-3 and Cytc, and enhancing expression of Bcl-XL expression (P<0.05). Osthole of 20 μmol significantly decreased the generation of intracellar superoxidase, NADPH, and NADPH activity in myocardial cells treated with doxorubicin (P<0.05). Moreover, Osthole of 20 μmol could significantly increase phosphorylated elF2α level in cells. Conclusion: Our study suggested that Osthole may play a protective role in suppressing myocardial apoptosis induced by doxorubicin through inhibiting NADPH and superoxidase production and downstream phosphorylated elF2α. PMID:26617794

Dasatinib and Doxorubicin Treatment of Sarcoma Initiating Cells: A Possible New Treatment Strategy.

PubMed

Aggerholm-Pedersen, Ninna; Demuth, Christina; Safwat, Akmal; Meldgaard, Peter; Kassem, Moustapha; Sandahl Sorensen, Boe

2016-01-01

Background. One of the major challenges affecting sarcoma treatment outcome, particularly that of metastatic disease, is resistance to chemotherapy. Cancer-initiating cells are considered a major contributor to this resistance. Methods. An immortalised nontransformed human stromal (mesenchymal) stem cell line hMSC-TERT4 and a transformed cell line hMSC-TERT20-CE8, known to form sarcoma-like tumours when implanted in immune-deficient mice, were used as models. Receptor tyrosine kinase (RTK) activation was analysed by RTK arrays and cellular viability after tyrosine kinases inhibitor (TKI) treatment with or without doxorubicin was assessed by MTS assay. Results. Initial results showed that the hMSC-TERT4 was more doxorubicin-sensitive while hMSC-TERT20-CE8 was less doxorubicin-sensitive evidenced by monitoring cell viability in the presence of doxorubicin at different doses. The epidermal growth factor receptor (EGFR) was activated in both cell lines. However hMSC-TERT20-CE8 exhibited significantly higher expression of the EGFR ligands. EGFR inhibitors such as erlotinib and afatinib alone or in combination with doxorubicin failed to further decrease cell viability of hMSC-TERT20-CE8. However, inhibition with the TKI dasatinib in combination with doxorubicin decreased cell viability of the hMSC-TERT20-CE8 cell line. Conclusion. Our results demonstrate that dasatinib, but not EGFR-directed treatment, can decrease cell viability of stromal cancer stem cells less sensitive to doxorubicin.

Structural and phase transition changes of sodium dodecyl sulfate micellar solution in alcohols probed by small-angle neutron scattering (SANS)

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

Putra, Edy Giri Rachman; Patriati, Arum; Department of Chemistry, Faculty of Mathematics and Natural Sciences, University of Gadjah Mada, Bulaksumur, Yogyakarta 55281, Indonesia giri@batan.go.id

2015-04-16

Small-angle neutron scattering (SANS) measurements on 0.3M sodium dodecyl sulfate (SDS) micellar solutions have been performed in the presence of n-alcohols, from ethanol to decanol at different alcohol concentrations, 2–10 wt%. The ellipsoid micellar structure which occurred in the 0.3M SDS in aqueous solution with the size range of 30–50 Å has different behavior at various hydrocarbon chain length and concentration of alcohols. At low concentration and short chain-length of alcohols, such as ethanol, propanol, and butanol, the size of micelles reduced and had a spherical-like structure. The opposite effect occurred as medium to long chain alcohols, such as hexanol,more » octanol and decanol was added into the 0.3M SDS micellar solutions. The micelles structure changed to be more elongated in major axis and then crossed the critical phase transition from micellar solution into liquid crystal phase as lamellar structure emerged by further addition of alcohols. The inter-lamellar distances were also depending on the hydrocarbon chain length and concentration of alcohols. In the meantime, the persistent micellar structures occurred in addition of medium chain of n-alcohol, pentanol at all concentrations.« less

High fat diet-fed obese rats are highly sensitive to doxorubicin-induced cardiotoxicity

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

Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent

Often, chemotherapy by doxorubicin (Adriamycin) is limited due to life threatening cardiotoxicity in patients during and posttherapy. Recently, we have shown that moderate diet restriction remarkably protects against doxorubicin-induced cardiotoxicity. This cardioprotection is accompanied by decreased cardiac oxidative stress and triglycerides and increased cardiac fatty-acid oxidation, ATP synthesis, and upregulated JAK/STAT3 pathway. In the current study, we investigated whether a physiological intervention by feeding 40% high fat diet (HFD), which induces obesity in male Sprague-Dawley rats (250-275 g), sensitizes to doxorubicin-induced cardiotoxicity. A LD{sub 10} dose (8 mg doxorubicin/kg, ip) administered on day 43 of the HFD feeding regimen ledmore » to higher cardiotoxicity, cardiac dysfunction, lipid peroxidation, and 80% mortality in the obese (OB) rats in the absence of any significant renal or hepatic toxicity. Doxorubicin toxicokinetics studies revealed no change in accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the normal diet-fed (ND) and OB hearts. Mechanistic studies revealed that OB rats are sensitized due to: (1) higher oxyradical stress leading to upregulation of uncoupling proteins 2 and 3, (2) downregulation of cardiac peroxisome proliferators activated receptor-{alpha}, (3) decreased plasma adiponectin levels, (4) decreased cardiac fatty-acid oxidation (666.9 {+-} 14.0 nmol/min/g heart in ND versus 400.2 {+-} 11.8 nmol/min/g heart in OB), (5) decreased mitochondrial AMP-{alpha}2 protein kinase, and (6) 86% drop in cardiac ATP levels accompanied by decreased ATP/ADP ratio after doxorubicin administration. Decreased cardiac erythropoietin and increased SOCS3 further downregulated the cardioprotective JAK/STAT3 pathway. In conclusion, HFD-induced obese rats are highly sensitized to doxorubicin-induced cardiotoxicity by substantially downregulating cardiac mitochondrial ATP generation, increasing oxidative stress and

Formation of DNA Adducts by Ellipticine and Its Micellar Form in Rats — A Comparative Study

PubMed Central

Stiborova, Marie; Manhartova, Zuzana; Hodek, Petr; Adam, Vojtech; Kizek, Rene; Frei, Eva

2014-01-01

The requirements for early diagnostics as well as effective treatment of cancer diseases have increased the pressure on development of efficient methods for targeted drug delivery as well as imaging of the treatment success. One of the most recent approaches covering the drug delivery aspects is benefitting from the unique properties of nanomaterials. Ellipticine and its derivatives are efficient anticancer compounds that function through multiple mechanisms. Formation of covalent DNA adducts after ellipticine enzymatic activation is one of the most important mechanisms of its pharmacological action. In this study, we investigated whether ellipticine might be released from its micellar (encapsulated) form to generate covalent adducts analogous to those formed by free ellipticine. The 32P-postlabeling technique was used as a useful imaging method to detect and quantify covalent ellipticine-derived DNA adducts. We compared the efficiencies of free ellipticine and its micellar form (the poly(ethylene oxide)-block-poly(allyl glycidyl ether) (PAGE-PEO) block copolymer, P 119 nanoparticles) to form ellipticine-DNA adducts in rats in vivo. Here, we demonstrate for the first time that treatment of rats with ellipticine in micelles resulted in formation of ellipticine-derived DNA adducts in vivo and suggest that a gradual release of ellipticine from its micellar form might produce the enhanced permeation and retention effect of this ellipticine-micellar delivery system. PMID:25479328

Geranylgeranylacetone blocks doxorubicin-induced cardiac toxicity and reduces cancer cell growth and invasion through RHO pathway inhibition.

PubMed

Sysa-Shah, Polina; Xu, Yi; Guo, Xin; Pin, Scott; Bedja, Djahida; Bartock, Rachel; Tsao, Allison; Hsieh, Angela; Wolin, Michael S; Moens, An; Raman, Venu; Orita, Hajime; Gabrielson, Kathleen L

2014-07-01

Doxorubicin is a widely used chemotherapy for solid tumors and hematologic malignancies, but its use is limited due to cardiotoxicity. Geranylgeranylacetone (GGA), an antiulcer agent used in Japan for 30 years, has no significant adverse effects, and unexpectedly reduces ovarian cancer progression in mice. Because GGA reduces oxidative stress in brain and heart, we hypothesized that GGA would prevent oxidative stress of doxorubicin cardiac toxicity and improve doxorubicin's chemotherapeutic effects. Nude mice implanted with MDA-MB-231 breast cancer cells were studied after chronic treatment with doxorubicin, doxorubicin/GGA, GGA, or saline. Transthoracic echocardiography was used to monitor systolic heart function and xenografts evaluated. Mice were euthanized and cardiac tissue evaluated for reactive oxygen species generation, TUNEL assay, and RHO/ROCK pathway analysis. Tumor metastases were evaluated in lung sections. In vitro studies using Boyden chambers were performed to evaluate GGA effects on RHO pathway activator lysophosphatidic acid (LPA)-induced motility and invasion. We found that GGA reduced doxorubicin cardiac toxicity, preserved cardiac function, prevented TUNEL-positive cardiac cell death, and reduced doxorubicin-induced oxidant production in a nitric oxide synthase-dependent and independent manner. GGA also reduced heart doxorubicin-induced ROCK1 cleavage. Remarkably, in xenograft-implanted mice, combined GGA/doxorubicin treatment decreased tumor growth more effectively than doxorubicin treatment alone. As evidence of antitumor effect, GGA inhibited LPA-induced motility and invasion by MDA-MB-231 cells. These anti-invasive effects of GGA were suppressed by geranylgeraniol suggesting GGA inhibits RHO pathway through blocking geranylation. Thus, GGA protects the heart from doxorubicin chemotherapy-induced injury and improves anticancer efficacy of doxorubicin in breast cancer. ©2014 American Association for Cancer Research.

6-gingerol ameliorated doxorubicin-induced cardiotoxicity: role of nuclear factor kappa B and protein glycation.

PubMed

El-Bakly, Wesam M; Louka, Manal L; El-Halawany, Ali M; Schaalan, Mona F

2012-12-01

Doxorubicin is a widely used antitumour drug. Cardiotoxicity is considered a major limitation for its clinical use. The present study was designed to assess the possible antioxidant and antiapoptotic effects of 6-gingerol in attenuating doxorubicin-induced cardiac damage. Male albino rats were treated with either intraperitoneal doxorubicin (18 mg/kg divided into six equal doses for 2 weeks) and/or oral 6-gingerol (10 mg/kg starting 5 days before and continued till the end of the experiment). 6-gingerol significantly ameliorated the doxorubicin-induced elevation in the cardiac enzymes. The stimulation of oxidative stress by doxorubicin was evidenced by the significant decrease in the serum soluble receptor for advanced glycation endproduct allowing unopposed serum advanced glycation endproduct availability. Moreover, doxorubicin activated nuclear factor kappa B (NF-κB) which was indicated by an increase in its immunohistochemical staining in the nucleus. In addition, doxorubicin-induced cardiotoxicity was accompanied by elevation of cardiac caspase-3. Notably, pretreatment with 6-gingerol significantly ameliorated the changes in sRAGE, NF-κB and cardiac caspase-3. Cardiac enzymes showed significant positive correlation with NF-κB and caspase-3 but negative with serum sRAGE, suggesting their role in doxorubicin-induced cardiac injury. These findings were confirmed by cardiac tissue histopathology. 6-gingerol, a known single compound from ginger with anticancer activity, was shown to have a promising role in cardioprotection against doxorubicin-induced cardiotoxicity. This study suggested a novel mechanism for 6-gingerol cardioprotection, which might be mediated through its antioxidative effect and modulation of NF-κB as well as apoptosis.

[Stability study of oxaliplatin and doxorubicin for intraperitoneal administration with hyperthermia].

PubMed

Escudero-Ortiz, V; Duart-Duart, M J; Pérez-Ruixo, C; Pérez-Ruixo, J J; Valenzuela, B

2014-05-01

To evaluate the in vitro physicochemical stability of oxaliplatin and doxorubicin when the in vivo hyperthermic intraperitoneal conditions are reproduced. Three solutions were prepared, A (oxaliplatin 200 mg/L), B(doxorubicin 15 mg/L) and C (oxaliplatin 200 mg/L with doxorubicin 15mg/L) in glucose 5%. The three solutions were subjected to the maximum temperature reached in vivo (49° C) for two hours. Physical stability was focused on visual control of particles or precipitates in solutions, discharge of gases, odor and color. Samples were taken every 15 minutes and the chemical stability was evaluated by determining the concentration of oxaliplatin and doxorubicin remaining in the samples. Oxaliplatin concentrations were determined by atomic absorption graphite chamber while doxorubicin was determined by high performance liquid chromatography.The chemical stability criteria selected was the one described by the American Pharmacopoeia, which sets a permissible variation range between the 90-110% of the initial concentration. During the assay there was no appearance of particles, precipitates in the samples, discharge of gases, nor colour changes in the solutions. The samples showed a remaining concentration of oxaliplatin and doxorubicin within the 90-110% limit. The stability of the samples that follow to two cycles of freeze-thaw after hyperthermia was also found within the specified limits. A, B and c solutions in 5% glucose, are physically and chemically stable at 49° C for two hours. Under these conditions, these solutions could be used with guarantees of stability in patients with peritoneal carcinomatosis subsidiary of intraperitoneal hyperthermic chemotherapy based in these antineoplastic agents. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Retention of bile salts in micellar electrokinetic chromatography: relation of capacity factor to octanol-water partition coefficient and critical micellar concentration.

PubMed

Lucangioli, S E; Carducci, C N; Tripodi, V P; Kenndler, E

2001-12-25

The capacity factors of 16 anionic cholates (from six bile salts, including their glyco- and tauro-conjugates) were determined in a micellar electrokinetic chromatography (MEKC) system consisting of buffer, pH 7.5 (phosphate-boric acid; 20 mmol/l) with 50 mmol/l sodium dodecyl sulfate (SDS) as micelle former and 10% acetonitrile as organic modifier. The capacity factors of the fully dissociated, negatively charged analytes (ranging between 0.2 and 60) were calculated from their mobilities, with a reference background electrolyte (BGE) without SDS representing "free" solution. For comparison, the capacity factors were derived for a second reference BGE where the SDS concentration (5 mmol/l) is close to the critical micellar concentration (CMC). The capacity factors are compared with the logarithm of the octanol-water partition coefficient, log Pow, as measure for lipophilicity. Clear disagreement between these two parameters is found especially for epimeric cholates with the hydroxy group in position 7. In contrast, fair relation between the capacity factor of the analytes and their CMC is observed both depending strongly on the orientation of the OH groups, and tauro-conjugation as well. In this respect the retention behaviour of the bile salts in MEKC seems to reflect their role as detergents in living systems, and might serve as model parameter beyond lipophilicity.

Dynamics of adsorption in micellar and non micellar solutions of derivatives of lysosomotropic substances.

PubMed

Dopierala, Katarzyna; Prochaska, Krystyna

2010-04-22

Dynamics of adsorption in micellar and non micellar solutions of derivatives of lysosomotropic substances was studied. The following compounds were considered in our research work: alkyl N,N-dimethyl-alaninates methobromides (DMALM-n), alkyl N,N-dimethylglycinates methobromides (DMGM-n), fatty acids N,N-dimethylaminoethylesters methobromides (DMM-n), fatty acids N,N-dimethylaminopropylesters methobromides (DMPM-n), fatty acids 1-dimethylamino-2-propyl methobromides (DMP(2)M-n), and derivatives of aminoesters with double alkyl chains (M(2)M-n). The examined compounds show interesting biological properties which can be useful, especially in medicine. The exact mechanism of interaction of such compounds with biological membrane is not fully known. However, it is supposed that the presence of micelles has an important role in biological systems. In this paper we show the results of dynamic surface tension measurements in solutions containing the investigated compounds at concentrations above and below cmc. Moreover, we analyzed the influence of the chemical structure of molecules on the diameters of the micelles formed in the solutions. It was found that adsorption dynamics for the studied compounds is strongly affected by the chemical structure of the considered derivatives, especially by the presence of the ester bond, linearity of the molecule, as well as its hydrophobicity. The obtained results show that the structure of the bromide M(2)M-n with two short hydrocarbon chains favors a faster and more efficient adsorption of the molecules at the air/water interface, compared with compounds having one long alkyl chain. Moreover, the double chained derivatives of the M(2)M-n type do not form typical spherical micelles but bilayer structures probably exist in these solutions. The micelles present in the solutions influence the dynamics of adsorption drastically. Moreover, the obtained results indicated that the compounds with especially high biological activity form

Increasing role of the cancer chemotherapeutic doxorubicin in cellular metabolism.

PubMed

Meredith, Ann-Marie; Dass, Crispin R

2016-06-01

The use of doxorubicin, a drug utilised for many years to treat a wide variety of cancers, has long been limited due to the significant toxicity that can occur not only during, but also years after treatment. It has multiple mechanisms of action including the intercalation of DNA, inhibition of topoisomerase II and the production of free radicals. We review the literature, with the aim of highlighting the role of drug concentration being an important determinant on the unfolding cell biological events that lead to cell stasis or death. The PubMed database was consulted to compile this review. It has been found that the various mechanisms of action at the disposal of doxorubicin culminate in either cell death or cell growth arrest through various cell biological events, such as apoptosis, autophagy, senescence and necrosis. Which of these events is the eventual cause of cell death or growth arrest appears to vary depending on factors such as the patient, cell and cancer type, doxorubicin concentration and the duration of treatment. Further understanding of doxorubicin's influence on cell biological events could lead to an improvement in the drug's efficacy and reduce toxicity. © 2016 Royal Pharmaceutical Society.

Micellar versus hydro-organic mobile phases for retention-hydrophobicity relationship studies with ionizable diuretics and an anionic surfactant.

PubMed

Ruiz-Angel, M J; Carda-Broch, S; García-Alvarez-Coque, M C; Berthod, A

2004-03-19

Logarithm of retention factors (log k) of a group of 14 ionizable diuretics were correlated with the molecular (log P o/w) and apparent (log P(app)) octanol-water partition coefficients. The compounds were chromatographed using aqueous-organic (reversed-phase liquid chromatography, RPLC) and micellar-organic mobile phases (micellar liquid chromatography, MLC) with the anionic surfactant sodium dodecyl sulfate (SDS), in the pH range 3-7, and a conventional octadecylsilane column. Acetonitrile was used as the organic modifier in both modes. The quality of the correlations obtained for log P(app) at varying ionization degree confirms that this correction is required in the aqueous-organic mixtures. The correlation is less improved with SDS micellar media because the acid-base equilibriums are shifted towards higher pH values for acidic compounds. In micellar chromatography, an electrostatic interaction with charged solutes is added to hydrophobic forces; consequently, different correlations should be established for neutral and acidic compounds, and for basic compounds. Correlations between log k and the isocratic descriptors log k(w), log k(wm) (extrapolated retention to pure water in the aqueous-organic and micellar-organic systems, respectively), and psi0 (extrapolated mobile phase composition giving a k = 1 retention factor or twice the dead time), and between these descriptors and log P(app) were also satisfactory, although poorer than those between log k and log P(app) due to the extrapolation. The study shows that, in the particular case of the ionizable diuretics studied, classical RPLC gives better results than MLC with SDS in the retention hydrophobicity correlations.

Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy

NASA Astrophysics Data System (ADS)

Chung, Joo Eun; Tan, Susi; Gao, Shu Jun; Yongvongsoontorn, Nunnarpas; Kim, Soon Hee; Lee, Jeong Heon; Choi, Hak Soo; Yano, Hirohisa; Zhuo, Lang; Kurisawa, Motoichi; Ying, Jackie Y.

2014-11-01

When designing drug carriers, the drug-to-carrier ratio is an important consideration, because the use of high quantities of carriers can result in toxicity as a consequence of poor metabolism and elimination of the carriers. However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects, anti-HIV effects, neuroprotective effects and DNA-protective effects. Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein. The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)-EGCG to form the shell. When injected into mice, the Herceptin-loaded micellar nanocomplex demonstrates better tumour selectivity and growth reduction, as well as longer blood half-life, than free Herceptin.

In vitro effects of doxorubicin and tetrathiomolybdate on canine hemangiosarcoma cells.

PubMed

Sloan, Caroline Q; Rodriguez, Carlos O

2018-02-01

OBJECTIVE To assess the in vitro effects of doxorubicin and tetrathiomolybdate (TM) on cells from a canine hemangiosarcoma cell line. SAMPLE Cultured cells from the canine hemangiosarcoma-derived cell line DEN-HSA. PROCEDURES Cells were treated with TM (0 to 1.5μM), doxorubicin (0 to 5μM), or both with or without 24 hours of pretreatment with ascorbic acid (750μM). Degree of cellular cytotoxicity was measured with a colorimetric assay. Long-term growth inhibition was assessed with a 10-day colony-formation assay. Induction of apoptosis was quantitated by fluorometric assessment of caspase-3 and -7 activation. Formation of reactive oxygen species (ROS) was also detected fluorometrically. RESULTS Exposure of cells to the combination of TM and doxorubicin resulted in a greater decrease in proliferation and clonogenic survival rates than exposure to each drug alone. This treatment combination increased ROS formation and apoptosis to a greater extent than did doxorubicin or TM alone. Ascorbic acid inhibited both TM-induced ROS formation and apoptosis. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that the enhancement in cytotoxic effects observed with DEN-HSA cell exposure to the combination of doxorubicin and TM was achieved through an increase in ROS production. These findings provide a rationale for a clinical trial of this treatment combination in dogs with hemangiosarcoma.

Enzyme and Thermal Dual Responsive Amphiphilic Polymer Core-Shell Nanoparticle for Doxorubicin Delivery to Cancer Cells.

PubMed

Kashyap, Smita; Singh, Nitesh; Surnar, Bapurao; Jayakannan, Manickam

2016-01-11

Dual responsive polymer nanoscaffolds for administering anticancer drugs both at the tumor site and intracellular compartments are made for improving treatment in cancers. The present work reports the design and development of new thermo- and enzyme-responsive amphiphilic copolymer core-shell nanoparticles for doxorubicin delivery at extracellular and intracellular compartments, respectively. A hydrophobic acrylate monomer was tailor-made from 3-pentadecylphenol (PDP, a natural resource) and copolymerized with oligoethylene glycol acrylate (as a hydrophilic monomer) to make new classes of thermo and enzyme dual responsive polymeric amphiphiles. Both radical and reversible addition-fragmentation chain transfer (RAFT) methodologies were adapted for making the amphiphilic copolymers. These amphiphilic copolymers were self-assembled to produce spherical core-shell nanoparticles in water. Upon heating, the core-shell nanoparticles underwent segregation to produce larger sized aggregates above the lower critical solution temperature (LCST). The dual responsive polymer scaffold was found to be capable of loading water insoluble drug, such as doxorubicin (DOX), and fluorescent probe-like Nile Red. The drug release kinetics revealed that DOX was preserved in the core-shell assemblies at normal body temperature (below LCST, ≤ 37 °C). At closer to cancer tissue temperature (above LCST, ∼43 °C), the polymeric scaffold underwent burst release to deliver 90% of loaded drugs within 2 h. At the intracellular environment (pH 7.4, 37 °C) in the presence of esterase enzyme, the amphiphilic copolymer ruptured in a slow and controlled manner to release >95% of the drugs in 12 h. Thus, both burst release of cargo at the tumor microenvironment and control delivery at intracellular compartments were accomplished in a single polymer scaffold. Cytotoxicity assays of the nascent and DOX-loaded polymer were carried out in breast cancer (MCF-7) and cervical cancer (HeLa) cells. Among

Doxorubicin induced myocardial injury is exacerbated following ischaemic stress via opening of the mitochondrial permeability transition pore

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

Gharanei, M.; Hussain, A.; Janneh, O.

Chemotherapeutic agents such as doxorubicin are known to cause or exacerbate cardiovascular cell death when an underlying heart condition is present. However, the mechanism of doxorubicin-induced cardiotoxicity is unclear. Here we assess the cardiotoxic effects of doxorubicin in conditions of myocardial ischaemia reperfusion and the mechanistic basis of protection, in particular the role of the mitochondrial permeability transition pore (mPTP) in such protection. The effects of doxorubicin (1 μM) ± cyclosporine A (CsA, 0.2 μM; inhibits mPTP) were investigated in isolated male Sprague–Dawley rats using Langendorff heart and papillary muscle contraction models subjected to simulated ischaemia and reperfusion injury. Isolatedmore » rat cardiac myocytes were used in an oxidative stress model to study the effects of drug treatment on mPTP by confocal microscopy. Western blot analysis evaluated the effects of drug treatment on p-Akt and p-Erk 1/2 levels. Langendorff and the isometric contraction models showed a detrimental effect of doxorubicin throughout reperfusion/reoxygenation as well as increased p-Akt and p-Erk levels. Interestingly, CsA not only reversed the detrimental effects of doxorubicin, but also reduced p-Akt and p-Erk levels. In the sustained oxidative stress assay to study mPTP opening, doxorubicin decreased the time taken to depolarization and hypercontracture, but these effects were delayed in the presence of CsA. Collectively, our data suggest for the first that doxorubicin exacerbates myocardial injury in an ischaemia reperfusion model. If the inhibition of mPTP ameliorates the cardiotoxic effects of doxorubicin, then more selective inhibitors of mPTP should be further investigated for their utility in patients receiving doxorubicin. - Highlights: ► Doxorubicin exacerbates myocardial ischaemia reperfusion injury. ► Co-treatment with CsA protects against doxorubicin induced myocardial injury. ► CsA delays doxorubicin induced mPTP opening

Doxorubicin-loaded QuadraSphere microspheres: plasma pharmacokinetics and intratumoral drug concentration in an animal model of liver cancer.

PubMed

Lee, Kwang-Hun; Liapi, Eleni A; Cornell, Curt; Reb, Philippe; Buijs, Manon; Vossen, Josephina A; Ventura, Veronica Prieto; Geschwind, Jean-Francois H

2010-06-01

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20 ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.

Doxorubicin-Loaded QuadraSphere Microspheres: Plasma Pharmacokinetics and Intratumoral Drug Concentration in an Animal Model of Liver Cancer

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

Lee, Kwang-Hun; Liapi, Eleni A.; Cornell, Curt

The purpose of this study was to evaluate, in vitro and in vivo, doxorubicin-loaded poly (vinyl alcohol-sodium acrylate) copolymer microspheres [QuadraSphere microspheres (QSMs)] for transcatheter arterial delivery in an animal model of liver cancer. Doxorubicin loading efficiency and release profile were first tested in vitro. In vivo, 15 rabbits, implanted with a Vx-2 tumor in the liver, were divided into three groups of five rabbits each, based on the time of euthanasia. Twenty-five milligrams of QSMs was diluted in 10 ml of a 10 mg/ml doxorubicin solution and 10 ml of nonionic contrast medium for a total volume of 20more » ml. One milliliter of a drug-loaded QSM solution containing 5 mg of doxorubicin was injected into the tumor feeding artery. Plasma doxorubicin and doxorubicinol concentrations, and intratumoral and peritumoral doxorubicin tissue concentrations, were measured. Tumor specimens were pathologically evaluated to record tumor necrosis. As a control, one animal was blandly embolized with plain QSMs in each group. In vitro testing of QSM doxorubicin loadability and release over time showed 82-94% doxorubicin loadability within 2 h and 6% release within the first 6 h after loading, followed by a slow release pattern. In vivo, the doxorubicin plasma concentration declined at 40 min. The peak doxorubicin intratumoral concentration was observed at 3 days and remained detectable till the study's end point (7 days). Mean percentage tumor cell death in the doxorubicin QSM group was 90% at 7 days and 60% in the bland QSM embolization group. In conclusion, QSMs can be efficiently loaded with doxorubicin. Initial experiments with doxorubicin-loaded QSMs show a safe pharmacokinetic profile and effective tumor killing in an animal model of liver cancer.« less

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

Tuning Micellar Structures in Supercritical CO2 Using Surfactant and Amphiphile Mixtures.

PubMed

Peach, Jocelyn; Czajka, Adam; Hazell, Gavin; Hill, Christopher; Mohamed, Azmi; Pegg, Jonathan C; Rogers, Sarah E; Eastoe, Julian

2017-03-14

For equivalent micellar volume fraction (ϕ), systems containing anisotropic micelles are generally more viscous than those comprising spherical micelles. Many surfactants used in water-in-CO 2 (w/c) microemulsions are fluorinated analogues of sodium bis(2-ethylhexyl) sulfosuccinate (AOT): here it is proposed that mixtures of CO 2 -philic surfactants with hydrotropes and cosurfactants may generate elongated micelles in w/c systems at high-pressures (e.g., 100-400 bar). A range of novel w/c microemulsions, stabilized by new custom-synthesized CO 2 -phillic, partially fluorinated surfactants, were formulated with hydrotropes and cosurfactant. The effects of water content (w = [water]/[surfactant]), surfactant structure, and hydrotrope tail length were all investigated. Dispersed water domains were probed using high pressure small-angle neutron scattering (HP-SANS), which provided evidence for elongated reversed micelles in supercritical CO 2 . These new micelles have significantly lower fluorination levels than previously reported (6-29 wt % cf. 14-52 wt %), and furthermore, they support higher water dispersion levels than other related systems (w = 15 cf. w = 5). The intrinsic viscosities of these w/c microemulsions were estimated based on micelle aspect ratio; from this value a relative viscosity value can be estimated through combination with the micellar volume fraction (ϕ). Combining these new results with those for all other reported systems, it has been possible to "map" predicted viscosity increases in CO 2 arising from elongated reversed micelles, as a function of surfactant fluorination and micellar aspect ratio.

A new insight on the dynamics of sodium dodecyl sulfate aqueous micellar solutions by dielectric spectroscopy.

PubMed

Lanzi, Leandro; Carlà, Marcello; Lanzi, Leonardo; Gambi, Cecilia M C

2009-02-01

Aqueous sodium dodecyl sulfate micellar solutions were investigated by a recently developed double-differential dielectric spectroscopy technique in the frequency range 100 MHz-3 GHz at 22 degrees C, in the surfactant concentration range 29.8-524 mM, explored for the first time above 104 mM. The micellar contribution to dielectric spectra was analyzed according to three models containing, respectively, a single Debye relaxation, a Cole-Cole relaxation and a double Debye relaxation. The single Debye model is not accurate enough. Both Cole-Cole and double Debye models fit well the experimental dielectric spectra. With the double Debye model, two characteristic relaxation times were identified: the slower one, in the range 400-900 ps, is due to the motion of counterions bound to the micellar surface (lateral motion); the faster one, in the range 100-130 ps, is due to interfacial bound water. Time constants and amplitudes of both processes are in fair agreement with Grosse's theoretical model, except at the largest concentration values, where interactions between micelles increase. For each sample, the volume fraction of bulk water and the effect of bound water as well as the conductivity in the low frequency limit were computed. The bound water increases as the surfactant concentration increases, in quantitative agreement with the micellar properties. The number of water molecules per surfactant molecule was also computed. The conductivity values are in agreement with Kallay's model over the whole surfactant concentration range.

Inhibitory effects of Silibinin combined with doxorubicin in hepatocellular carcinoma; an in vivo study.

PubMed

Li, Wei-Guo; Wang, He-Qun

2016-01-01

Hepatocellular carcinoma (HCC) is the one of the most common cancers and the third leading cause of cancer related mortality in the world. Unacceptable side effect and development of treatment resistance are the major concerns with the conventional chemotherapeutic agents. Combination therapy using phytotherapeutic agents is attracting the attention of investigators in view of the current needs. In the present study we have evaluated the synergistic effect of silibinin, a nontoxic phytotherapeutic agent in combination with doxorubicin, in advanced HCC using HEPG2 cells and an orthotopic rat model of HCC. The results showed that silibinin strongly synergized with doxorubicin-induced growth inhibition, G2-M arrest, and apoptosis of HEPG2 cells. Silibinin-doxorubicin combination also inhibited cdc2/p34 kinase activity when histone H1 was used as substrate. The combination regimen also moderately increased the expression of cdc25C-cyclin B1-cdc2/p34 associated upstream kinases (Chk1). Simultaneous treatment with silibinin-doxorubicin combination showed a 41% increase in the apoptotic cell death (p=0.01), which was 3-fold higher than what was observed with silibinin or doxorubicin individually. In the orthotopic rat model treatment with silibinin-doxorubicin reduced tumor growth by close to 30% at nearly twice lower dose of individual drugs in the combination group. Our study suggests that combination therapy using silibinin-doxorubicin may show a better therapeutic efficacy in patients with HCC. These findings need to be further validated in human clinical trials.

Effect of tartarate and citrate based food additives on the micellar properties of sodium dodecylsulfate for prospective use as food emulsifier.

PubMed

Banipal, Tarlok S; Kaur, Harjinder; Kaur, Amanpreet; Banipal, Parampaul K

2016-01-01

Citrate and tartarate based food preservatives can be used to enhance the emulsifying properties of sodium dodecylsulfate (SDS) based micellar system and thus making it appropriate for food applications. Exploration of interactions between the two species is the key constraint for execution of such ideas. In this work various micellar and thermodynamic parameters of SDS like critical micellar concentration (CMC), standard Gibbs free energy of micellization (ΔG(0)mic.) etc. have been calculated in different concentrations of disodium tartarate (DST) and trisodium citrate (TSC) in the temperature range (288.15-318.15)K from the conductivity and surface tension measurements. The parameters obtained from these studies reveal the competitive nature of both the additives with SDS for available positions at the air/water interface. TSC is found to be more effective additive in order to make SDS micellar system better for its potential applications as food emulsifier. Copyright © 2015 Elsevier Ltd. All rights reserved.

Determination of patulin in commercial apple juice by micellar electrokinetic chromatography.

PubMed

Murillo, M; González-Peñas, E; Amézqueta, S

2008-01-01

A novel and validated micellar electrokinetic capillary chromatography (MEKC) method using ultraviolet detection (UV) has been applied to the quantitative analysis of patulin (PAT) in commercial apple juice. Patulin was extracted from samples with an ethylacetate solution. The micellar electrokinetic capillary chromatography (MECK) parameters studied for method optimization were buffer composition, voltage, temperature, and a separation between PAT and 5-hydroxymethylfurfural (HMF) (main interference in apple juice PAT analysis) peaks until reaching baseline. The method passes a series of validation tests including selectivity, linearity, limit of detection and quantification (0.7 and 2.5 microgL(-1), respectively), precision (within and between-day variability) and recovery (80.2% RSD=4%), accuracy, and robustness. This method was successfully applied to the measurement of 20 apple juice samples obtained from different supermarkets. One hundred percent of the samples were contaminated with a level greater than the limit of detection, with mean and median values of 41.3 and 35.7 microgL(-1), respectively.

Probing the amphiphile micellar to hexagonal phase transition using Positron Annihilation Lifetime Spectroscopy.

PubMed

Dong, Aurelia W; Fong, Celesta; Hill, Anita J; Boyd, Ben J; Drummond, Calum J

2013-07-15

Positron Annihilation Lifetime Spectroscopy (PALS) has been utilised only sparingly for structural characterisation in self assembled materials. Inconsistencies in approaches to experimental configuration and data analysis between studies has complicated comparisons between studies, meaning that the technique has not provided a cohesive data set across the study of different self assembled systems that advance the technique towards an important tool in soft matter research. In the current work a systematic study was conducted using ionic and non-ionic micellar systems with increasing surfactant concentration to probe positron behaviour on changes between micellar phase structures, and data analysed using contemporary approaches to fit four component spectra. A characteristic orthopositronium lifetime (in the organic regions) of 3.5±0.2 ns was obtained for the hexagonal phase for surfactants with C12 alkyl chains. Chemical quenching of the positron species was also observed for systems with ionic amphiphiles. The application of PALS has also highlighted an inconsistency in the published phase diagram for the octa(ethylene oxide) monododecyl ether (C12EO8) system. These results provide new insight into how the physical properties of micellar systems can be related to PALS parameters and means that the PALS technique can be applied to other more complex self-assembled amphiphile systems. Copyright © 2013 Elsevier Inc. All rights reserved.

Targeted Doxorubicin-Loaded Bacterially Derived Nano-Cells for the Treatment of Neuroblastoma.

PubMed

Sagnella, Sharon M; Trieu, Jennifer; Brahmbhatt, Himanshu; MacDiarmid, Jennifer A; MacMillan, Alex; Whan, Renee M; Fife, Christopher M; McCarroll, Joshua A; Gifford, Andrew J; Ziegler, David S; Kavallaris, Maria

2018-05-01

Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug-resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC Dream Vector (EDV TM ) is a nanocell, which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase I trials in adults with refractory tumors have shown an acceptable safety profile. Herein we investigated the activity of EGFR-targeted and doxorubicin-loaded EDV TM ( EGFR EDV TM Dox ) for the treatment of neuroblastoma. Two independent neuroblastoma cell lines with variable expression of EGFR protein [SK-N-BE(2), high; SH-SY-5Y, low] were used. EGFR EDV TM Dox induced apoptosis in these cells compared to control, doxorubicin, or non-doxorubicin loaded EGFR EDV TM In three-dimensional tumor spheroids, imaging and fluorescence life-time microscopy revealed that EGFR EDV TM Dox had a marked enhancement of doxorubicin penetration compared to doxorubicin alone, and improved penetration compared to non-EGFR-targeted EDV TM Dox , with enhanced spheroid penetration leading to increased apoptosis. In two independent orthotopic human neuroblastoma xenograft models, short-term studies (28 days) of tumor-bearing mice led to a significant decrease in tumor size in EGFR EDV TM Dox -treated animals compared to control, doxorubicin, or non-EGFR EDV TM Dox There was increased TUNEL staining of tumors at day 28 compared to control, doxorubicin, or non-EGFR EDV TM Dox Moreover, overall survival was increased in neuroblastoma mice treated with EGFR EDV TM Dox ( P < 0007) compared to control. Drug-loaded bispecific-antibody targeted EDVs TM offer a highly promising approach for the treatment of aggressive pediatric malignancies such as neuroblastoma. Mol Cancer Ther; 17(5); 1012-23. ©2018 AACR . ©2018 American

A Randomized Trial Investigating the Efficacy and Safety of Water Soluble Micellar Paclitaxel (Paccal Vet) for Treatment of Nonresectable Grade 2 or 3 Mast Cell Tumors in Dogs

PubMed Central

Vail, D.M.; von Euler, H.; Rusk, A.W.; Barber, L.; Clifford, C.; Elmslie, R.; Fulton, L.; Hirschberger, J.; Klein, M.; London, C.; Martano, M.; McNiel, E.A.; Morris, J.S.; Northrup, N.; Phillips, B.; Polton, G.; Post, G.; Rosenberg, M.; Ruslander, D.; Sahora, A.; Siegel, S.; Thamm, D.; Westberg, S.; Winter, J.; Khanna, C.

2013-01-01

Background Effective treatments for dogs with advanced stage mast cell tumors (MCT) remain a pressing need. A micellar formulation of paclitaxel (paclitaxel [micellar]) has shown promise in early-phase studies. Hypothesis/Objectives The objective was to demonstrate greater activity for paclitaxel (micellar) compared with lomustine. The null hypothesis was μp = μL (ie, proportion of responders for the paclitaxel [micellar] and lomustine groups, respectively). Animals Two hundred and fifty-two dogs with advanced stage nonresectable grade 2 or 3 MCT. Methods Prospective multicenter randomized double-blind positive-controlled clinical trial. The primary endpoint was confirmed overall response rate (CORR) at 14 weeks. A secondary endpoint, biologic observed response rate (BORR), also was calculated. Safety was assessed by the characterization and grading of adverse events (AE). Results Overall CORR (7% versus 1%; P = .048) and BORR (23% versus 10%; P = .012) were greater for paclitaxel (micellar) compared with lomustine. Paclitaxel (micellar)-treated dogs were 6.5 times more likely to have a confirmed response and 3.1 times more likely to experience a biologic observed response. The majority of AE with paclitaxel (micellar) were transient and clinically manageable. Twenty-seven dogs (33%) receiving lomustine were discontinued because of hepatopathy compared with 3 dogs (2%) receiving paclitaxel (micellar) (P < .0001; odds ratio 26.7). Conclusions and Clinical Importance Paclitaxel (micellar)’s activity and safety profile are superior to lomustine. The addition of an active and novel taxane to the veterinary armamentarium could fill a substantial need and, as its mechanism of action and AE profile do not overlap with currently available TKI, its availability could lead to effective combination protocols. PMID:22390318

Surface Attachment of Gold Nanoparticles Guided by Block Copolymer Micellar Films and Its Application in Silicon Etching

PubMed Central

Wei, Mingjie; Wang, Yong

2015-01-01

Patterning metallic nanoparticles on substrate surfaces is important in a number of applications. However, it remains challenging to fabricate such patterned nanoparticles with easily controlled structural parameters, including particle sizes and densities, from simple methods. We report on a new route to directly pattern pre-formed gold nanoparticles with different diameters on block copolymer micellar monolayers coated on silicon substrates. Due to the synergetic effect of complexation and electrostatic interactions between the micellar cores and the gold particles, incubating the copolymer-coated silicon in a gold nanoparticles suspension leads to a monolayer of gold particles attached on the coated silicon. The intermediate micellar film was then removed using oxygen plasma treatment, allowing the direct contact of the gold particles with the Si substrate. We further demonstrate that the gold nanoparticles can serve as catalysts for the localized etching of the silicon substrate, resulting in nanoporous Si with a top layer of straight pores. PMID:28793407

Effect of citral on the cytotoxicity of doxorubicin in human B-lymphoma cells.

PubMed

Dangkong, Darinee; Limpanasithikul, Wacharee

2015-02-01

Doxorubicin is a chemotherapy agent used in non-Hodgkin's lymphoma but side effects limit its use. Citral is a mixture of neral and geranial found in essential oils of lemon grass. We evaluated the activity of citral, doxorubicin, and combination on cytotoxicity, apoptosis, and anti-proliferative effects using human lymphoma Ramos cells. Cells were treated with doxorubicin alone or in combination with citral (10, 20, and 40 μM). Cytotoxic and apoptosis studies were done after 24 and 18 h incubations, respectively. Cytotoxic effects of citral on normal human peripheral blood mononuclear cells (PBMCs) were also investigated for its safety. Changes in the expression of BCL-2 family genes were analyzed by quantitative RT-PCR. Citral had cytotoxicity on cells with an IC50 value of 77.19 ± 4.95 µM. Citral at concentrations of 10, 20, and 40 µM additively increased the cytotoxic and apoptotic effects of doxorubicin, leading to decreased IC50 (µM) of the drug from 2.50 ± 0.01 to 2.16 ± 0.03, 1.90 ± 0.04, and 1.23 ± 0.04, respectively. Enhanced cytotoxicity was not observed in normal human PBMCs. Citral (40 µM) in combination with doxorubicin (1.5 µM) increased the expression of pro-apoptotic protein BAK but significantly decreased the expression of anti-apoptotic protein BCL-XL to 5.26-fold compared with doxorubicin-treated cells. It did not change the anti-proliferative activity of drug. Citral potentiated cytotoxicity of doxorubicin by increasing apoptotic effects. We conclude that citral may have beneficial effects in patients with B cell lymphoma treated with chemotherapy.

Effects of Streptococcus thermophilus TH-4 in a rat model of doxorubicin-induced mucositis.

PubMed

Wang, Hanru; Brook, Caitlin L; Whittaker, Alexandra L; Lawrence, Andrew; Yazbeck, Roger; Howarth, Gordon S

2013-08-01

Mucositis is a debilitating intestinal side effect of chemotherapeutic regimens. Probiotics have been considered a possible preventative treatment for mucositis. Streptococcus thermophilus TH-4 (TH-4), a newly identified probiotic, has been shown to partially alleviate mucositis induced by administration of the antimetabolite chemotherapy drug, methotrexate in rats; likely mediated through a mechanism of folate production. However, its effects against other classes of chemotherapy drug have yet to be determined. The authors investigated the effects of TH-4 in a rat model of mucositis induced by the anthracycline chemotherapy drug, doxorubicin. Gastrointestinal damage was induced in female Dark Agouti rats (148.3 ± 1.5 g) by intraperitoneal injection of doxorubicin (20 mg/kg). Animals recieved a daily oral gavage of TH-4 at 10(9) cfu/ml or skim milk (vehicle) from days 0 to 8. At day 6, rats were injected with either saline or doxorubicin. At kill, small intestinal tissues were collected for determination of sucrase and myeloperoxidase (MPO) activities and histological assessment. Body weight was significantly decreased by doxorubicin compared with normal controls (p < 0.05). Histological parameters, such as crypt depth and villus height, were also significantly decreased by doxorubicin. TH-4 partially prevented the loss of body weight induced by doxorubicin (2.3% compared with 4%), but provided no further therapeutic benefit. The minimal amelioration of doxorubicin-induced mucositis by TH-4 further supports folate production as a likely mechanism of TH-4 action against methotrexate-induced mucositis. Further studies into TH-4 are required to confirm its applicability to other conventional chemotherapy regimens.

Concomitant liposomal doxorubicin and daily palliative radiotherapy in advanced feline soft tissue sarcomas.

PubMed

Kleiter, Miriam; Tichy, Alexander; Willmann, Michael; Pagitz, Maximilian; Wolfesberger, Birgitt

2010-01-01

Local recurrence of feline soft tissue sarcomas is common despite aggressive treatment. Liposomal doxorubicin might serve as a depot radiosensitizer if administered concomitantly with daily radiotherapy and thus improve tumor control. In this pilot study, the feasibility of concomitant liposomal radiochemotherapy was evaluated in a palliative setting in 10 cats with advanced soft tissue sarcomas. Cats were treated with median number of 5 (range 5-7) daily fractions of radiotherapy and a median total dose of 20 Gy (range 20-31.5 Gy). One dose of liposomal doxorubicin was administered at the beginning of radiotherapy. Seven cats received further free or liposomal doxorubicin after completion of the liposomal doxorubicin/radiation protocol. Seven of the treated 10 cats (70%) achieved a partial (n=5) or complete (n=2) response with a median response duration of 237 days. The median progression free interval in all 10 cats was 117 days and the median overall survival time was 324 days. Concomitant liposomal radiochemotherapy was tolerated well in nine cats, one cat experienced temporary anorexia. Although the number of patients is too small to make definitive conclusions, results appear promising enough to investigate the role of liposomal doxorubicin as a radiosensitizer further.

A facile strategy for fine-tuning the stability and drug release of stimuli-responsive cross-linked micellar nanoparticles towards precision drug delivery.

PubMed

Xiao, Kai; Lin, Tzu-Yin; Lam, Kit S; Li, Yuanpei

2017-06-14

Precision drug delivery has a great impact on the application of precision oncology for better patient care. Here we report a facile strategy for fine-tuning the stability, drug release and responsiveness of stimuli-responsive cross-linked nanoparticles towards precision drug delivery. A series of micellar nanoparticles with different levels of intramicellar disulfide crosslinkages could be conveniently produced with a mixed micelle approach. These micellar nanoparticles were all within a size range of 25-40 nm so that they could take full advantage of the enhanced permeability and retention (EPR) effect for tumor-targeted drug delivery. The properties of these nanoparticles such as critical micelle concentration (CMC), stability, drug release and responsiveness to a reductive environment could be well correlated with the levels of crosslinking (LOC). Compared to the micellar nanoparticles with a LOC at 0% that caused the death of animals of two species (mouse and rat) due to the acute toxicity such as hemolysis, the nanoparticles at all other levels of crosslinking were much safer to be administered into animals. The in vitro antitumor efficacy of micellar nanoparticles crosslinked at lower levels (20% & 50%) were much more effective than that of 100% crosslinked micellar nanoparticles in SKOV-3 ovarian cancer cells.

Photoresponsive lipid-polymer hybrid nanoparticles for controlled doxorubicin release

NASA Astrophysics Data System (ADS)

Yao, Cuiping; Wu, Ming; Zhang, Cecheng; Lin, Xinyi; Wei, Zuwu; Zheng, Youshi; Zhang, Da; Zhang, Zhenxi; Liu, Xiaolong

2017-06-01

Currently, photoresponsive nanomaterials are particularly attractive due to their spatial and temporal controlled drug release abilities. In this work, we report a photoresponsive lipid-polymer hybrid nanoparticle for remote controlled delivery of anticancer drugs. This hybrid nanoparticle comprises three distinct functional components: (i) a poly(D,L-lactide-co-glycolide) (PLGA) core to encapsulate doxorubicin; (ii) a soybean lecithin monolayer at the interface of the core and shell to act as a molecular fence to prevent drug leakage; (iii) a photoresponsive polymeric shell with anti-biofouling properties to enhance nanoparticle stability, which could be detached from the nanoparticle to trigger the drug release via a decrease in the nanoparticle’s stability under light irradiation. In vitro results revealed that this core-shell nanoparticle had excellent light-controlled drug release behavior (76% release with light irradiation versus 10% release without light irradiation). The confocal microscopy and flow cytometry results also further demonstrated the light-controlled drug release behavior inside the cancer cells. Furthermore, a CCK8 assay demonstrated that light irradiation could significantly improve the efficiency of killing cancer cells. Meanwhile, whole-animal fluorescence imaging of a tumor-bearing mouse also confirmed that light irradiation could trigger drug release in vivo. Taken together, our data suggested that a hybrid nanoparticle could be a novel light controlled drug delivery system for cancer therapy.

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

Effects of antioxidants and hyperbaric oxygen in ameliorating experimental doxorubicin skin toxicity in the rat.

PubMed

Upton, P G; Yamaguchi, K T; Myers, S; Kidwell, T P; Anderson, R J

1986-04-01

Doxorubicin, an antineoplastic drug, can cause severe ulceration if extravasated when iv injected. In this study, the effects of hyperbaric oxygenation (HBO) and the antioxidants butylated hydroxytoluene (BHT) and beta-carotene were tested on such ulcers using female Sprague-Dawley rats. It was found that HBO and vitamin A did not greatly ameliorate the ulcers produced by doxorubicin, but BHT prefed for 1 week before doxorubicin was injected was able to significantly reduce lesion size (P less than 0.05). Doxorubicin with HBO was a lethal combination, with an 87% mortality among the animals by the fourth week after injection. This was probably due to doxorubicin and HBO both promoting the formation of free radicals which are highly destructive to cells. BHT, when prefed (and to a lesser extent, beta-carotene), demonstrated a protective effect by lowering the death rate (P less than 0.05), probably due to their ability to scavenge free radicals. This experiment also tested more conventionally recommended treatments such as sodium bicarbonate (NaHCO3), hydrocortisone, and ice. NaHCO3 and hydrocortisone decreased lesion size although only at a significance of P less than 0.10. Ice did not aid in the healing of the doxorubicin-induced ulcers and even proved deleterious. Multiple injections of hydrocortisone or NaHCO3 appeared to deepen ulceration. Of all the treatments tested, free radical scavengers appear to most significantly reduce skin toxicity of doxorubicin.

Sensitization of breast cancer cells to doxorubicin via stable cell line generation and overexpression of DFF40.

PubMed

Bagheri, Fatemeh; Safarian, Shahrokh; Eslaminejad, Mohamadreza Baghaban; Sheibani, Nader

2015-12-01

There are a number of reports demonstrating a relationship between the alterations in DFF40 expression and development of some cancers. Here, increased DFF40 expression in T-47D cells in the presence of doxorubicin was envisaged for therapeutic usage. The T-47D cells were transfected with an eukaryotic expression vector encoding the DFF40 cDNA. Following incubation with doxorubicin, propidium iodide (PI) staining was used for cell cycle distribution analysis. The rates of apoptosis were determined by annexin V/PI staining. Apoptosis was also evaluated using the DNA laddering analysis. The viability of DFF40-transfected cells incubated with doxorubicin was significantly decreased compared with control cells. However, there were no substantial changes in the cell cycle distribution of pIRES2-DFF40 cells incubated with doxorubicin compared to control cells. The expression of DFF40, without doxorubicin incubation, had also no significant effect on the cell cycle distribution. There was no DNA laddering in cells transfected with the empty pIRES2 vector when incubated with doxorubicin. In contrast, DNA laddering was observed in DFF40 transfected cells in the presence of doxorubicin after 48 h. Also, the expression of DFF40 and DFF45 was increased in DFF40 transfected cells in the presence of doxorubicin enhancing cell death. Collectively our results indicated that co-treatment of DFF40-transfected cells with doxorubicin can enhance the killing of these tumor cells via apoptosis. Thus, modulation of DFF40 level may be a beneficial strategy for treatment of chemo-resistant cancers.

TVP1022 Protects Neonatal Rat Ventricular Myocytes against Doxorubicin-Induced Functional Derangements

PubMed Central

Berdichevski, Alexandra; Meiry, Gideon; Milman, Felix; Reiter, Irena; Sedan, Oshra; Eliyahu, Sivan; Duffy, Heather S.; Youdim, Moussa B.; Binah, Ofer

2010-01-01

Our recent studies demonstrated that propargylamine derivatives such as rasagiline (Azilect, Food and Drug Administration-approved anti-Parkinson drug) and its S-isomer TVP1022 protect cardiac and neuronal cell cultures against apoptotic-inducing stimuli. Studies on structure-activity relationship revealed that their neuroprotective effect is associated with the propargylamine moiety, which protects mitochondrial viability and prevents apoptosis by activating Bcl-2 and protein kinase C-ε and by down-regulating the proapoptotic protein Bax. Based on the established cytoprotective and neuroprotective efficacies of propargylamine derivatives, as well as on our recent study showing that TVP1022 attenuates serum starvation-induced and doxorubicin-induced apoptosis in neonatal rat ventricular myocytes (NRVMs), we tested the hypothesis that TVP1022 will also provide protection against doxorubicin-induced NRVM functional derangements. The present study demonstrates that pretreatment of NRVMs with TVP1022 (1 μM, 24 h) prevented doxorubicin (0.5 μM, 24 h)-induced elevation of diastolic [Ca2+]i, the slowing of [Ca2+]i relaxation kinetics, and the decrease in the rates of myocyte contraction and relaxation. Furthermore, pretreatment with TVP1022 attenuated the doxorubicin-induced reduction in the protein expression of sarco/endoplasmic reticulum calcium (Ca2+) ATPase, Na+/Ca2+ exchanger 1, and total connexin 43. Finally, TVP1022 diminished the inhibitory effect of doxorubicin on gap junctional intercellular coupling (measured by means of Lucifer yellow transfer) and on conduction velocity, the amplitude of the activation phase, and the maximal rate of activation (dv/dtmax) measured by the Micro-Electrode-Array system. In summary, our results indicate that TVP1022 acts as a novel cardioprotective agent against anthracycline cardiotoxicity, and therefore potentially can be coadmhence, the inistered with doxorubicin in the treatment of malignancies in humans. PMID:19915070

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.

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.

Human colon cancer HT-29 cell death responses to doxorubicin and Morus Alba leaves flavonoid extract.

PubMed

Fallah, S; Karimi, A; Panahi, G; Gerayesh Nejad, S; Fadaei, R; Seifi, M

2016-03-31

The mechanistic basis for the biological properties of Morus alba flavonoid extract (MFE) and chemotherapy drug of doxorubicin on human colon cancer HT-29 cell line death are unknown. The effect of doxorubicin and flavonoid extract on colon cancer HT-29 cell line death and identification of APC gene expression and PARP concentration of HT-29 cell line were investigated. The results showed that flavonoid extract and doxorubicin induce a dose dependent cell death in HT-29 cell line. MFE and doxorubicin exert a cytotoxic effect on human colon cancer HT-29 cell line by probably promoting or induction of apoptosis.

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.

Interactions between N-acetyl-L-cysteine protected CdTe quantum dots and doxorubicin through spectroscopic method

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

Yang, Xiupei, E-mail: xiupeiyang@163.com; College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637000; Lin, Jia

2015-06-15

Highlights: • CdTe quantum dots with the diameter of 3–5 nm were synthesized in aqueous solution. • The modified CdTe quantum dots showed well fluorescence properties. • The interaction between the CdTe quantum dots and doxorubicin (DR) was investigated. - Abstract: N-acetyl-L-cysteine protected cadmium telluride quantum dots with a diameter of 3–5 nm were synthesized in aqueous solution. The interaction between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin was investigated by ultraviolet–visible absorption and fluorescence spectroscopy at physiological conditions (pH 7.2, 37 °C). The results indicate that electron transfer has occurred between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin under light illumination.more » The quantum dots react readily with doxorubicin to form a N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex via electrostatic attraction between the −NH{sub 3}{sup +} moiety of doxorubicin and the −COO{sup −} moiety of N-acetyl-L-cysteine/cadmium telluride quantum dots. The interaction of N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex with bovine serum albumin was studied as well, showing that the complex might induce the conformation change of bovine serum due to changes in microenvironment of bovine serum.« less

Microstructural evolution of a model, shear-banding micellar solution during shear startup and cessation.

PubMed

López-Barrón, Carlos R; Gurnon, A Kate; Eberle, Aaron P R; Porcar, Lionel; Wagner, Norman J

2014-04-01

We present direct measurements of the evolution of the segmental-level microstructure of a stable shear-banding polymerlike micelle solution during flow startup and cessation in the plane of flow. These measurements provide a definitive, quantitative microstructural understanding of the stages observed during flow startup: an initial elastic response with limited alignment that yields with a large stress overshoot to a homogeneous flow with associated micellar alignment that persists for approximately three relaxation times. This transient is followed by a shear (kink) band formation with a flow-aligned low-viscosity band that exhibits shear-induced concentration fluctuations and coexists with a nearly isotropic band of homogenous, highly viscoelastic micellar solution. Stable, steady banding flow is achieved only after approximately two reptation times. Flow cessation from this shear-banded state is also found to be nontrivial, exhibiting an initial fast relaxation with only minor structural relaxation, followed by a slower relaxation of the aligned micellar fluid with the equilibrium fluid's characteristic relaxation time. These measurements resolve a controversy in the literature surrounding the mechanism of shear banding in entangled wormlike micelles and, by means of comparison to existing literature, provide further insights into the mechanisms driving shear-banding instabilities in related systems. The methods and instrumentation described should find broad use in exploring complex fluid rheology and testing microstructure-based constitutive equations.

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

Oxidative DNA Base Damage in MCF-10A Breast Epithelial Cells at Clinically Achievable Concentrations of Doxorubicin

PubMed Central

Gajewski, Ewa; Gaur, Shikha; Akman, Steven A.; Matsumoto, Linda; van Balgooy, Josephus N.A.; Doroshow, James H.

2009-01-01

The cellular metabolism of doxorubicin generates reactive oxygen species with significant potential to damage DNA. Such DNA damage can result in mutations if not adequately repaired by cellular DNA repair pathways. Secondary malignancies have been reported in patients who have received doxorubicin-containing chemotherapeutic regimens; however, the underlying molecular mechanism(s) to explain the development of these tumors remains under active investigation. We have previously demonstrated the presence of DNA bases modified by oxidation in the peripheral blood mononuclear cells of patients with breast cancer following treatment with doxorubicin. In those studies, doxorubicin was administered by continuous infusion over 96 hours to minimize the risk of cardiac toxicity. To evaluate potential mechanisms underlying doxorubicin-induced DNA base oxidation in non-malignant tissues, MCF-10A breast epithelial cells were cultured for 96 hours with the same doxorubicin concentration achieved in vivo (0.1 μM). During doxorubicin exposure, MCF-10A cells underwent growth arrest and apoptosis, developed elevated levels of reactive oxygen species, and demonstrated a time-dependent and significant increase in the levels of 11 oxidized DNA bases, as determined by gas chromatography/mass spectroscopy. Diminished expression of DNA repair enzymes was also observed over the same time course. Thus, clinically achievable concentrations of doxorubicin induce a level of oxidative stress in MCF-10A cells that is capable of oxidizing DNA bases and significantly altering cellular proliferation. PMID:17445777

Rapid ultrasonic and microwave-assisted micellar extraction of zingiberone, shogaol and gingerols from gingers using biosurfactants.

PubMed

Peng, Li-Qing; Cao, Jun; Du, Li-Jing; Zhang, Qi-Dong; Xu, Jing-Jing; Chen, Yu-Bo; Shi, Yu-Ting; Li, Rong-Rong

2017-09-15

Two kinds of extraction methods ultrasonic-assisted micellar extraction (UAME) and microwave-assisted micellar extraction (MAME) coupled with ultra-high performance liquid chromatography with ultraviolet detector (UHPLC-UV) were developed and evaluated for extraction and determination of zingerone, 6-gingerol, 8-gingerol, 6-shogaol and 10-gingerol in Rhizoma Zingiberis and Rhizoma Zingiberis Preparata. A biosurfactant, hyodeoxycholic acid sodium salt, was used in micellar extraction. Several experimental parameters were studied separately by a univariate method. The result indicated that the MAME was more efficient than UAME. The optimal conditions of MAME were as follows: 100mM of hyodeoxycholic acid sodium salt was used as surfactant, the irradiation time was set at 10s and the extraction temperature was set at 60°C. The validation results indicated that the limits of detection were in the range of 3.80-8.11ng/mL. The average recoveries were in the range of 87.32-103.12% for the two samples at two spiking levels. Compared with other reported methods, the proposed MAME-UHPLC-UV method was more effective, quicker (10s) and more eco-friendly. Copyright © 2017 Elsevier B.V. All rights reserved.

Essential Oil from Myrica rubra Leaves Potentiated Antiproliferative and Prooxidative Effect of Doxorubicin and its Accumulation in Intestinal Cancer Cells.

PubMed

Ambrož, Martin; Hanušová, Veronika; Skarka, Adam; Boušová, Iva; Králová, Věra; Langhasová, Lenka; Skálová, Lenka

2016-01-01

Essential oil from the leaves of Myrica rubra, a subtropical Asian fruit tree traditionally used in folk medicines, has a significant antiproliferative effect in several intestinal cancer cell lines. Doxorubicin belongs to the most important cytostatics used in cancer therapy. The present study was designed to evaluate the effects of defined essential oil from M. rubra leaves on efficacy, prooxidative effect, and accumulation of doxorubicin in cancer cell lines and in non-cancerous cells. For this purpose, intestinal adenocarcinoma CaCo2 cells were used. Human fibroblasts (periodontal ligament) and a primary culture of rat hepatocytes served as models of non-cancerous cells. The results showed that the sole essential oil from M. rubra has a strong prooxidative effect in cancer cells while it acts as a mild antioxidant in hepatocytes. Combined with doxorubicin, the essential oil enhanced the antiproliferative and prooxidative effects of doxorubicin in cancer cells. At higher concentrations, synergism of doxorubicin and essential oil from M. rubra was proved. In non-cancerous cells, the essential oil did not affect the toxicity of doxorubicin and the doxorubicin-mediated reactive oxygen species formation. The essential oil increased the intracellular concentration of doxorubicin and enhanced selectively the doxorubicin accumulation in nuclei of cancer cells. Taken together, essential oil from M. rubra leaves could be able to improve the doxorubicin efficacy in cancer cells due to an increased reactive oxygen species production, and the doxorubicin accumulation in nuclei of cancer cells. Georg Thieme Verlag KG Stuttgart · New York.

Backbone degradable multiblock N-(2-hydroxypropyl)methacrylamide copolymer conjugates via reversible addition-fragmentation chain transfer polymerization and thiol-ene coupling reaction.

PubMed

Pan, Huaizhong; Yang, Jiyuan; Kopecková, Pavla; Kopecek, Jindrich

2011-01-10

Telechelic water-soluble HPMA copolymers and HPMA copolymer-doxorubicin (DOX) conjugates have been synthesized by RAFT polymerization mediated by a new bifunctional chain transfer agent (CTA) that contains an enzymatically degradable oligopeptide sequence. Postpolymerization aminolysis followed by chain extension with a bis-maleimide resulted in linear high molecular weight multiblock HPMA copolymer conjugates. These polymers are enzymatically degradable; in addition to releasing the drug (DOX), the degradation of the polymer backbone resulted in products with molecular weights similar to the starting material and below the renal threshold. The new multiblock HPMA copolymers hold potential as new carriers of anticancer drugs.

Efficacy of maropitant in the prevention of delayed vomiting associated with administration of doxorubicin to dogs.

PubMed

Rau, S E; Barber, L G; Burgess, K E

2010-01-01

Vomiting, nausea, inappetence, and diarrhea are common delayed adverse effects of doxorubicin. Maropitant, a neurokinin-1 receptor antagonist, is known to prevent acute vomiting in dogs receiving cisplatin. To evaluate the efficacy of maropitant in preventing delayed vomiting after administration of doxorubicin to dogs. Fifty-nine dogs with cancer. This randomized, double-blind, placebo-controlled study used a cross-over design. Dogs were randomized into 1 of 2 treatment groups. Group A received maropitant after the 1st doxorubicin, and placebo after the 2nd. Group B received placebo first, and maropitant second. Maropitant (2 mg/kg) or placebo tablets were administered PO for 5 days after doxorubicin treatment. Owners completed visual analog scales based on Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events to grade their pet's clinical signs during the week after administration of doxorubicin. Statistical differences in gastrointestinal toxicosis and myelosuppression between maropitant and placebo treatments were evaluated. Significantly fewer dogs had vomiting (P=.001) or diarrhea (P=.041), and the severity of vomiting (P<.001) and diarrhea (P=.024) was less the week after doxorubicin when receiving maropitant compared with placebo. No differences were found between maropitant and placebo for other gastrointestinal and bone marrow toxicoses. Maropitant is effective in preventing delayed vomiting induced by doxorubicin. Its prophylactic use might improve quality of life and decrease the need for dose reductions in certain dogs. Copyright © 2010 by the American College of Veterinary Internal Medicine.

Minoxidil (Mx) as a prophylaxis of doxorubicin--induced alopecia.

PubMed

Rodriguez, R; Machiavelli, M; Leone, B; Romero, A; Cuevas, M A; Langhi, M; Romero Acuña, L; Romero Acuña, J; Amato, S; Barbieri, M

1994-10-01

Minoxidil (Mx) is known to induce hair growth in men with male-pattern baldness. Based on this potential, the effectiveness of Mx 2% topical solution was evaluated in cancer patients (pts) to prevent doxorubicin-induced alopecia. 48 female pts with different types of solid tumors treated with doxorubicin-based chemotherapy in a dose range of 50-60 mg/m2/cycle were randomly assigned to receive Mx 2% topical solution or placebo. 88% and 92% of pts in both arms showed severe alopecia (p = ns). No adverse effects were observed. In this study Mx 2% topical solution was non-toxic but was not effective in the prevention of chemotherapy-induced alopecia.

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.

Bacterial inactivation of the anticancer drug doxorubicin.

PubMed

Westman, Erin L; Canova, Marc J; Radhi, Inas J; Koteva, Kalinka; Kireeva, Inga; Waglechner, Nicholas; Wright, Gerard D

2012-10-26

Microbes are exposed to compounds produced by members of their ecological niche, including molecules with antibiotic or antineoplastic activities. As a result, even bacteria that do not produce such compounds can harbor the genetic machinery to inactivate or degrade these molecules. Here, we investigated environmental actinomycetes for their ability to inactivate doxorubicin, an aminoglycosylated anthracycline anticancer drug. One strain, Streptomyces WAC04685, inactivates doxorubicin via a deglycosylation mechanism. Activity-based purification of the enzymes responsible for drug inactivation identified the NADH dehydrogenase component of respiratory electron transport complex I, which was confirmed by gene inactivation studies. A mechanism where reduction of the quinone ring of the anthracycline by NADH dehydrogenase leads to deglycosylation is proposed. This work adds anticancer drug inactivation to the enzymatic inactivation portfolio of actinomycetes and offers possibilities for novel applications in drug detoxification. Copyright © 2012 Elsevier Ltd. All rights reserved.

Extensive preclinical investigation of polymersomal formulation of doxorubicin versus Doxil-mimic formulation.

PubMed

Alibolandi, Mona; Abnous, Khalil; Mohammadi, Marzieh; Hadizadeh, Farzin; Sadeghi, Fatemeh; Taghavi, Sahar; Jaafari, Mahmoud Reza; Ramezani, Mohammad

2017-10-28

Due to the severe cardiotoxicity of doxorubicin, its usage is limited. This shortcoming could be overcome by modifying pharmacokinetics of the drugs via preparation of various nanoplatforms. Doxil, a well-known FDA-approved nanoplatform of doxorubicin as antineoplastic agent, is frequently used in clinics in order to reduce cardiotoxicity of doxorubicin. Since Doxil shows some shortcomings in clinics including hand and food syndrome and very slow release pattern thus, there is a demand for the development and preparation of new doxorubicin nanoformulation with fewer side effects. The new formulation of the doxorubicin, synthesized previously by our group was extensively examined in the current study. This new formulation is doxorubicin encapsulated in PEG-PLGA polymersomes (PolyDOX). The main aim of the study was to compare the distribution and treatment efficacy of a new doxorubicin-polymersomal formulation (PolyDOX) with regular liposomal formulation (Doxil-mimic) in murine colon adenocarcinoma model. Additionally, the pathological, hematological changes, pharmacodynamics, biodistribution, tolerated dose and survival rate in vivo were evaluated and compared. Murine colon cancer model was induced by subcutaneous inoculation of BALB/c mice with C26 cells. Afterwards, either Doxil-mimic or PolyDOX was administered intravenously. The obtained results from biodistribution study showed a remarkable difference in the distribution of drugs in murine organs. In this regard, Doxil-mimic exhibited prolonged (48h) presence within liver tissues while PolyDOX preferentially accumulate in tumor and the presence in liver 48h post-treatment was significantly lower than that of Doxil-mimic. Obtained results demonstrated comparable final length of life for mice receiving either Doxil-mimic or PolyDOX formulations whereas tolerated dose of mice receiving Doxil-mimic was remarkably higher than those receiving PolyDOX. Therapeutic efficacy of formulation in term of tumor growth rate

Assembled microcapsules by doxorubicin and polysaccharide as high effective anticancer drug carriers.

PubMed

Du, Cuiling; Zhao, Jie; Fei, Jinbo; Cui, Yue; Li, Junbai

2013-09-01

Doxorubicin, together with the modified polysaccharide (alginate dialdehyde), was used as a wall material to fabricate microcapsules through self-cross-linking by a template method. The microcapsules as-prepared are pH-responsive. Relevant scanning electronic microscopy, atom force microscopy and confocal laser scanning microscopy confirm the morphology of the uniform microcapsules. The spectroscopic results show that the microcapsules are assembled through electrostatic interaction and Schiff's base covalent bonding. Doxorubicin can be released sustainably from the capsules in buffer solution at a lower pH value. The cellular uptake of the microcapsules and drug release induced by acidic microenvironment are time-dependent processes. The cell cytotoxicity experiments in vitro demonstrate that the doxorubicin-based microcapsules have high efficiency to kill the cancer cells. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Targeting doxorubicin encapsulated in stealth liposomes to solid tumors by non thermal diode laser.

PubMed

Ghannam, Magdy M; El Gebaly, Reem; Fadel, Maha

2016-04-05

The use of liposomes as drug delivery systems is the most promising technique for targeting drug especially for anticancer therapy. In this study sterically stabilized liposomes was prepared from DPPC/Cholesterol/PEG-PE encapsulated doxorubicin. The effect of lyophilization on liposomal stability and hence expiration date were studied. Moreover, the effect of diode laser on the drug released from liposomesin vitro and in vivo in mice carrying implanted solid tumor were also studied. The results indicated that lyophilization of the prepared liposomes encapsulating doxorubicin led to marked stability when stored at 5 °C and it is possible to use the re-hydrated lyophilized liposomes within 12 days post reconstitution. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells is a promising method in cancer therapy. We can conclude that lyophilization of the liposomes encapsulating doxorubicin lead to marked stability for the liposomes when stored at 5 °C. Moreover, the use of low energy diode laser for targeting anticancer drug to the tumor cells through the use of photosensitive sterically stabilized liposomes loaded with doxorubicin is a promising method. It proved to be applicable and successful for treatment of Ehrlich solid tumors implanted in mice and eliminated toxic side effects of doxorubicin.

Micellar modification of drug stability: analysis of the effect of hexadecyltrimethylammonium halides on the rate of degradation of cephaclor.

PubMed

Oliveira, A G; Cuccovia, I M; Chaimovich, H

1990-01-01

The intra- and intermolecular rates of degradation of cephaclor were determined with and without hexadecyltrimethylammonium bromide (CTABr). Micellar-derived spectral shifts were used to measure the association of the ionic forms as well as to determine the effect of CTABr on the apparent acid dissociation constant of the antibiotic. The rate of degradation of cephaclor increased with detergent and was salt sensitive. Micellar effects were analyzed quantitatively within the framework of the pseudophase ion exchange model. All experimental data were fitted to this model which was used to predict the combined effects of pH and detergent concentration. Micelles increased the rate of OH- attack on cephaclor; most of the effect was due to the concentration of reagents in the micellar pseudophase. The intramolecular degradation was catalyzed 25-fold by micelles, and a working hypothesis to rationalize this effect is proposed. The results demonstrate that quantitative analysis can be utilized to assess and predict effects of detergents on drug stability.

High-Performance Liquid Chromatography (HPLC) Quantification of Liposome-Delivered Doxorubicin in Arthritic Joints of Collagen-Induced Arthritis Rats.

PubMed

Niu, Hongqing; Xu, Menghua; Li, Shuangtian; Chen, Junwei; Luo, Jing; Zhao, Xiangcong; Gao, Chong; Li, Xiaofeng

2017-04-14

BACKGROUND Neoangiogenesis occurring in inflamed articular synovium in early rheumatoid arthritis (RA) is characterized by enhanced vascular permeability that allows nanoparticle agents, including liposomes, to deliver encapsulated drugs to arthritic joints and subsequently improve therapeutic efficacy and reduce adverse effects. However, the targeting distribution of liposomes in arthritic joints during RA has not been quantitatively demonstrated. We performed this study to evaluate the targeting distribution of PEGylated doxorubicin liposomes in the arthritic joints of collagen-induced arthritis (CIA) rats by high-performance liquid chromatography (HPLC). MATERIAL AND METHODS Two doxorubicin formulations were administered to CIA rats via tail intravenous injection at a single dose (50 mg/m²). CIA rats were sacrificed and the tissues of the inflamed ankle joints were collected. The content of doxorubicin in the arthritic joints was analyzed by a validated and reproducible HPLC method. A two-way ANOVA for 2×5 factorial design was used for statistical analysis. RESULTS The developed HPLC method was sensitive, precise, and reproducible. The method was successfully applied to quantify doxorubicin content in arthritic tissues. At each time point (6, 12, 24, 48, and 72 h), doxorubicin content in the arthritic joints of the doxorubicin liposome group (DOX-LIP group) was higher than in the free doxorubicin group (DOX group) (P<0.05). In the DOX-LIP group, doxorubicin levels in the arthritic joints increased gradually and significantly in the interval of 6-72 h post-administration. CONCLUSIONS PEGylated doxorubicin liposomes were targeted to, accumulated, and retained in the arthritic joints of CIA rats. The present study indicates that liposome encapsulation increases the therapeutic efficacy of antirheumatic drugs, presenting a promising therapeutic strategy for RA.

[The therapeutic effect of HSV1-hGM-CSF combined with doxorubicin on the mouse breast cancer model].

PubMed

Zhuang, X F; Zhang, S R; Liu, B L; Wu, J L; Li, X Q; Gu, H G; Shu, Y

2018-03-23

Objective: To evaluate the oncolytic effect of herpes simplex virus type 1 which carried recombined human granulocyte-macrophage colony-stimulating factor (HSV1-hGM-CSF) on the mouse breast cancer cell line 4T1 and compare the anticancer effects of HSV1-hGM-CSF, doxorubicin alone or combination on the breast cancer in mice. Methods: We investigated the cytotoxic effect on 4T1 cells in vitro, the cell growth, cell apoptosis and cell cycle of 4T1 cells treated with oncolytic HSV1-hGM-CSF at different MOIs (0, 0.5, 1 and 2) and doxorubicin at different concentrations (0, 2, 4 and 8 μg/ml). The effects of oncolytic HSV1-hGM-CSF and doxorubicin on the tumor growth, survival time and their side effects on the mouse breast cancer model were observed. Results: Both oncolytic HSV1-hGM-CSF and doxorubicin significantly inhibited the proliferation of 4T1 cells in vitro . Doxorubicin induced the G(2)/M phase arrest of 4T1 cells, while the cytotoxicity of oncolytic HSV1-hGM-CSF was no cell cycle-dependent.At day 16 after treatment with doxorubicin and HSV1-hGM-CSF, the tumor volume of 4T1 tumor bearing mice were (144.40±27.68)mm(3,) (216.80±57.18)mm(3,) (246.10±21.90)mm(3,) (327.50±44.24)mm(3,) (213.30±32.31)mm(3) and (495.80±75.87)mm(3) in the groups of doxorubicin combined with high dose HSV1-hGM-CSF, doxorubicin combined with low dose HSV1-hGM-CSF, doxorubicin alone, high dose HSV1-hGM-CSF alone, low dose HSV1-hGM-CSF alone and control, respectively.Compared with the control group, both doxorubicin and HSV1-hGM-CSF treatment exhibited significant reduction of primary tumor volume in vivo ( P <0.001). The median survival times were 48, 50, 40, 42, 43 and 37 days in the six groups mentioned above, respectively. The median survival period of doxorubicin alone, high dose HSV1-hGM-CSF alone and low dose HSV1-hGM-CSF alone were significantly longer than that of control ( P <0.05). Conclusion: Synergistic effect of sequential treatment with doxorubicin and oncolytic HSV1-h

Analysis of different beta-lactams antibiotics in pharmaceutical preparations using micellar electrokinetic capillary chromatography.

PubMed

Pérez, M I Bailón; Rodríguez, L Cuadros; Cruces-Blanco, C

2007-01-17

The potential of micellar electrokinetic capillary chromatography (MEKC) for analyzing nine beta-lactams antibiotics (cloxacillin, dicloxacillin, oxacillin, penicillin G, penicillin V, ampicillin, nafcillin, piperacillin, amoxicillin) in different pharmaceutical preparations, have been demonstrated. An experimental design strategy has been applied to optimize the main variables: pH and buffer concentration, concentration of the micellar medium, separation voltage and capillary temperature. Borate buffer (26mM) at pH 8.5 containing 100mM sodium dodecyl sulphate (SDS) was used as the background electrolyte. The method was validated. Linearity, limit of detection and quantitation and precision were established for each compound. The analysis of some of the beta-lactams in Orbenin capsules, Britapen tables and in Veterin-Micipen injectable, all used in human and veterinary medicine, have demonstrated the applicability of these technique for quality control in the pharmaceutical industry.

Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice.

PubMed

Kim, Tae Hwan; Shin, Soyoung; Yoo, Sun Dong; Shin, Beom Soo

2018-02-07

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, K p , for the liver and kidney were higher in the piperine-pretreated group, while the K p for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

Mixtures of lecithin and bile salt can form highly viscous wormlike micellar solutions in water.

PubMed

Cheng, Chih-Yang; Oh, Hyuntaek; Wang, Ting-Yu; Raghavan, Srinivasa R; Tung, Shih-Huang

2014-09-02

The self-assembly of biological surfactants in water is an important topic for study because of its relevance to physiological processes. Two common types of biosurfactants are lecithin (phosphatidylcholine) and bile salts, which are both present in bile and involved in digestion. Previous studies on lecithin-bile salt mixtures have reported the formation of short, rodlike micelles. Here, we show that lecithin-bile salt micelles can be further induced to grow into long, flexible wormlike structures. The formation of long worms and their resultant entanglement into transient networks is reflected in the rheology: the fluids become viscoelastic and exhibit Maxwellian behavior, and their zero-shear viscosity can be up to a 1000-fold higher than that of water. The presence of worms is further confirmed by data from small-angle neutron and X-ray scattering and from cryo-transmission electron microscopy (cryo-TEM). We find that micellar growth peaks at a specific molar ratio (near equimolar) of bile salt:lecithin, which suggests a strong binding interaction between the two species. In addition, micellar growth also requires a sufficient concentration of background electrolyte such as NaCl or sodium citrate that serves to screen the electrostatic repulsion of the amphiphiles and to "salt out" the amphiphiles. We postulate a mechanism based on changes in the molecular geometry caused by bile salts and electrolytes to explain the micellar growth.

Can neutral analytes be concentrated by transient isotachophoresis in micellar electrokinetic chromatography and how much?

PubMed

Matczuk, Magdalena; Foteeva, Lidia S; Jarosz, Maciej; Galanski, Markus; Keppler, Bernhard K; Hirokawa, Takeshi; Timerbaev, Andrei R

2014-06-06

Transient isotachophoresis (tITP) is a versatile sample preconcentration technique that uses ITP to focus electrically charged analytes at the initial stage of CE analysis. However, according to the ruling principle of tITP, uncharged analytes are beyond its capacity while being separated and detected by micellar electrokinetic chromatography (MEKC). On the other hand, when these are charged micelles that undergo the tITP focusing, one can anticipate the concentration effect, resulting from the formation of transient micellar stack at moving sample/background electrolyte (BGE) boundary, which increasingly accumulates the analytes. This work expands the enrichment potential of tITP for MEKC by demonstrating the quantitative analysis of uncharged metal-based drugs from highly saline samples and introducing to the BGE solution anionic surfactants and buffer (terminating) co-ions of different mobility and concentration to optimize performance. Metallodrugs of assorted lipophilicity were chosen so as to explore whether their varying affinity toward micelles plays the role. In addition to altering the sample and BGE composition, optimization of the detection capability was achieved due to fine-tuning operational variables such as sample volume, separation voltage and pressure, etc. The results of optimization trials shed light on the mechanism of micellar tITP and render effective determination of selected drugs in human urine, with practical limits of detection using conventional UV detector. Copyright © 2014 Elsevier B.V. All rights reserved.

Micellar catalyzed degradation of fenitrothion, an organophosphorus pesticide, in solution and soils.

PubMed

Balakrishnan, Vimal K; Buncel, Erwin; Vanloon, Gary W

2005-08-01

We report on a study of the decomposition of fenitrothion (an organophosphorus pesticide that is a persistent contaminant in soils and groundwater) as catalyzed by cetyltrimethylammonium (CTA+) micelles. The CTA micelles were associated with two types of counterions: (1) inert counterions (e.g. CTABr) and (2) reactive counterions (e.g. CTAOH). The reactive counterion surfactants used were hydroxide anion (HO-) as a normal nucleophile and hydroperoxide anion (HOO-) and the anion of pyruvaldehyde oxime (MINA-) as two alpha-nucleophiles. The reactivity order followed: CTABr < CTAOH < CTAMINA < CTAOOH. Treatment of the rate data using the Pseudo-Phase Ion Exchange (PPIE) model of micellar catalysis showed the ratio k2M/k2w to be less than unity for all the surfactants employed. Rather than arising from a "true catalysis", we attributed the observed rate enhancements to a "concentration effect", where both pesticide and nucleophile were incorporated into the small micellar phase volume. Furthermore, the CTAOOH/CTAOH pair gave an alpha-effect of 57, showing that the alpha-effect can play an important role in micellar systems. We further investigated the effectiveness of reactive counterion surfactants in decontaminating selected environmental solids that were spiked with 27 ppb fenitrothion. The solids were as follows: the clay mineral montmorillonite and SO-1 and S0-2 soils (obtained from the Canadian Certified Reference Materials Project). The reactive counterion surfactant solutions significantly enhanced the rate of fenitrothion degradation in the spiked solids over that obtained when the spiked solid was placed in contact with either 0.02 M KOH or water. The rate enhancements followed the order CTAOOH > CTAMINA approximately CTAOH > KOH > water. We conclude that reactive counterion surfactants, especially with alpha-nucleophiles, hold great potential in terms of remediating soils contaminated by toxic organophosphorus esters.

A glucose-targeted mixed micellar formulation outperforms Genexol in breast cancer cells.

PubMed

Moretton, Marcela A; Bernabeu, Ezequiel; Grotz, Estefanía; Gonzalez, Lorena; Zubillaga, Marcela; Chiappetta, Diego A

2017-05-01

Breast cancer represents the top cancer among women, accounting 521.000 deaths per year. Development of targeted nanomedicines to breast cancer tissues represents a milestone to reduce chemotherapy side effects. Taking advantage of the over-expression of glucose (Glu) membrane transporters in breast cancer cells, we aim to expand the potential of a paclitaxel (PTX)-loaded mixed micellar formulation based on polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus®) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) by its surface decoration with Glu moieties. The glycopolymer (Soluplus(Glu)) was obtained by microwave-assisted ring opening reaction of δ-gluconolactone initiated by Soluplus®. The glycosylation was confirmed by 1 H NMR and by agglutination assays employing Concanavalin A. The hydrodynamic diameter of Soluplus(Glu) micelles was characterized by dynamic light scattering (100.3±3.8nm) as well as the critical micellar concentration value (0.0151% w/v). Then, a mixed micelle formulation employing Soluplus®, Soluplus(Glu) and TPGS (3:1:1wt ratio) loaded with PTX (4mg/mL) was developed as a multifunctional nanocarrier. Its in vitro anticancer performance in MCF-7 (1.6-fold) and MDA-MB-231 (14.1-fold) was significantly enhanced (p<0.05) versus the unique commercially available micellar-based PTX-nanoformulation (Genexol®). Furthermore, the in vitro PTX cellular uptake assays revealed that the drug intracellular/cell content was significantly (p<0.05) higher for the Glu-containing mixed micelles versus Genexol® after 6h of incubation with MCF-7 (30.5-fold) and MDA-MB-231 (5-fold). Overall, results confirmed the potential of our Glu-decorated mixed colloidal formulation as an intelligent nanocarrier for PTX-targeted breast cancer chemotherapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Thermo-sensitive liposomes loaded with doxorubicin and lysine modified single-walled carbon nanotubes as tumor-targeting drug delivery system.

PubMed

Zhu, Xiali; Xie, Yingxia; Zhang, Yingjie; Huang, Heqing; Huang, Shengnan; Hou, Lin; Zhang, Huijuan; Li, Zhi; Shi, Jinjin; Zhang, Zhenzhong

2014-11-01

This report focuses on the thermo-sensitive liposomes loaded with doxorubicin and lysine-modified single-walled carbon nanotube drug delivery system, which was designed to enhance the anti-tumor effect and reduce the side effects of doxorubicin. Doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes was prepared by reverse-phase evaporation method, the mean particle size was 232.0 ± 5.6 nm, and drug entrapment efficiency was 86.5 ± 3.7%. The drug release test showed that doxorubicin released more quickly at 42℃ than at 37℃. Compared with free doxorubicin, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes could efficiently cross the cell membranes and afford higher anti-tumor efficacy on the human hepatic carcinoma cell line (SMMC-7721) cells in vitro. For in vivo experiments, the relative tumor volumes of the sarcomaia 180-bearing mice in thermo-sensitive liposomes group and doxorubicin group were significantly smaller than those of N.S. group. Meanwhile, the combination of near-infrared laser irradiation at 808 nm significantly enhanced the tumor growth inhibition both on SMMC-7721 cells and the sarcomaia 180-bearing mice. The quality of life such as body weight, mental state, food and water intake of sarcomaia 180 tumor-bearing mice treated with doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes were much higher than those treated with doxorubicin. In conclusion, doxorubicin-lysine/single-walled carbon nanotube-thermo-sensitive liposomes combined with near-infrared laser irradiation at 808 nm may potentially provide viable clinical strategies for targeting delivery of anti-cancer drugs. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Effects of silymarin and silymarin-doxorubicin applications on telomerase activity of human hepatocellular carcinoma cell line HepG2.

PubMed

Yurtcu, Erkan; Darcansoy Iseri, Ozlem; Iffet Sahin, Feride

2015-01-01

Hepatocellular carcinoma (HCC) is resistant to conventional chemotherapeutics such as doxorubicin. Milk thistle extract, or its active constituent silymarin has been used by cancer patients as an alternative and complementary agent. Telomerase activation is one of the initial events of HCC. In this study, we applied doxorubicin and silymarin for 72 hrs in order to test individual and combined effect of the agents on telomerase activity. The effects of doxorubicin, silymarin, and their combination on the proliferation of HepG2 cell line were tested by MTT assay, and Checkerboard micro plate method was applied to define the nature of doxorubicin and silymarin interactions on the cells. Lipid peroxidations were assessed by thiobarbituric acid reactive substance (TBARS) level. Telomerase activity was determined according to the telomeric repeat amplification protocol (TRAP). Untreated cells were used as control group. Doxorubicin-silymarin combination had indifferent antiproliferative effects on HepG2 cells. Telomerase activity of the cells incubated with IC50 of doxorubicin and silymarin decreased to 72% (p<0.05). IC50 combinations of doxorubicin and silymarin caused 70% (p<0.05) reduction. All treatments except for the 1/2IC50 of silymarin caused significant increase in lipid peroxidation levels when compared to controls. TBARS levels did not significantly increase when doxorubicin and silymarin were applied in combination, which is in concordance with the indifferent drug interaction. IC50 of both doxorubicin and silymarin alone and in combination inhibited telomerase activity. Mechanism of inhibition may be elucidated by further molecular studies.

Experimental Study of Magnetic Multi-Walled Carbon Nanotube-Doxorubicin Conjugate in a Lymph Node Metastatic Model of Breast Cancer.

PubMed

Ji, Jian; Liu, Minfeng; Meng, Yue; Liu, Runqi; Yan, Yan; Dong, Jianyu; Guo, Zhaoze; Ye, Changsheng

2016-07-07

BACKGROUND The lymphatic system plays a significant role in the defense of a subject against breast cancer and is one of the major pathways for the metastasis of breast cancer. To improve the prognosis, many means, including surgery, radiotherapy, and chemotherapy, have been used. However, the combination of all these modalities has limited efficacy. Lymph nodes, therefore, have become an exceptionally potential target organ in cancer chemotherapy. MATERIAL AND METHODS A lymph node metastatic model of breast cancer was established in BALB/c mice. Magnetic multi-walled carbon nanotube carrier with good adsorption and lymph node-targeting capacity was prepared and conjugated with doxorubicin to make the magnetic multi-walled carbon nanotube-doxorubicin suspension. Dispersions of doxorubicin, magnetic multi-walled carbon nanotube-doxorubicin, and magnetic multi-walled carbon nanotube were injected into lymph node metastatic mice to compare their inhibitory effects on tumor cells in vivo. Inhibition of these dispersions on EMT-6 breast cancer cells was detected via MTT assay in vitro. RESULTS Although no significant difference was found between the effects of doxorubicin and magnetic multi-walled carbon nanotube-doxorubicin with the same concentration of doxorubicin on EMT-6 breast cancer cells in vitro, in terms of sizes of metastatic lymph nodes and xenograft tumors, apoptosis in metastatic lymph nodes, and adverse reactions, the magnetic multi-walled carbon nanotube-doxorubicin group differed significantly from the other groups. CONCLUSIONS The magnetic multi-walled carbon nanotube-doxorubicin clearly played an inhibitory role in lymph node metastases to EMT-6 breast cancer cells.

Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient.

PubMed

Fritze, Andreas; Hens, Felicitas; Kimpfler, Andrea; Schubert, Rolf; Peschka-Süss, Regine

2006-10-01

This study examines a new method for the remote loading of doxorubicin into liposomes. It was shown that doxorubicin can be loaded to a level of up to 98% into large unilamellar vesicles composed of egg phosphatidylcholine/cholesterol (7/3 mol/mol) with a transmembrane phosphate gradient. The different encapsulation efficiencies which were achieved with ammonium salts (citrate 100%, phosphate 98%, sulfate 95%, acetate 77%) were significantly higher as compared to the loading via sodium salts (citrate 54%, phosphate 52%, sulfate 44%, acetate 16%). Various factors, including pH-value, buffer capacity, solubility of doxorubicin in different salt solutions and base counter-flow, which likely has an influence on drug accumulation in the intraliposomal interior are taken into account. In contrast to other methods, the newly developed remote loading method exhibits a pH-dependent drug release property which may be effective in tumor tissues. At physiological pH-value doxorubicin is retained in the liposomes, whereas drug release is achieved by lowering the pH to 5.5 (approximately 25% release at 25 degrees C or 30% at 37 degrees C within two h). The DXR release of liposomes which were loaded via a sulfate gradient showed a maximum of 3% at pH 5.5.

Design, synthesis and molecular modeling of new 4-phenylcoumarin derivatives as tubulin polymerization inhibitors targeting MCF-7 breast cancer cells.

PubMed

Batran, Rasha Z; Kassem, Asmaa F; Abbas, Eman M H; Elseginy, Samia A; Mounier, Marwa M

2018-07-23

A new set of 4-phenylcoumarin derivatives was designed and synthesized aiming to introduce new tubulin polymerization inhibitors as anti-breast cancer candidates. All the target compounds were evaluated for their cytotoxic effects against MCF-7 cell line, where compounds 2f, 3a, 3b, 3f, 7a and 7b, showed higher cytotoxic effect (IC 50  = 4.3-21.2 μg/mL) than the reference drug doxorubicin (IC 50  = 26.1 μg/mL), additionally, compounds 1 and 6b exhibited the same potency as doxorubicin (IC 50  = 25.2 and 28.0 μg/mL, respectively). The thiazolidinone derivatives 3a, 3b and 3f with potent and selective anticancer effects towards MCF-7 cells (IC 50  = 11.1, 16.7 and 21.2 μg/mL) were further assessed for tubulin polymerization inhibition effects which showed that the three compounds were potent tubulin polymerization suppressors with IC 50 values of 9.37, 2.89 and 6.13 μM, respectively, compared to the reference drug colchicine (IC 50  = 6.93 μM). The mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cells were determined for compound 3a due to its potent and selective cytotoxic effects in addition to its promising tubulin polymerization inhibition potency. The results revealed that compound 3a induced cell cycle cessation at G2/M phase and accumulation of cells in pre-G1 phase and prevented its mitotic cycle, in addition to its activation of caspase-7 mediating apoptosis of MCF-7 cells. Molecular modeling studies for compounds 3a, 3b and 3f were carried out on tubulin crystallography, the results indicated that the compounds showed binding mode similar to the co-crystalized ligand; colchicine. Moreover, pharmacophore constructed models and docking studies revealed that thiazolidinone, acetamide and coumarin moieties are crucial for the activity. Molecular dynamics (MD) studies were carried out for the three compounds over 100 ps. MD results of compound 3a showed that it reached the stable state

Combining doxorubicin-nanobubbles and shockwaves for anaplastic thyroid cancer treatment: preclinical study in a xenograft mouse model.

PubMed

Marano, Francesca; Frairia, Roberto; Rinella, Letizia; Argenziano, Monica; Bussolati, Benedetta; Grange, Cristina; Mastrocola, Raffaella; Castellano, Isabella; Berta, Laura; Cavalli, Roberta; Catalano, Maria Graziella

2017-06-01

Anaplastic thyroid cancer is one of the most lethal diseases, and a curative therapy does not exist. Doxorubicin, the only drug approved for anaplastic thyroid cancer treatment, has a very low response rate and causes numerous side effects among which cardiotoxicity is the most prominent. Thus, doxorubicin delivery to the tumor site could be an import goal aimed to improve the drug efficacy and to reduce its systemic side effects. We recently reported that, in human anaplastic thyroid cancer cell lines, combining doxorubicin-loaded nanobubbles with extracorporeal shock waves, acoustic waves used in lithotripsy and orthopedics without side effects, increased the intracellular drug content and in vitro cytotoxicity. In the present study, we tested the efficacy of this treatment on a human anaplastic thyroid cancer xenograft mouse model. After 21 days, the combined treatment determined the greatest drug accumulation in tumors with consequent reduction of tumor volume and weight, and an extension of the tumor doubling time. Mechanistically, the treatment induced tumor apoptosis and decreased cell proliferation. Finally, although doxorubicin caused the increase of fibrosis markers and oxidative stress in animal hearts, loading doxorubicin into nanobubbles avoided these effects preventing heart damage. The improvement of doxorubicin anti-tumor effects together with the prevention of heart damage suggests that the combination of doxorubicin-loaded nanobubbles with extracorporeal shock waves might be a promising drug delivery system for anaplastic thyroid cancer treatment. © 2017 Society for Endocrinology.

Albumin Binding Domain Fusing R/K-X-X-R/K Sequence for Enhancing Tumor Delivery of Doxorubicin.

PubMed

Liu, Liping; Zhang, Chun; Li, Zenglan; Wang, Chunyue; Bi, Jingxiu; Yin, Shuang; Wang, Qi; Yu, Rong; Liu, Yongdong; Su, Zhiguo

2017-11-06

For the purpose of improving the tumor delivery of doxorubicin (DOX), a kind of peptide-DOXO conjugate was designed and prepared, in which the peptide composed of an albumin-binding domain (ABD) and a tumor-specific internalizing sequence (RGDK or RPARPAR) was conjugated to a (6-maleimidocaproyl) hydrazone derivative of doxorubicin (DOXO-EMCH). The doxorubicin uptake by lung cancer cell line of A549 evidenced that the conjugates are capable of being internalized through a tumor-specific sequence mediated manner, and the intracellular imaging of distribution in A549 cell demonstrated that the conjugated doxorubicin can be delivered to the cell nucleus. The A549 cell cytotoxicity of peptide-DOXO conjugates was presented with IC 50 values and shown in the range of about 9-11 μM. Pharmacokinetics study revealed that both conjugates exhibited nearly 5.5 times longer half-time than DOX, and about 4 times than DOXO-EMCH. The in vivo growth inhibitions of the two peptide-DOXO conjugates on BALB/c nude mice bearing A549 tumor (47.78% for ABD-RGDK-DOXO and 47.09% for ABD-RPARPAR-DOXO) were much stronger than that of doxorubicin and DOXO-EMCH (24.28% and 25.67% respectively) at a doxorubicin equivalent dose. Besides, the in vivo fluorescence imaging study confirmed that the peptide markedly increased the payload accumulation in tumor tissues and indicated that albumin binding domain fusing tumor-specific sequence effectively enhanced the tumor delivery of doxorubicin and thus improved its therapeutic potency.

The use of micellar solutions for novel separation techniques

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

Roberts, Bruce Lynn

1993-01-01

Surfactant based separation techniques based on the solubilization of organic compounds into the nonpolar interior of a micelle or electrostatic attraction of ionized metals and metal complexes to the charged surface of a micelle were studied in this work. Micellar solutions were used to recover two model volatile organic compounds emitted by the printing and painting industries (toluene and amyl acetate) and to investigate the effect of the most important variables in the surfactant enhanced carbon regeneration (SECR) process. SECR for liquid phase applications was also investigated in which the equilibrium adsorption of cetyl pyridinium chloride (CPC) and sodium dodecylmore » sulfate (SDS) on activated carbon were measured. Micellar-enhanced ultrafiltration (MEUF) was investigated using spiral wound membranes for the simultaneous removal of organic compounds, metals and metal complexes dissolved in water, with emphasis on pollution control applications. Investigations of MEUF to remove 99+ per cent of trichloroethylene (TCE) from contaminated groundwater using criteria such as: membrane flux, solubilization equilibrium constant, surfactant molecular weight, and Krafft temperature led to the selection of an anionic disulfonate with a molecular weight of 642 (DOWFAX 8390). These data and results from supporting experiments were used to design a system which could clean-up water in a 100,000 gallon/day operation. A four stage process was found to be an effective design and estimated cost for such an operation were found to be in the range of the cost of mature competitive technologies.« less

Unsteady sedimentation of a sphere in wormlike micellar fluids

NASA Astrophysics Data System (ADS)

Zhang, Yiran; Muller, Susan J.

2018-04-01

The unsteady sedimentation of a sphere in wormlike micellar fluids is studied experimentally through shear and extensional rheometry, sphere trajectory tracking, and particle image velocimetry. Unsteady sphere sedimentation characterized by fluctuations in the sphere settling velocity was observed for a range of sphere size and density in two non-shear-banding wormlike micellar solutions, a cetylpyridinium chloride (CpCl)-sodium salicylate (NaSal) solution and a cetyltrimethylammonium p-toluenesulfonate (CTAT)-NaCl solution. The onset of the transition from steady to unsteady sphere motion is characterized by an extensional Deborah number, D eext , defined locally in the negative wake of the falling sphere. This instability criterion is in agreement with previous findings by Mohammadigoushki and Muller [J. Rheol. 60, 587 (2016), 10.1122/1.4948800] in the wormlike micelle system of cetyltrimethylammonium bromide (CTAB) and NaSal, and appears to be universally valid independent of micelle chemistry or solution rheology (e.g., shear banding or not). Moreover, the frequency at which the sphere velocity fluctuates is found to be linearly correlated with an average shear Deborah number D es , which is a measure of the overall flow strength. This suggests that a constant critical strain is accumulated before the flow instability takes place in each velocity oscillation. The velocity fluctuations are found to become increasingly disordered with increasing elastic Mach number, M ae , indicating that the interactions between the flow instability and elastic wave propagation result in more chaotic velocity fluctuations.

Fluorescence resonance energy transfer between green fluorescent protein and doxorubicin enabled by DNA nanotechnology.

PubMed

Heger, Zbynek; Kominkova, Marketa; Cernei, Natalia; Krejcova, Ludmila; Kopel, Pavel; Zitka, Ondrej; Adam, Vojtech; Kizek, Rene

2014-12-01

DNA nanotechnology is a rapidly growing research area, where DNA may be used for wide range of applications such as construction of nanodevices serving for large scale of diverse purposes. Likewise a panel of various purified fluorescent proteins is investigated for their ability to emit their typical fluorescence spectra under influence of particular excitation. Hence these proteins may form ideal donor molecules for assembly of fluorescence resonance emission transfer (FRET) constructions. To extend the application possibilities of fluorescent proteins, while using DNA nanotechnology, we developed nanoconstruction comprising green fluorescent protein (GFP) bound onto surface of surface active nanomaghemite and functionalized with gold nanoparticles. We took advantage of natural affinity between gold and thiol moieties, which were modified to bind DNA fragment. Finally we enclosed doxorubicin into fullerene cages. Doxorubicin intercalated in DNA fragment bound on the particles and thus we were able to connect these parts together. Because GFP behaved as a donor and doxorubicin as an acceptor using excitation wavelength for GFP (395 nm) in emission wavelength of doxorubicin (590 nm) FRET was observed. This nanoconstruction may serve as a double-labeled transporter of doxorubicin guided by force of external magnetic force owing to the presence of nanomaghemite. Further nanomaghemite offers the possibility of using this technology for thermotherapy. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Treatment of extravasation of both doxorubicin and vincristine administration in a Y-site infusion.

PubMed

Comas, D; Mateu, J

1996-03-01

To describe a patient treated with vincristine, doxorubicin, and dexamethasone who experienced extravasation of both doxorubicin and vincristine during a Y-site infusion. A 74-year-old white woman was diagnosed with multiple myeloma IgA kappa in stage IIA. One year after a complete remission she relapsed. Her treatment included daily doxorubicin 16 mg in 500 mL of dextrose 5% and vincristine 0.4 mg in 500 mL of dextrose 5% administered in a Y-site continuous infusion into a peripheral vein of her left forearm. Extravasation occurred during administration of these drugs. Immediately, chondroitinsulfatase, a mucopolysaccharidase similar to hyaluronidase, was administered subcutaneously around the extravasation area and repeated 24 hours later. Furthermore, dimethyl sulfoxide 90% v/v was applied topically on the area four times daily for 2 weeks. All inflammatory signs resolved and no necrosis developed. Ths is the first report of an extravasation of two cytotoxic drugs. Doxorubicin and vincristine have different antidotes and opposite physical treatments for their extravasation. The antidotes dimethyl sulfoxide and chondroitinsulfatase have different mechanisms of action, but both cause uptake of the cytotoxic agent from the tissue and are likely to be administered together. No warming or cooling was performed. Topical dimethyl sulfoxide four times daily for 14 days plus subcutaneous chondroitinsulfatase in one or two applications effectively treated an extravasation of both doxorubicin and vincristine in our patient.

A novel individual-cell-based mathematical model based on multicellular tumour spheroids for evaluating doxorubicin-related delivery in avascular regions.

PubMed

Liu, Jiali; Yan, Fangrong; Chen, Hongzhu; Wang, Wenjie; Liu, Wenyue; Hao, Kun; Wang, Guangji; Zhou, Fang; Zhang, Jingwei

2017-09-01

Effective drug delivery in the avascular regions of tumours, which is crucial for the promising antitumour activity of doxorubicin-related therapy, is governed by two inseparable processes: intercellular diffusion and intracellular retention. To accurately evaluate doxorubicin-related delivery in the avascular regions, these two processes should be assessed together. Here we describe a new approach to such an assessment. An individual-cell-based mathematical model based on multicellular tumour spheroids was developed that describes the different intercellular diffusion and intracellular retention kinetics of doxorubicin in each cell layer. The different effects of a P-glycoprotein inhibitor (LY335979) and a hypoxia inhibitor (YC-1) were quantitatively evaluated and compared, in vitro (tumour spheroids) and in vivo (HepG2 tumours in mice). This approach was further tested by evaluating in these models, an experimental doxorubicin derivative, INNO 206, which is in Phase II clinical trials. Inhomogeneous, hypoxia-induced, P-glycoprotein expression compromised active transport of doxorubicin in the central area, that is, far from the vasculature. LY335979 inhibited efflux due to P-glycoprotein but limited levels of doxorubicin outside the inner cells, whereas YC-1 co-administration specifically increased doxorubicin accumulation in the inner cells without affecting the extracellular levels. INNO 206 exhibited a more effective distribution profile than doxorubicin. The individual-cell-based mathematical model accurately evaluated and predicted doxorubicin-related delivery and regulation in the avascular regions of tumours. The described framework provides a mechanistic basis for the proper development of doxorubicin-related drug co-administration profiles and nanoparticle development and could avoid unnecessary clinical trials. © 2017 The British Pharmacological Society.

A phase I study of Triapine in combination with doxorubicin in patients with advanced solid tumors.

PubMed

Schelman, William R; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M; Ivy, Percy; Wilding, George; Traynor, Anne M

2009-05-01

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine administered in combination with doxorubicin. Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m(2) and Triapine 25 mg/m(2). PK analysis was performed at various time-points before and after treatment. Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m(2), Triapine 45 mg/m(2)), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m(2)) with Triapine 45 mg/m(2). The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine were reduced to 45 and 25 mg/m(2), respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Pretreated patients with advanced malignancies can tolerate the combination of Triapine and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m(2) on day 1 and Triapine 25 mg/m(2) on days 1-4 of a 21-day cycle.

Organisation and shape of micellar solutions of block copolymers

NASA Astrophysics Data System (ADS)

Gaspard, J. P.; Creutz, S.; Bouchat, Ph.; Jérôme, R.; Cohen Stuart, M.

1997-02-01

Diblock copolymers of polymethacrylic acid sodium salt, forming the hair, and styrene derivatives have been studied in aqueous solutions by SANS and SAXS. The influence of both the chemical nature and the length of the hydrophobic bloxk on the size and shape of micelles have been investigated. The micellar core size is in agreement with the theoretical evaluation for copolymers with a short hydrophobic sequence. In contrast, in case of larger hydrophobic blocks, the measured size is incompatible with a star-like model. Various hypotheses are presented for the latter.

Formononetin sensitizes glioma cells to doxorubicin through preventing EMT via inhibition of histone deacetylase 5.

PubMed

Liu, Quan; Sun, Yan; Zheng, Jie-Min; Yan, Xian-Lei; Chen, Hong-Mou; Chen, Jia-Kang; Huang, He-Qing

2015-01-01

Chemoresistance is a major obstacle to successful chemotherapy for glioma. Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus and possesses antitumorigenic properties. In the present study, we investigated the anti-proliferative effects of formononetin on human glioma cells, and further elucidated the molecular mechanism underlying the anti-tumor property. We found that formononetin enhanced doxorubicin cytotoxicity in glioma cells. Combined treatment with formononetin reversed the doxorubicin-induced epithelial-mesenchymal transition (EMT) in tumor cells. Moreover, we found that formononetin treatment significantly decreased the expression of HDAC5. Overexpression of HDAC5 diminished the suppressive effects of formononetin on glioma cell viability. Furthermore, knockdown of HDAC5 by siRNA inhibited the doxorubicin-induced EMT in glioma cells. Taken together, these results demonstrated that formononetin-combined therapy may enhance the therapeutic efficacy of doxorubicin in glioma cells by preventing EMT through inhibition of HDAC5.

Formononetin sensitizes glioma cells to doxorubicin through preventing EMT via inhibition of histone deacetylase 5

PubMed Central

Liu, Quan; Sun, Yan; Zheng, Jie-Min; Yan, Xian-Lei; Chen, Hong-Mou; Chen, Jia-Kang; Huang, He-Qing

2015-01-01

Chemoresistance is a major obstacle to successful chemotherapy for glioma. Formononetin is a novel herbal isoflavonoid isolated from Astragalus membranaceus and possesses antitumorigenic properties. In the present study, we investigated the anti-proliferative effects of formononetin on human glioma cells, and further elucidated the molecular mechanism underlying the anti-tumor property. We found that formononetin enhanced doxorubicin cytotoxicity in glioma cells. Combined treatment with formononetin reversed the doxorubicin-induced epithelial-mesenchymal transition (EMT) in tumor cells. Moreover, we found that formononetin treatment significantly decreased the expression of HDAC5. Overexpression of HDAC5 diminished the suppressive effects of formononetin on glioma cell viability. Furthermore, knockdown of HDAC5 by siRNA inhibited the doxorubicin-induced EMT in glioma cells. Taken together, these results demonstrated that formononetin-combined therapy may enhance the therapeutic efficacy of doxorubicin in glioma cells by preventing EMT through inhibition of HDAC5. PMID:26261519

Self-organization of polymerizable bolaamphiphiles bearing diacetylene mesogenic group.

PubMed

Yin, Shouchun; Song, Bo; Liu, Guanqing; Wang, Zhiqiang; Zhang, Xi

2007-05-22

We report herein the synthesis of a series of polymerizable bolaamphiphiles containing a diacetylene group and mesogenic unit and their self-organization behaviors in bulk and at interface. The polymerizable bolaamphiphiles are noted as DPDA-n, where n refers to the spacer length of alkyl chain. DPDA-10 with suitable spacer length can self-organize into stable cylindrical micellar nanostructures, and these nanostructures have preferred orientation regionally when adsorbed at the mica/water interface. It is confirmed that the micellar nanostructure of DPDA-10 can be polymerized both in the bulk solution and in the film by UV irradiation. The emission property of DPDA-10 after UV irradiation has been significantly enhanced in comparison to that before polymerization, which may be due to the extension of the conjugated system arising from the transformation of the diacetylene group into polydiacetylene upon polymerization. In addition, the self-organization of DPDA-n is dependent on the spacer length. DPDA-7 with a short spacer length forms an irregular flat sheet structure with many defects; DPDA-15 with a long spacer length forms rodlike micellar structures. Thus, this work may provide a new approach for designing and fabricating organic functional nanostructured materials.

Quantitation of antihistamines in pharmaceutical preparations by liquid chromatography with a micellar mobile phase of sodium dodecyl sulfate and pentanol.

PubMed

Gil-Agustí, M; Monferrer-Pons, L; Esteve-Romero, J; García-Alvarez-Coque, M C

2001-01-01

A reversed-phase liquid chromatographic procedure with a micellar mobile phase of sodium dodecyl sulfate (SDS), containing a small amount of pentanol, was developed for the control of 7 antihistamines of diverse action in pharmaceutical preparations (tablets, capsules, powders, solutions, and syrups): azatadine, carbinoxamine, cyclizine, cyproheptadine, diphenhydramine, doxylamine, and tripelennamine. The retention times of the drugs were <9 min with a mobile phase of 0.15M SDS-6% (v/v) pentanol. The recoveries with respect to the declared compositions were in the range of 93-110%, and the intra- and interday repeatabilities and interday reproducibility were <1.2%. The results were similar to those obtained with a conventional 60 + 40 (v/v) methanol-water mixture, with the advantage of reduced toxicity, flammability, environmental impact, and cost of the micellar-pentanol solutions. The lower risk of evaporation of the organic solvent dissolved in the micellar solutions also increased the stability of the mobile phase.

SOLUBILIZATION OF DODECANE, TETRACHLOROETHYLENE, AND 1,2-DICHLOROBENZENE IN MICELLAR SOLUTIONS OF ETHOXYLATED NONIONIC SURFACTANTS

EPA Science Inventory

Although surfactants have received considerable attention as a potential means for enhancing the recovery of organic compounds from the subsurface, only limited information is available regarding the micellar solubilization of common groundwater contaminants by nonionic surfactan...

Nuclear Localizing Peptide-Conjugated, Redox-Sensitive Polymersomes for Delivering Curcumin and Doxorubicin to Pancreatic Cancer Microtumors.

PubMed

Anajafi, Tayebeh; Yu, Junru; Sedigh, Abbas; Haldar, Manas K; Muhonen, Wallace W; Oberlander, Seth; Wasness, Heather; Froberg, Jamie; Molla, Md Shahjahan; Katti, Kalpana S; Choi, Yongki; Shabb, John B; Srivastava, D K; Mallik, Sanku

2017-06-05

Improving the therapeutic index of anticancer agents is an enormous challenge. Targeting decreases the side effects of the therapeutic agents by delivering the drugs to the intended destination. Nanocarriers containing the nuclear localizing peptide sequences (NLS) translocate to the cell nuclei. However, the nuclear localization peptides are nonselective and cannot distinguish the malignant cells from the healthy counterparts. In this study, we designed a "masked" NLS peptide which is activated only in the presence of overexpressed matrix metalloproteinase-7 (MMP-7) enzyme in the pancreatic cancer microenvironment. This peptide is conjugated to the surface of redox responsive polymersomes to deliver doxorubicin and curcumin to the pancreatic cancer cell nucleus. We have tested the formulation in both two- and three-dimensional cultures of pancreatic cancer and normal cells. Our studies revealed that the drug-encapsulated polymeric vesicles are significantly more toxic toward the cancer cells (shrinking the spheroids up to 49%) compared to the normal cells (shrinking the spheroids up to 24%). This study can lead to the development of other organelle targeted drug delivery systems for various human malignancies.

Combinational effects of non n-Hexane Fractions of ant-plant (Myrmecodia tuberosa Jack) hypocotyl with doxorubicin against lymphocyte and cancer cells.

PubMed

Sasmito, Ediati; Mulyadi, Sri Mulyani; Hertiani, Triana; Fathdhieny, Annisa Qisthia; Witsqa, Ade Azka Surya; Laksono, Yogi Sotya

2017-09-01

Doxorubicin is widely used as a chemotherapeutic drug despite having many side effects. It may cause the dysfunction of macrophage, decreasing proliferation of lymphocytes, decreasing CD4+/CD8+ ratio and inducing hepatotoxicity. Doxorubicin inhibits the growth of Vero, HeLa, and T47D cell lines, and also induces a resistance of MCF-7 cells. Previous studies showed that ethanolic extract and ethyl acetate fraction of ant-plant (Myrmecodia tuberose Jack) hipocotyl could increase macrophage phagocytosis activity and lymphocyte proliferation in vitro. Therefore, antplant is a potential immune stimulator. Combinational treatment of non n-hexane fraction (NHF) of ant-plant with doxorubicin did not affect the doxorubicin's potency. Nevertheless, increased lymphocyte viability induced by doxorubicin in varied dosages of NHF that lethal to HeLa, MCF-7 and T47D cells. Moreover, on Vero cells, doxorubicin became less toxic when induced together with NHF. Thus, NHF of ant-plant is potential to be proposed as doxorubicin co-chemotherapeutic agent against cancer cells.

Anti-cancer effect of oncolytic adenovirus-armed shRNA targeting MYCN gene on doxorubicin-resistant neuroblastoma cells.

PubMed

Li, Yuan; Zhuo, Baobiao; Yin, Yiyu; Han, Tao; Li, Shixian; Li, Zhengwei; Wang, Jian

2017-09-09

Chemotherapy is one of the few effective choices for patients with neuroblastoma. However, the development of muti-drug resistance (MDR) to chemotherapy is a major obstacle to the effective treatment of advanced or recurrent neuroblastoma. The muti-drug resistance-associated protein (MRP), which encodes a transmembrane glycoprotein, is a key regulator of MDR. The expression of MRP is a close correlation with MYCN oncogene in neuroblastoma. We have recently shown ZD55-shMYCN (oncolytic virus armed with shRNA against MYCN) can down-regulate MYCN to inhibit tumor cells proliferation and induce apoptosis in neuroblastoma. Here we further report ZD55-shMYCN re-sensitized doxorubicin-resistant cells to doxorubicin (as shown by reduced proliferation, increased apoptosis, and inhibited cell migration), and reduced the in vivo growth rate of neuroblastoma xenografts by down-regulation of MRP expression. Sequential therapy with doxorubicin did not affect the replication of ZD55-shMYCN in doxorubicin-resistant neuroblastoma cells, but decreased the expression of Bcl-2, Bcl-X L , MMP-1. Thus, this synergistic effect of ZD55-shMYCN in combination with doxorubicin provides a novel therapy strategy for doxorubicin-resistant neuroblastoma, and is a promising approach for further clinical development. Copyright © 2017 Elsevier Inc. All rights reserved.

Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate) nanoparticles

PubMed Central

Melguizo, Consolación; Cabeza, Laura; Prados, Jose; Ortiz, Raúl; Caba, Octavio; Rama, Ana R; Delgado, Ángel V; Arias, José L

2015-01-01

Doxorubicin (Dox) is widely used for the combined chemotherapy of solid tumors. However, the use of these drug associations in lung cancer has low antitumor efficacy. To improve its efficacious delivery and activity in lung adenocarcinoma cells, we developed a biodegradable and noncytotoxic nanoplatform based on biodegradable poly(butylcyanoacrylate) (PBCA). The reproducible formulation method was based on an anionic polymerization process of the PBCA monomer, with the antitumor drug being entrapped within the nanoparticle (NP) matrix during its formation. Improved drug-entrapment efficiencies and sustained (biphasic) drug-release properties were made possible by taking advantage of the synthesis conditions (drug, monomer, and surfactant-agent concentrations). Dox-loaded NPs significantly enhanced cellular uptake of the drug in the A549 and LL/2 lung cancer cell lines, leading to a significant improvement of the drug’s antitumoral activity. In vivo studies demonstrated that Dox-loaded NPs clearly reduced tumor volumes and increased mouse-survival rates compared to the free drug. These results demonstrated that PBCA NPs may be used to optimize the antitumor activity of Dox, thus exhibiting a potential application in chemotherapy against lung adenocarcinoma. PMID:26715840

Doxorubicin-Loaded Nanobubbles Combined with Extracorporeal Shock Waves: Basis for a New Drug Delivery Tool in Anaplastic Thyroid Cancer.

PubMed

Marano, Francesca; Argenziano, Monica; Frairia, Roberto; Adamini, Aloe; Bosco, Ornella; Rinella, Letizia; Fortunati, Nicoletta; Cavalli, Roberta; Catalano, Maria Graziella

2016-05-01

No standard chemotherapy is available for anaplastic thyroid cancer (ATC). Drug-loaded nanobubbles (NBs) are a promising innovative anticancer drug formulation, and combining them with an externally applied trigger may further control drug release at the target region. Extracorporeal shock waves (ESWs) are acoustic waves widely used in urology and orthopedics, with no side effects. The aim of the present work was to combine ESWs and new doxorubicin-loaded glycol chitosan NBs in order to target doxorubicin and enhance its antitumor effect in ATC cell lines. CAL-62 and 8305C cells were treated with empty NBs, fluorescent NBs, free doxorubicin, and doxorubicin-loaded NBs in the presence or in the absence of ESWs. NB entrance was evaluated by fluorescence microscopy and flow cytofluorimetry. Cell viability was assessed by Trypan Blue exclusion and WST-1 proliferation assays. Doxorubicin intracellular content was measured by high-performance liquid chromatography. Treatment with empty NBs and ESWs, even in combination, was safe, as cell viability and growth were not affected. Loading NBs with doxorubicin and combining them with ESWs generated the highest cytotoxic effect, resulting in drug GI50 reduction of about 40%. Mechanistically, ESWs triggered intracellular drug release from NBs, resulting in the highest nuclear drug content. Combined treatment with doxorubicin-loaded NBs and ESWs is a promising drug delivery tool for ATC treatment with the possibility of using lower doxorubicin doses and thus limiting its systemic side effects.

Toxicity of Doxorubicin on Pig Liver After Chemoembolization with Doxorubicin-loaded Microspheres: A Pilot DNA-microarrays and Histology Study

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

Verret, Valentin, E-mail: valentin.verret@archimmed.com; Namur, Julien; Ghegediban, Saieda Homayra

The potential mechanisms accounting for the hepatotoxicity of doxorubicin-loaded microspheres in chemoembolization were examined by combining histology and DNA-microarray techniques.The left hepatic arteries of two pigs were embolized with 1 mL of doxorubicin-loaded (25 mg; (DoxMS)) or non-loaded (BlandMS) microspheres. The histopathological effects of the embolization were analyzed at 1 week. RNAs extracted from both the embolized and control liver areas were hybridized onto Agilent porcine microarrays. Genes showing significantly different expression (p < 0.01; fold-change > 2) between two groups were classified by biological process. At 1 week after embolization, DoxMS caused arterial and parenchymal necrosis in 51 andmore » 38 % of embolized vessels, respectively. By contrast, BlandMS did not cause any tissue damage. Up-regulated genes following embolization with DoxMS (vs. BlandMS, n = 353) were mainly involved in cell death, apoptosis, and metabolism of doxorubicin. Down-regulated genes (n = 120) were mainly related to hepatic functions, including enzymes of lipid and carbohydrate metabolisms. Up-regulated genes included genes related to cell proliferation (growth factors and transcription factors), tissue remodeling (MMPs and several collagen types), inflammatory reaction (interleukins and chemokines), and angiogenesis (angiogenic factors and HIF1a pathway), all of which play an important role in liver healing and regeneration. DoxMS caused lesions to the liver, provoked cell death, and disturbed liver metabolism. An inflammatory repair process with cell proliferation, tissue remodeling, and angiogenesis was rapidly initiated during the first week after chemoembolization. This pilot study provides a comprehensive method to compare different types of DoxMS in healthy animals or tumor models.« less

Combined doxorubicin and cyclophosphamide chemotherapy for nonresectable feline fibrosarcoma.

PubMed

Barber, L G; Sørenmo, K U; Cronin, K L; Shofer, F S

2000-01-01

A retrospective evaluation was performed on 12 cats with nonresectable, histopathologically confirmed fibrosarcomas that were treated with doxorubicin and cyclophosphamide chemotherapy. All of the tumors were located in sites potentially used for vaccination. Six cats had a greater than 50% decrease in gross tumor burden. However, the responses were not durable, with a median response duration of 125 days. All cats developed progressive disease. When animals that received other treatments after doxorubicin-based chemotherapy were eliminated from the analysis, median survival time was significantly longer for cats that responded to chemotherapy compared with the median survival time for nonresponders (242 and 83 days, respectively). These findings may serve as a basis for further evaluating the role of chemotherapy in the treatment of vaccine-associated sarcomas.

Chronic supplementation of creatine and vitamins C and E increases survival and improves biochemical parameters after Doxorubicin treatment in rats.

PubMed

Santos, Ronaldo V T; Batista, Miguel L; Caperuto, Erico C; Costa Rosa, Luis Fbp

2007-12-01

1. Doxorubicin is an anti-cancer drug with well-described effects against a wide range of tumours. However, doxorubicin also exhibits dose-dependent cytotoxicity. The purpose of the present study was to determine whether chronic supplementation of creatine or a mix of vitamins C and E could increase survival and improve plasma parameters 48 h after doxorubicin treatment. 2. Rats were divided into four groups: (i) saline (control); (ii) doxorubicin treated; (iii) a creatine (0.2 g/kg per day)-supplemented group; and (iv) a vitamin C (250 mg/kg per day) and E (400 IU/kg per day)-supplemented group. After 30 days supplementation of rats with either creatine or the vitamins, one dose of doxorubicin (15 mg/kg, i.p.) was administered. 3. There was no difference in weight loss among the groups until the 3rd day after doxorubicin treatment, but the creatine- and vitamin-supplemented groups lived longer compared with the doxorubicin only treated group (6, 7 and 3 days, respectively). The doxorubicin-treated group lost 13.4% bodyweight over 3 days, whereas the creatine- and vitamin-supplemented groups lost approximately 35% 3 days after the administration of doxorubicin. Doxorubicin treatment resulted in an increase in alanine aminotransferase (ALT; P < 0.05), lactate dehydrogenase (LDH; P < 0.05), urea (P < 0.05) and creatinine (P < 0.05) compared with levels observed in the control group. Conversely, creatine supplementation promoted a partial return to control values for LDH (P < 0.05) and creatinine (P < 0.05), whereas the vitamin mix reversed the changes in ALT (P < 0.05), LDH (P < 0.05), urea (P < 0.05) and creatinine (P < 0.05). 4. In conclusion, the results of the present study indicate that the two supplementation protocols decreased the cytotoxic effects of doxorubicin and that a protective effect was more noticeable in animals supplemented with the mixture of vitamins C and E.

Effect of micellar collisions and polyvinylpyrrolidone confinement on the electrical conductivity percolation parameters of water/AOT/isooctane reverse micelles

NASA Astrophysics Data System (ADS)

Guettari, Moez; Aferni, Ahmed E. L.; Tajouri, Tahar

2017-12-01

The main aim of this paper is the analysis of micellar collisions and polymer confinement effects on the electrical conductivity percolative behavior of water/sodium bis(2-ethylhexyl) sulfosuccinate (AOT)/isooctane reverse micelles. Firstly, we have performed conductance measurements of the system for three AOT to isooctane volume ratio, φm = 0.1 , 0.15 and 0.2 to examine the influence of micellar collisions on the percolation parameters. All the measurements were carried out over the 298.15 K-333.15 K temperature range at a fixed water to AOT molar ratio, W0 = 45 . We have assessed that the rise of micellar collisions frequency enhances the conductance percolation. Secondly, the confinement effect of a water-soluble polymer, polyvinylpyrrolidone (PVP), on the reverse micelles conductance behavior was investigated. Temperature-induced percolation, Tp , have shown a dependence on the polymer concentration, CPVP . It was also observed that for various PVP concentrations, the activation energy of percolation decreases. Finally, the values of the critical exponents determined in the presence and absence of PVP prove that the polymer affects the dynamic of percolation.

Micellar hexagonal phases in lyotropic liquid crystals

NASA Astrophysics Data System (ADS)

Amaral, L. Q.; Gulik, A.; Itri, R.; Mariani, P.

1992-09-01

The hexagonal cell parameter a of the system sodium dodecyl lauryl sulfate and water as a function of volume concentration cv in phase Hα shows the functional behavior expected for micelles of finite length: a~c-1/3v. The interpretation of x-ray data based on finite micelles leads to an alternative description of the hexagonal phase Hα: spherocylindrical micelles of constant radius with length that may grow along the range of the Hα phase. Results are compared with recent statistical-mechanical calculations for the isotropic I-Hα transition. The absence of diffraction in the direction perpendicular to the hexagonal plane is ascribed to polydispersity of micellar length, which also is a necessary condition for the occurrence of direct I-Hα transitions.

Side-chain amino-acid-based pH-responsive self-assembled block copolymers for drug delivery and gene transfer.

PubMed

Kumar, Sonu; Acharya, Rituparna; Chatterji, Urmi; De, Priyadarsi

2013-12-10

Developing safe and effective nanocarriers for multitype of delivery system is advantageous for several kinds of successful biomedicinal therapy with the same carrier. In the present study, we have designed amino acid biomolecules derived hybrid block copolymers which can act as a promising vehicle for both drug delivery and gene transfer. Two representative natural chiral amino acid-containing (l-phenylalanine and l-alanine) vinyl monomers were polymerized via reversible addition-fragmentation chain transfer (RAFT) process in the presence of monomethoxy poly(ethylene glycol) based macro-chain transfer agents (mPEGn-CTA) for the synthesis of well-defined side-chain amino-acid-based amphiphilic block copolymers, monomethoxy poly(ethylene glycol)-b-poly(Boc-amino acid methacryloyloxyethyl ester) (mPEGn-b-P(Boc-AA-EMA)). The self-assembled micellar aggregation of these amphiphilic block copolymers were studied by fluorescence spectroscopy, atomic force microscopy (AFM) and scanning electron microscopy (SEM). Potential applications of these hybrid polymers as drug carrier have been demonstrated in vitro by encapsulation of nile red dye or doxorubicin drug into the core of the micellar nanoaggregates. Deprotection of side-chain Boc- groups in the amphiphilic block copolymers subsequently transformed them into double hydrophilic pH-responsive cationic block copolymers having primary amino groups in the side-chain terminal. The DNA binding ability of these cationic block copolymers were further investigated by using agarose gel retardation assay and AFM. The in vitro cytotoxicity assay demonstrated their biocompatible nature and these polymers can serve as "smart" materials for promising bioapplications.

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.

Bim directly antagonizes Bcl-xl in doxorubicin-induced prostate cancer cell apoptosis independently of p53.

PubMed

Yang, Min-Chi; Lin, Ru-Wei; Huang, Shih-Bo; Huang, Shin-Yuan; Chen, Wen-Jie; Wang, Shiaw; Hong, Yi-Ren; Wang, Chihuei

2016-01-01

Doxorubicin and other anthracycline compounds exert their anti-cancer effects by causing DNA damage and initiating cell cycle arrest in cancer cells, followed by apoptosis. DNA damage generally activates a p53-mediated pathway to initiate apoptosis by increasing the level of the BH3-only protein, Puma. However, p53-mediated apoptosis in response to DNA damage has not yet been validated in prostate cancers. In the current study, we used LNCaP and PC3 prostate cancer cells, representing wild type p53 and a p53-null model, to determine if DNA damage activates p53-mediated apoptosis in prostate cancers. Our results revealed that PC3 cells were 4 to 8-fold less sensitive than LNCaP cells to doxorubicin-inuced apoptosis. We proved that the differential response of LNCaP and PC3 to doxorubicin was p53-independent by introducing wild-type or dominant negative p53 into PC3 or LNCaP cells, respectively. By comparing several apoptosis-related proteins in both cell lines, we found that Bcl-xl proteins were much more abundant in PC3 cells than in LNCaP cells. We further demonstrated that Bcl-xl protects LNCaP and PC3 cells from doxorubicin-induced apoptosis by using ABT-263, an inhibitor of Bcl-xl, as a single agent or in combination with doxorubicin to treat LNCaP or PC3 cells. Bcl-xl rather than p53, likely contributes to the differential response of LNCaP and PC3 to doxorubicin in apoptosis. Finally, co-immunoprecipitation and siRNA analysis revealed that a BH3-only protein, Bim, is involved in doxorubicin-induced apoptosis by directly counteracting Bcl-xl.

Antitumor activity of monomethoxy poly(ethylene glycol)-poly (ε-caprolactone) micelle-encapsulated doxorubicin against mouse melanoma.

PubMed

Zheng, Lan; Gou, Maling; Zhou, Shengtao; Yi, Tao; Zhong, Qian; Li, Zhengyu; He, Xiang; Chen, Xiancheng; Zhou, Lina; Wei, Yuquan; Qian, Zhiyong; Zhao, Xia

2011-06-01

Doxorubicin (Dox) is one of the most commonly used and highly effective antineoplastic agents, but the clinical application of this broad spectrum drug is largely hampered by its poor stability and serious toxicity to normal tissues. Hence, it is essential to improve the therapeutic effect and decrease the systematic toxicity for the administration of doxorubicin. In our study, doxorubicin was incorporated into monomethoxy poly(ethylene glycol)-poly(ε-caprolactone) (MPEG-PCL) micelle by a self-assembly method. The cytotoxicity and cellular uptake efficiency of Dox-loaded MPEG-PCL (Dox/MPEG-PCL) micelle against B16-F10 murine melanoma cells was examined by the methylthiazoltetrazolium (MTT) test and flow cytometry. The antitumor activity of Dox/MPEG-PCL was evaluated in C57BL/6 mice injected subcutaneously with B16-F10 cells. Toxicity was evaluated in tumor-free mice. Meanwhile, tumor proliferation, intratumoal angiogenesis and apoptotic cells were evaluated by PCNA, CD31 staining and TUNEL assay, respectively. Encapsulation of doxorubicin in MPEG-PCL micelle improved the cytotoxicity of doxorubicin and enhanced its cellular uptake on B16-F10 cell in vitro. Administration of Dox/MPEG-PCL micelle resulted in significant inhibition (75% maximum inhibition relative to controls) in the growth of B16-F10 tumor xenografts and prolonged the survival of the treated mice (P<0.05). These anti-tumor responses were associated with marked increase of tumor apoptosis and notable reduction of cell proliferation and intratumoral microvessel density (P<0.05). The system toxicity also decreased in the Dox/MPEG-PCL group compared with free doxorubicin group. Our data indicate that the encapsulation of doxorubicin in MPEG-PCL micelle improved the anti-tumor activity in vivo without conspicuous systemic toxic effects.

Bioadhesive chitosan-coated cyclodextrin-based superamolecular nanomicelles to enhance the oral bioavailability of doxorubicin

NASA Astrophysics Data System (ADS)

Liu, Yuhai; Zhai, Yinglei; Han, Xiaopeng; Liu, Xiaohong; Liu, Wanjun; Wu, Chunnuan; Li, Lin; Du, Yuqian; Lian, He; Wang, Yongjun; He, Zhonggui; Sun, Jin

2014-10-01

In order to improve the oral bioavailability of doxorubicin (Dox), a novel bioadhesive nanomicelle based on host-guest interaction was developed in this study. Hyaluronic acid-linked β-cyclodextrin (HA-CD) was synthesized. The primary nanomicelles were formed through the self-assemble of HA-CD and retinoic acid (RA) which was included as the hydrophobic core to anchor CD cavity by host-guest interaction. Chitosan (CS) was then coated on the surface of primary nanomicelles by ionic interaction with the negatively charged HA. The critical micellar concentration of HA-CD-RA was as low as 22.5 μg/mL. Dox was successfully encapsulated into the hydrophobic core of CS-coated HA-CD-RA nanomicelles (CS/HA-CD-RA-Dox), with encapsulation efficiency as high as 89.2 %. The CS/HA-CD-RA-Dox particle size was 234 nm and was stable over 30 days. In vitro Dox release showed that CS/HA-CD-RA nanomicelles were more sustained than HA-CD-RA nanomicelles, and Dox encapsulated into CS-coated nanomicelles was stable at low pH. The in situ single pass intestinal perfusion revealed that encapsulation of Dox into CS/HA-CD-RA nanomicelles could significantly improve the intestinal permeability of Dox. The mucoadhesion results indicated that the retention percentage of CS/HA-CD-RA nanomicelles was significantly higher than that of HA-CD-RA nanomicelles in gastrointestinal tract. In vivo pharmacokinetic study revealed that AUC(0-∞) of CS/HA-CD-RA nanomicelles was about fourfold higher than that of Dox solution. The present study suggested that CS/HA-CD-RA nanomicelles as biodegradable, biocompatible, and bioadhesive nanostructure can be a promising nanocarrier in improving the bioavailability of anticancer drugs to facilitate the oral chemotherapy.

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.

Differential thermodynamic signature of carbon nanomaterials using amphiphilic micellar probe

NASA Astrophysics Data System (ADS)

Bhattacharyya, Tamoghna; Dasgupta, Anjan Kr

2018-04-01

The thermodynamic signature of single-wall carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs) and reduced graphene oxide (rG-O) using amphiphilic micellar probe has been explored. The study reveals an intricate correlation between nano-surface topology and calorimetric profile of SWCNTs, MWCNTs and rG-O. The critical micelle concentration (CMC) is found to be sensitive to the topological diversity of nanomaterials. The study explores a thermodynamic approach to characterize the nano-surface topology of SWCNTs, MWCNTs and graphene surface.

Click polymerization for the synthesis of reduction-responsive polymeric prodrug

NASA Astrophysics Data System (ADS)

Zhang, Xiaojin; Wang, Hongquan; Dai, Yu

2018-05-01

Click polymerization is a powerful polymerization technique for the construction of new macromolecules with well-defined structures and multifaceted functionalities. Here, we synthesize reduction-responsive polymeric prodrug PEG- b-(PSS- g-MTX)- b-PEG containing disulfide bonds and pendant methotrexate (MTX) via two-step click polymerization followed by conjugating MTX to pendant hydroxyl. MTX content in polymeric prodrug is 13.5%. Polymeric prodrug is able to form polymeric micelles by self-assembly in aqueous solution. Polymeric micelles are spherical nanoparticles with tens of nanometers in size. Of note, polymeric micelles are reduction-responsive due to disulfide bonds in the backbone of PEG- b-(PSS- g-MTX)- b-PEG and could release pendant drugs in the presence of the reducing agents such as dl-dithiothreitol (DTT).

Microwave enhanced electroanalysis of formulations: processes in micellar media at glassy carbon and at platinum electrodes.

PubMed

Ghanem, Mohamed A; Compton, Richard G; Coles, Barry A; Canals, Antonio; Marken, Frank

2005-10-01

The direct electroanalysis of complex formulations containing alpha-tocopherol (vitamin E) is possible in micellar solution and employing microwave-enhanced voltammetry. In the presence of microwave radiation substantial heating and current enhancement effects have been observed at 330 microm diameter glassy carbon electrodes placed into a micellar aqueous solution and both hydrophilic and highly hydrophobic redox systems are detected. For the water soluble Fe(CN)(6)(3-/4-) redox system in micellar aqueous solutions of 0.1 M NaCl and 0.1 M sodium dodecylsulfate (SDS) at low to intermediate microwave power, thermal effects and convection effects are observed. At higher microwave power, thermal cavitation is induced and dominates the mass transport at the electrode surface. For the micelle-soluble redox systems tert-butylferrocene and 2,5-di-tert-butyl-1,4-benzoquinone, strong and concentration dependent current responses are observed only in the presence of microwave radiation. For the oxidation of micelle-soluble alpha-tocopherol current responses at glassy carbon electrodes are affected by adsorption and desorption processes whereas at platinum electrodes, analytical limiting currents are obtained over a wide range of alpha-tocopherol concentrations. However, for the determination of alpha-tocopherol in a commercial formulation interference from proteins is observed at platinum electrodes and direct measurements are possible only over a limited concentration range and at glassy carbon electrodes.

Thermodynamics of sodium dodecyl sulphate-salicylic acid based micellar systems and their potential use in fruits postharvest.

PubMed

Cid, A; Morales, J; Mejuto, J C; Briz-Cid, N; Rial-Otero, R; Simal-Gándara, J

2014-05-15

Micellar systems have excellent food applications due to their capability to solubilise a large range of hydrophilic and hydrophobic substances. In this work, the mixed micelle formation between the ionic surfactant sodium dodecyl sulphate (SDS) and the phenolic acid salicylic acid have been studied at several temperatures in aqueous solution. The critical micelle concentration and the micellization degree were determined by conductometric techniques and the experimental data used to calculate several useful thermodynamic parameters, like standard free energy, enthalpy and entropy of micelle formation. Salicylic acid helps the micellization of SDS, both by increasing the additive concentration at a constant temperature and by increasing temperature at a constant concentration of additive. The formation of micelles of SDS in the presence of salicylic acid was a thermodynamically spontaneous process, and is also entropically controlled. Salicylic acid plays the role of a stabilizer, and gives a pathway to control the three-dimensional water matrix structure. The driving force of the micellization process is provided by the hydrophobic interactions. The isostructural temperature was found to be 307.5 K for the mixed micellar system. This article explores the use of SDS-salicylic acid based micellar systems for their potential use in fruits postharvest. Copyright © 2013 Elsevier Ltd. All rights reserved.

Downregulation of transcription factor GATA4 sensitizes human hepatoblastoma cells to doxorubicin-induced apoptosis.

PubMed

Soini, Tea; Pihlajoki, Marjut; Kyrönlahti, Antti; Andersson, Leif C; Wilson, David B; Heikinheimo, Markku

2017-03-01

Hepatoblastoma, the most common type of pediatric liver cancer, is treated with a combination of surgery and chemotherapy. An essential drug in the treatment of hepatoblastoma is doxorubicin, which in high doses is cardiotoxic. This adverse effect is due to downregulation of cardiac expression of transcription factor GATA4, leading in turn to diminished levels of anti-apoptotic BCL2 (B-cell lymphoma 2) protein family members. GATA4 is also expressed in early fetal liver, but absent from normal postnatal hepatocytes. However, GATA4 is highly expressed in hepatoblastoma tissue. In this study, we assessed the role of GATA4 in doxorubicin-induced apoptosis of hepatoblastoma cells. Herein, we demonstrate that doxorubicin decreases GATA4 expression and alters the expression pattern of BCL2 family members, most profoundly that of BCL2 and BAK, in the HUH6 hepatoblastoma cell line. Silencing of GATA4 by siRNA prior to doxorubicin treatment sensitizes HUH6 cells to the apoptotic effect of this drug by further shifting the balance of BCL2 family members to the pro-apoptotic direction. Specifically, expression levels of anti-apoptotic BCL2 were decreased and pro-apoptotic BID were increased after GATA4 silencing. On the whole, our results indicate that since high endogenous levels of transcription factor GATA4 likely protect hepatoblastoma cells from doxorubicin-induced apoptosis, these cells can be rendered more sensitive to the drug by downregulation of GATA4.

Metformin augments doxorubicin cytotoxicity in mammary carcinoma through activation of adenosine monophosphate protein kinase pathway.

PubMed

El-Ashmawy, Nahla E; Khedr, Naglaa F; El-Bahrawy, Hoda A; Abo Mansour, Hend E

2017-05-01

Since the incidence of breast cancer increases dramatically all over the world, the search for effective treatment is an urgent need. Metformin has demonstrated anti-tumorigenic effect both in vivo and in vitro in different cancer types. This work was designed to examine on molecular level the mode of action of metformin in mice bearing solid Ehrlich carcinoma and to evaluate the use of metformin in conjunction with doxorubicin as a combined therapy against solid Ehrlich carcinoma. Ehrlich ascites carcinoma cells were inoculated in 60 female mice as a model of breast cancer. The mice were divided into four equal groups: Control tumor, metformin, doxorubicin, and co-treatment. Metformin (15 mg/kg) and doxorubicin (4 mg/kg) were given intraperitoneally (i.p.) for four cycles every 5 days starting on day 12 of inoculation. The anti-tumorigenic effect of metformin was mediated by enhancement of adenosine monophosphate protein kinase activity and elevation of P53 protein as well as the suppression of nuclear factor-kappa B, DNA contents, and cyclin D1 gene expression. Metformin and doxorubicin mono-treatments exhibited opposing action regarding cyclin D1 gene expression, phosphorylated adenosine monophosphate protein kinase, and nuclear factor-kappa B levels. Co-treatment markedly decreased tumor volume, increased survival rate, and improved other parameters compared to doxorubicin group. In parallel, the histopathological findings demonstrated enhanced apoptosis and absence of necrosis in tumor tissue of co-treatment group. Metformin proved chemotherapeutic effect which could be mediated by the activation of adenosine monophosphate protein kinase and related pathways. Combining metformin and doxorubicin, which exhibited different mechanisms of action, produced greater efficacy as anticancer therapeutic regimen.

Doxorubicin loaded magneto-niosomes for targeted drug delivery.

PubMed

Tavano, Lorena; Vivacqua, Marco; Carito, Valentina; Muzzalupo, Rita; Caroleo, Maria Cristina; Nicoletta, Fiore

2013-02-01

In chemotherapy the magnetic drug targeting to a specific organ or tissue is proposed on the assumption that magnetic fields are harmless to biological systems. In this light we have vehiculated doxorubicin as model drug by novel magneto-niosomes in order to evaluate the physico-chemical properties of the obtained formulations and the in vitro release profile. Tween 60 and Pluronic L64 have been used as surfactants and the formulation cytotoxicity has been performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide and trypan blue dye esclusion tests. Results show that niosome dimensions and doxorubicin entrapment efficiencies are influenced by bilayer composition. In addition, formulations are able to control the deliver and release of the drug active form in a retarded manner. No additional toxicity, due to the encapsulation of ferrofluid into niosomes core, has been detected. Copyright © 2012 Elsevier B.V. All rights reserved.

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.

Mechanistic Analysis of Cocrystal Dissolution as a Function of pH and Micellar Solubilization

PubMed Central

2016-01-01

The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick’s law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid–liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine–saccharin (CBZ-SAC) and carbamazepine–salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals. PMID:26877267

Mechanistic Analysis of Cocrystal Dissolution as a Function of pH and Micellar Solubilization.

PubMed

Cao, Fengjuan; Amidon, Gordon L; Rodriguez-Hornedo, Nair; Amidon, Gregory E

2016-03-07

The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid-liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals.

Interfacial instability of wormlike micellar solutions sheared in a Taylor-Couette cell

NASA Astrophysics Data System (ADS)

Mohammadigoushki, Hadi; Muller, Susan J.

2014-11-01

We report experiments on wormlike micellar solutions sheared in a custom-made Taylor-Couette (TC) cell. The computer controlled TC cell allows us to rotate both cylinders independently. Wormlike micellar solutions containing water, CTAB, and NaNo3 with different compositions are highly elastic and exhibit shear banding. We visualized the flow field in the θ-z as well as r-z planes, using multiple cameras. When subject to low shear rates, the flow is stable and azimuthal, but becomes unstable above a certain threshold shear rate. This shear rate coincides with the onset of shear banding. Visualizing the θ-z plane shows that this instability is characterized by stationary bands equally spaced in the z direction. Increasing the shear rate results to larger wave lengths. Above a critical shear rate, experiments reveal a chaotic behavior reminiscent of elastic turbulence. We also studied the effect of ramp speed on the onset of instability and report an acceleration below which the critical Weissenberg number for onset of instability is unaffected. Moreover, visualizations in the r-z direction reveals that the interface between the two bands undulates with shear bands evolving towards the outer cylinder regardless of which cylinder is rotating.

Stimuli-responsive supramolecular micellar assemblies of cetylpyridinium chloride with cucurbit[5/7]urils.

PubMed

Choudhury, Sharmistha Dutta; Barooah, Nilotpal; Aswal, Vinod Kumar; Pal, Haridas; Bhasikuttan, Achikanath C; Mohanty, Jyotirmayee

2014-05-21

This article demonstrates, for the first time, construction of novel cucurbituril (CB)-adorned supramolecular micellar assemblies of a cationic surfactant, cetylpyridinium chloride (CPC), through noncovalent host-guest interactions. The distinct cation receptor features and cavity dimensions of the CB5 and CB7 homologues assert that the macrocyclic hosts remain complexed with the CPC monomers and take part in the micelle formation, a unique observation in contrast to that of the classical host, β-cyclodextrin. The cooperative contributions of the CB macrocycles in the micelle formation have been documented by the photochemical, surface tension, conductivity, DOSY NMR, and SANS measurements. The contrasting downward and upward shifts in the cmc of the CPC surfactant, respectively, with CB5 and CB7 hosts provide a unique opportunity for the controlled tuning of the micellization region for CPC from 0.57 to 1.6 mM, by using a combination of the macrocyclic hosts. The article also establishes the reversible response of these soft supramolecular micellar structures to thermal-stimuli, which projects their utility for on-demand smart drug-delivery vehicles.

Comparative Study of Different Nano-Formulations of Curcumin for Reversal of Doxorubicin Resistance in K562R Cells.

PubMed

Dash, Tapan K; Konkimalla, V Badireenath

2017-02-01

Curcumin is very well established as a chemo-therapeutic, chemo-preventive and chemo-sensitizing agent in diverse disease conditions. As the isolated pure form has poor solubility and pharmacokinetic problems, therefore it is encapsulated in to several nano-formulations to improve its bioavailability. Here in the current study, we aim to compare different nano-formulations of curcumin for their chemo-sensitizing activity in doxorubicin (DOX) resistant K562 cells. Four different curcumin formulations were prepared namely DMSO assisted curcumin nano-dispersion (CurD, 260 nm), liposomal curcumin (CurL, 165 nm), MPEG-PCL micellar curcumin (CurM, 18 nm) and cyclodextrin encapsulated curcumin (CurN, 37 nm). The formulations were subjected to particle characterizations (size, zeta potential, release studies), followed by biological assays such as cellular uptake, P-gp inhibitory activity and reversal of DOX resistance by co-treatment with DOX. Curcumin uptake in K562N and K562R cells was mildly reduced when treated with CurL and CurM, while for CurD and CurN the uptake remained equivalent. However, CurL retained P-gp inhibitory activity of curcumin and with a considerable chemo-sensitizing effect but CurM showed no P-gp inhibitory activity. CurN retained above biological activities, but requires a secondary carrier under in vivo conditions. From the results, CurM was found to be most suitable for solubilization of curcumin where as CurL can be considered as most suitable nano-formulation for reversal of DOX resistance.

The semisynthetic flavonoid monoHER sensitises human soft tissue sarcoma cells to doxorubicin-induced apoptosis via inhibition of nuclear factor-κB

PubMed Central

Jacobs, H; Bast, A; Peters, G J; van der Vijgh, W J F; Haenen, G R M M

2011-01-01

Background: Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs. Methods: To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-κB (NF-κB) inactivation in the chemosensitising effect of monoHER. Results: MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-κB activation. Conclusion: These results suggest that reduction of doxorubicin-induced NF-κB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells. PMID:21245867

Doxorubicin Release Controlled by Induced Phase Separation and Use of a Co-Solvent.

PubMed

Park, Seok Chan; Yuan, Yue; Choi, Kyoungju; Choi, Seong-O; Kim, Jooyoun

2018-04-26

Electrospun-based drug delivery is emerging as a versatile means of localized therapy; however, controlling the release rates of active agents still remains as a key question. We propose a facile strategy to control the drug release behavior from electrospun fibers by a simple modification of polymer matrices. Polylactic acid (PLA) was used as a major component of the drug-carrier, and doxorubicin hydrochloride (Dox) was used as a model drug. The influences of a polar co-solvent, dimethyl sulfoxide (DMSO), and a hydrophilic polymer additive, polyvinylpyrrolidone (PVP), on the drug miscibility, loading efficiency and release behavior were investigated. The use of DMSO enabled the homogeneous internalization of the drug as well as higher drug loading efficiency within the electrospun fibers. The PVP additive induced phase separation in the PLA matrix and acted as a porogen. Preferable partitioning of Dox into the PVP domain resulted in increased drug loading efficiency in the PLA/PVP fiber. Fast dissolution of PVP domains created pores in the fibers, facilitating the release of internalized Dox. The novelty of this study lies in the detailed experimental investigation of the effect of additives in pre-spinning formulations, such as co-solvents and polymeric porogens, on the drug release behavior of nanofibers.

Doxorubicin Release Controlled by Induced Phase Separation and Use of a Co-Solvent

PubMed Central

Park, Seok Chan; Choi, Kyoungju; Choi, Seong-O

2018-01-01

Electrospun-based drug delivery is emerging as a versatile means of localized therapy; however, controlling the release rates of active agents still remains as a key question. We propose a facile strategy to control the drug release behavior from electrospun fibers by a simple modification of polymer matrices. Polylactic acid (PLA) was used as a major component of the drug-carrier, and doxorubicin hydrochloride (Dox) was used as a model drug. The influences of a polar co-solvent, dimethyl sulfoxide (DMSO), and a hydrophilic polymer additive, polyvinylpyrrolidone (PVP), on the drug miscibility, loading efficiency and release behavior were investigated. The use of DMSO enabled the homogeneous internalization of the drug as well as higher drug loading efficiency within the electrospun fibers. The PVP additive induced phase separation in the PLA matrix and acted as a porogen. Preferable partitioning of Dox into the PVP domain resulted in increased drug loading efficiency in the PLA/PVP fiber. Fast dissolution of PVP domains created pores in the fibers, facilitating the release of internalized Dox. The novelty of this study lies in the detailed experimental investigation of the effect of additives in pre-spinning formulations, such as co-solvents and polymeric porogens, on the drug release behavior of nanofibers. PMID:29701714

Apigenin sensitizes BEL-7402/ADM cells to doxorubicin through inhibiting miR-101/Nrf2 pathway

PubMed Central

Gao, Ai-Mei; Zhang, Xiao-Yu; Ke, Zun-Ping

2017-01-01

Chemo-resistance is one of the main obstacle in hepatocellular carcinoma therapy. Apigenin as a natural bioflavonoid has been exhibited anti-cancer properties in various malignant cancers. The aim of this study is to evaluate the potential chemo-sensitization effect of apigenin in doxorubicin-resistant hepatocellular carcinoma cell line BEL-7402/ADM and to investigate its possible mechanism. We found that apigenin significantly reversed doxorubicin sensitivity and induced caspase-dependent apoptosis in BEL-7402/ADM cells. Furthermore, apigenin induced miR-101 expression, and overexpression of miR-101 mimicked the doxorubicin-sensitizing effect of apigenin. Importantly, we showed that miR-101 was able to target the 3′-UTR of Nrf2. The results suggested that apigenin sensitizes BEL-7402/ADM cells to doxorubicin through miR-101/Nrf2 pathway, which furtherly supports apigenin as a potential chemo-sensitizer for hepatocellular carcinoma. PMID:29137246

Selective Killing of Breast Cancer Cells by Doxorubicin-Loaded Fluorescent Gold Nanoclusters: Confocal Microscopy and FRET.

PubMed

Chattoraj, Shyamtanu; Amin, Asif; Jana, Batakrishna; Mohapatra, Saswat; Ghosh, Surajit; Bhattacharyya, Kankan

2016-01-18

Fluorescent gold nanoclusters (AuNCs) capped with lysozymes are used to deliver the anticancer drug doxorubicin to cancer and noncancer cells. Doxorubicin-loaded AuNCs cause the highly selective and efficient killing (90 %) of breast cancer cells (MCF7) (IC50 =155 nm). In contrast, the killing of the noncancer breast cells (MCF10A) by doxorubicin-loaded AuNCs is only 40 % (IC50 =4500 nm). By using a confocal microscope, the fluorescence spectrum and decay of the AuNCs were recorded inside the cell. The fluorescence maxima (at ≈490-515 nm) and lifetime (≈2 ns), of the AuNCs inside the cells correspond to Au10-13 . The intracellular release of doxorubicin from AuNCs is monitored by Förster resonance energy transfer (FRET) imaging. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Simultaneous hyperthermia and doxorubicin delivery from polymer-coated magnetite nanoparticles

NASA Astrophysics Data System (ADS)

Iglesias, G. R.; Delgado, A. V.; González-Caballero, F.; Ramos-Tejada, M. M.

2017-06-01

In this work, the hyperthermia response, (i.e., heating induced by an externally applied alternating magnetic field) and the simultaneous release of an anti-cancer drug (doxorubicin) by polymer-coated magnetite nanoparticles have been investigated. After describing the setup for hyperthermia measurements in suspensions of magnetic nanoparticles, the hyperthermia (represented by the rate of suspension heating and, ultimately, by the specific absorption rate or SAR) of magnetite nanoparticles (both bare and polymer-coated as drug nanocarriers) is discussed. The effect of the applied ac magnetic field on doxorubicin release is also studied, and it is concluded that the field does not interfere with the release process, demonstrating the double functionality of the investigated particles.

Stimulus-Responsive Nanoparticles and Associated (Reversible) Polymorphism via Polymerization Induced Self-assembly (PISA).

PubMed

Pei, Yiwen; Lowe, Andrew B; Roth, Peter J

2017-01-01

Polymerization-induced self-assembly (PISA) is an extremely versatile method for the in situ preparation of soft-matter nanoparticles of defined size and morphologies at high concentrations, suitable for large-scale production. Recently, certain PISA-prepared nanoparticles have been shown to exhibit reversible polymorphism ("shape-shifting"), typically between micellar, worm-like, and vesicular phases (order-order transitions), in response to external stimuli including temperature, pH, electrolytes, and chemical modification. This review summarises the literature to date and describes molecular requirements for the design of stimulus-responsive nano-objects. Reversible pH-responsive behavior is rationalised in terms of increased solvation of reversibly ionized groups. Temperature-triggered order-order transitions, conversely, do not rely on inherently thermo-responsive polymers, but are explained based on interfacial LCST or UCST behavior that affects the volume fractions of the core and stabilizer blocks. Irreversible morphology transitions, on the other hand, can result from chemical post-modification of reactive PISA-made particles. Emerging applications and future research directions of this "smart" nanoparticle behavior are reviewed. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hypoxia-induced resistance to doxorubicin and methotrexate in human melanoma cell lines in vitro.

PubMed

Sanna, K; Rofstad, E K

1994-07-15

Rodent cell lines can develop resistance to doxorubicin and methotrexate during hypoxic stress. This has so far not been observed in human tumor cell lines. The purpose of our communication is to show that doxorubicin and methotrexate resistance can also develop in human melanoma cells during exposure to hypoxia. Four cell lines (BEX-c, COX-c, SAX-c, WIX-c) have been studied. Cells were exposed to hypoxia (O2 concentration < 10 ppm) for 24 hr prior to reoxygenation. Doxorubicin and methotrexate cell survival curves were determined immediately after as well as 18 and 42 hr after reoxygenation. The 4 cell lines were relatively sensitive to doxorubicin without hypoxia pre-treatment, and all developed resistance during exposure to hypoxia. Hypoxic stress also induced methotrexate resistance in BEX-c and SAX-c but not in COX-c and WIX-c. BEX-c and SAX-c were sensitive to methotrexate without hypoxia pre-treatment, whereas COX-c and WIX-c were resistant initially. Hypoxia-induced drug resistance was present immediately after reoxygenation and tended to decrease with time but remained statistically significant even 42 hr after reoxygenation.

Chain Reaction Polymerization.

ERIC Educational Resources Information Center

McGrath, James E.

1981-01-01

The salient features and importance of chain-reaction polymerization are discussed, including such topics as the thermodynamics of polymerization, free-radical polymerization kinetics, radical polymerization processes, copolymers, and free-radical chain, anionic, cationic, coordination, and ring-opening polymerizations. (JN)

Age-related effect of aerobic exercise training on antioxidant and oxidative markers in the liver challenged by doxorubicin in rats.

PubMed

Ahmadian, Mehdi; Dabidi Roshan, Valiollah; Leicht, Anthony S

2018-05-16

The aims of the current study were to investigate the oxidant and antioxidant status of liver tissue challenged by doxorubicin and to examine the possible protective effects of aerobic exercise on doxorubicin-induced oxidative stress. Seventy-two rats were divided into three age groups (Young, Adult, and Elderly) with three treatment subgroups consisting of eight rats per age group: doxorubicin, aerobic exercise + doxorubicin, and aerobic exercise + saline. The experimental groups performed regular treadmill running for 3 weeks. Doxorubicin was administered by i.p. injection at a dosage of 20 mg kg -1 while the aerobic exercise + saline group received saline of a comparable volume. Heat shock protein 70, malondialdehyde, glutathione peroxidase, and protein carbonyl were determined from the liver homogenates following the intervention period. Treatment with doxorubicin induced hepatotoxicity in all groups with lower values of oxidative stress in young compared with the older groups. The inclusion of aerobic exercise training significantly increased heat shock protein 70 and antioxidant enzyme levels (glutathione peroxidase) whereas it decreased oxidative stress biomarkers (malondialdehyde and protein carbonyl) for all age groups. These results suggest that aerobic exercise training may be a potential, non-drug strategy to modulate doxorubicin-induced hepatotoxicity through its positive impact on antioxidant levels and oxidative stress biomarkers.

Influence of doxorubicin on model cell membrane properties: insights from in vitro and in silico studies.

PubMed

Alves, Ana Catarina; Magarkar, Aniket; Horta, Miguel; Lima, Jose L F C; Bunker, Alex; Nunes, Cláudia; Reis, Salette

2017-07-24

Despite doxorubicin being commonly used in chemotherapy there still remain significant holes in our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible mechanism is the efflux by protein P-gp, which is found predominantly in cholesterol enriched domains. Thereby, a hypothesis for the vulnerability of doxorubicin to efflux through P-gp is its enhanced affinity for the ordered cholesterol rich regions of the plasma membrane. Thus, we have studied doxorubicin's interaction with model membranes in a cholesterol rich, ordered environment and in liquid-disordered cholesterol poor environment. We have combined three separate experimental protocols: UV-Vis spectrophotometry, fluorescence quenching and steady-state anisotropy and computational molecular dynamics modeling. Our results show that the presence of cholesterol induces a change in membrane structure and doesn't impair doxorubicin's membrane partitioning, but reduces drug's influence on membrane fluidity without directly interacting with it. It is thus possible that the resistance mechanism that lowers the efficacy of doxorubicin, results from an increased density in membrane regions where the efflux proteins are present. This work represents a successful approach, combining experimental and computational studies of membrane based systems to unveil the behavior of drugs and candidate drug molecules.

JS-K, a GST-activated nitric oxide donor prodrug, enhances chemo-sensitivity in renal carcinoma cells and prevents cardiac myocytes toxicity induced by Doxorubicin.

PubMed

Qiu, Mingning; Ke, Longzhi; Zhang, Sai; Zeng, Xin; Fang, Zesong; Liu, Jianjun

2017-08-01

Doxorubicin, a highly effective and widely used anthracycline antibiotic in multiple chemotherapy regimens, has been limited by its cardiotoxicity. The aim of this study is to investigate the effect of nitric oxide donor prodrug JS-K on proliferation and apoptosis in renal carcinoma cells and cardiac myocytes toxicity induced by Doxorubicin and to explore possible p53-related mechanism in renal carcinoma cells. The effect of JS-K on anti-cancer activity of Doxorubicin was investigated in renal carcinoma cells via detecting cell proliferation, cytotoxicity, cell death and apoptosis and expressions of apoptotic-related proteins. Effect of p53 on the combination of JS-K and Doxorubicin was determined using p53 inhibitor Pifithrin-α and p53 activator III. Furthermore, the effect of JS-K on cardiac myocytes toxicity of Doxorubicin was investigated in H9c2 (2-1) cardiac myocytes via measuring cell growth, cell death and apoptosis, expressions of proteins involved in apoptosis and intracellular reactive oxygen species. We demonstrated that JS-K could increase Doxorubicin-induced renal carcinoma cell growth suppression and apoptosis and could increase expressions of proteins that are involved in apoptosis. Additionally, Pifithrin-α reversed the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis; conversely, the p53 activator III exacerbated the promoting effect of JS-K on Doxorubicin-induced renal carcinoma cell apoptosis. Furthermore, JS-K protected H9c2 (2-1) cardiac myocytes against Doxorubicin-induced toxicity and decreased Doxorubicin-induced reactive oxygen species production. JS-K enhances the anti-cancer activity of Doxorubicin in renal carcinoma cells by upregulating p53 expression and prevents cardiac myocytes toxicity of Doxorubicin by decreasing oxidative stress.

Molecular simulations of micellar aggregation of polysorbate 20 ester fractions and their interaction with N-phenyl-1-naphthylamine dye.

PubMed

Lapelosa, Mauro; Patapoff, Thomas W; Zarraga, Isidro E

2016-06-01

Micellar aggregation behavior of polysorbate 20 (PS20) has generated significant interest because of the wide use of PS20 as a surfactant to minimize protein surface adsorption and mitigate protein aggregation. Thus, there is a need for better molecular understanding of what drives the biophysical behavior of PS20 in solution. We observe that a complex amphipathic PS20 molecule, which contains both hydrophobic tail and relatively large hydrophilic head, self-associates strongly within the course of a molecular dynamics simulation performed with a fully atomistic representation of the molecule and an explicit water solvent model. The in silico behavior is consistent with micellar models of PS20 in solution. The dynamics of this self-association is rather complex involving both internal reorganization of the molecule and diffusion to form stable micelle-like aggregates. The micellar aggregates of PS20 are long-lived and are formed by the balance between the large hydrophobic interactions associated with the aliphatic tail of PS20, and the steric repulsion of the hydrophilic sorbitan head structure. In the present work, molecular models of PS20 that represent naturally occurring PS20 fractions were produced and characterized in silico. The study investigated the monoester and diester fractions: PS20M, and PS20D. These fractions present differences in the strength of their hydrophobic effect, which influences the aggregation behavior. Adaptive biasing force (ABF) simulations were carried out with the PS20M and PS20D molecular constructs to calculate the free energy of their pairwise interaction. The free energy barrier for the dissociation is higher for PS20D compared with PS20M. The results show that hydrogen bonds can form when head groups are in close proximity, such as in the PS20 aggregate assembly, and the free energy of interaction can be used to predict the morphology of the micellar aggregate for the different PS20 fractions. We were also able to simulate PS20

Optimization of the separation of lysergic acid diethylamide in urine by a sweeping technique using micellar electrokinetic chromatography.

PubMed

Fang, Ching; Liu, Ju-Tsung; Lin, Cheng-Huang

2002-07-25

The separation and on-line concentrations of lysergic acid diethylamide (LSD), iso-lysergic acid diethylamide (iso-LSD) and lysergic acid N,N-methylpropylamide (LAMPA) in human urine were investigated by capillary electrophoresis-fluorescence spectroscopy using sodium dodecyl sulfate (SDS) as an anionic surfactant. A number of parameters such as buffer pH, SDS concentration, Brij-30 concentration and the content of organic solvent used in separation, were optimized. The techniques of sweeping-micellar electrokinetic chromatography (sweeping-MEKC) and cation-selective exhaustive injection-sweep-micellar electrokinetic chromatography (CSEI-sweep-MEKC) were used for determining on-line concentrations. The advantages and disadvantages of this procedure with respect to sensitivity, precision and simplicity are discussed and compared. Copyright 2002 Elsevier Science BV.

Evaluation of anticancer effects and enhanced doxorubicin cytotoxicity of xanthine derivatives using canine hemangiosarcoma cell lines.

PubMed

Motegi, Tomoki; Katayama, Masaaki; Uzuka, Yuji; Okamura, Yasuhiko

2013-10-01

Methylxanthine derivatives increase cAMP and are known to have diuretic, cardiac, and central nervous system stimulatory effects. Moreover, caffeine inhibits the development of tumors induced by various carcinogens. The aim of this work was to elucidate the anticancer effects on apoptosis of xanthine derivatives alone and with doxorubicin in canine hemangiosarcoma cells. Xanthine derivatives with or without doxorubicin were administered to cells, and the effects were investigated by measuring tumor cell proliferation, cell death (cytotoxicity) induction, and apoptosis by the expression of annexin V or caspase 3/7. Both caffeine and theophylline induced apoptosis, and the treated cells expressed annexin V and caspase 3/7. Both drugs enhanced doxorubicin-induced cytotoxicity; however, hypoxanthine showed no effect. These results indicate that theophylline is similar to caffeine; both drugs may enhance doxorubicin-induced cytotoxicity by inhibiting ATM/ATR kinases. Our data suggest that caffeine and theophylline have anticancer effects and can improve the treatment effect in canine hemangiosarcoma patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity

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

Mitra, Mayurranjan S.; Donthamsetty, Shashikiran; White, Brent

Clinical use of doxorubicin (Adriamycin (registered) ), an antitumor agent, is limited by its oxyradical-mediated cardiotoxicity. We tested the hypothesis that moderate diet restriction protects against doxorubicin-induced cardiotoxicity by decreasing oxidative stress and inducing cardioprotective mechanisms. Male Sprague-Dawley rats (250-275 g) were maintained on diet restriction [35% less food than ad libitum]. Cardiotoxicity was estimated by measuring biomarkers of cardiotoxicity, cardiac function, lipid peroxidation, and histopathology. A LD{sub 100} dose of doxorubicin (12 mg/kg, ip) administered on day 43 led to 100% mortality in ad libitum rats between 7 and 13 days due to higher cardiotoxicity and cardiac dysfunction, whereasmore » all the diet restricted rats exhibited normal cardiac function and survived. Toxicokinetic analysis revealed equal accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the ad libitum and diet restricted hearts. Mechanistic studies revealed that diet restricted rats were protected due to (1) lower oxyradical stress from increased cardiac antioxidants leading to downregulation of uncoupling proteins 2 and 3, (2) induction of cardiac peroxisome proliferators activated receptor-{alpha} and plasma adiponectin increased cardiac fatty acid oxidation (666.9 {+-}14.0 nmol/min/g heart in ad libitum versus 1035.6 {+-} 32.3 nmol/min/g heart in diet restriction) and mitochondrial AMP{alpha}2 protein kinase. The changes led to 51% higher cardiac ATP levels (17.7 {+-} 2.1 {mu}mol/g heart in ad libitum versus 26.7 {+-} 1.9 {mu}mol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK/STAT3 pathway. These findings collectively show that moderate diet restriction renders resiliency against doxorubicin cardiotoxicity by lowering oxidative stress, enhancing ATP synthesis, and inducing the JAK/STAT3 pathway.« less

In vitro and in vivo characterisation of PEG-lipid-based micellar complexes of salmon calcitonin for pulmonary delivery.

PubMed

Baginski, Leonie; Gobbo, Oliviero L; Tewes, Frederic; Salomon, Johanna J; Healy, Anne Marie; Bakowsky, Udo; Ehrhardt, Carsten

2012-06-01

To investigate DSPE-PEG(2000)-based micellar formulations of salmon calcitonin (sCT) for their ability to improve pulmonary delivery. Micelles were characterised by DLS and (31)P-NMR spectroscopy. Stability against sCT degrading peptidases, trypsin, α-chymotrypsin and neutrophil elastase as well as their influence on transepithelial absorption was investigated in vitro. In vivo performance of sCT micelles was studied in an experimental model of intratracheal aerosolisation into rats. Micelles with a mean hydrodynamic diameter of 12 nm spontaneously assembled, when a total concentration of 0.02 mM of PEG-lipid and sCT (at 1:1 molar ratio) was exceeded. Nuclear magnetic resonance confirmed the presence of small micellar structures. The micellar formulation showed increased stability against enzymatic digestion. In vitro studies also showed that sCT micelles were able to enhance transepithelial absorption. Data obtained from in vivo experiments provided evidence of significantly (P < 0.05) higher mean plasma concentrations of sCT, after inhalation of micelles compared to sCT solution, at 60 and 90 min, a significantly higher AUC (inf) and a relative bioavailability of 160 ± 55% when compared to plain sCT solution. The herein described PEG-lipid micelles are promising carriers for enhanced pulmonary delivery of sCT.

Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats

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

Wang, Yu; Mei, Xueting; Yuan, Jingquan

2015-11-15

The clinical efficacy of anthracycline anti-neoplastic agents is limited by cardiac and hepatic toxicities. The aim of this study was to assess the hepatoprotective and cardioprotective effects of taurine zinc solid dispersions, which is a newly-synthesized taurine zinc compound, against doxorubicin-induced toxicity in Sprague–Dawley rats intraperitoneally injected with doxorubicin hydrochloride (3 mg/kg) three times a week (seven injections) over 28 days. Hemodynamic parameters, levels of liver toxicity markers and oxidative stress were assessed. Taurine zinc significantly attenuated the reductions in blood pressure, left ventricular pressure and ± dp/dtmax, increases in serum alanine aminotransferase and aspartate aminotransferase activities, and reductions inmore » serum Zn{sup 2+} and albumin levels (P < 0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P < 0.01). qBase{sup +} was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P < 0.01). Western blotting demonstrated that taurine zinc inhibited c-Jun N-terminal kinase phosphorylation by upregulating dual-specificity phosphoprotein phosphatase-1. Additionally, taurine zinc inhibited cardiomyocyte apoptosis as there was decreased TUNEL/DAPI positivity and protein expression of caspase-3. These results indicate that taurine zinc solid dispersions prevent the side-effects of anthracycline-based anticancer therapy. The mechanisms might be associated with the enhancement of antioxidant defense system partly through activating transcription to synthesize endogenous phase II medicine enzymes and anti-apoptosis through inhibiting JNK phosphorylation

Development and characterization of niosomal formulations of doxorubicin aimed at brain targeting.

PubMed

Bragagni, Marco; Mennini, Natascia; Ghelardini, Carla; Mura, Paola

2012-01-01

The aim of the present work was the development and characterization of a niosomal formulation functionalized with the glucose-derivative N-palmitoylglucosamine (NPG) to obtain a potential brain targeted delivery system for the anticancer agent doxorubicin. Five different methods have been examined for vesicle preparation. Light scattering and transmission electron microscopy were used for vesicle characterization, in terms of mean size, homogeneity and Zeta potential, and selection of the best composition and preparation conditions for developing NPG-functionalized niosomes. Drug entrapment efficiency was determined after separation of loaded from unloaded drug by size exclusion chromatography or dialysis. Preliminary in vivo studies were performed on rats, injected i.v. with 12 mg/kg of doxorubicin as commercial solution (Ebewe, 2 mg/mL) or NPG-niosomal formulation. Drug amounts in the blood and in the major organs of the animals, sacrificed 60 min post injection, were determined by HPLC. The selected formulation consisted in Span:cholesterol:Solulan:NPG (50:40:10:10 mol ratio) vesicles obtained by thin-layer evaporation, leading to homogeneous vesicles of less than 200 nm diameter. This formulation was used for preparation of NPG-niosomes loaded with doxorubicin (mean size 161±4 nm, encapsulation efficacy 57.8±1.8%). No significant changes (P>0.05) in vesicle dimensions, Zeta potential or entrapment efficiency were observed after six months storage at room temperature, indicative of good stability. I.v. administration to rats of the NPG-niosomal formulation allowed for reducing drug accumulation in the heart and keeping it longer in the blood circulation with respect to the commercial formulation. Moreover, a doxorubicin brain concentration of 2.9±0.4 μg/g was achieved after 60 min, while the commercial solution yielded undetectable drug brain concentrations (<0.1 μg/g). The developed NPG-niosomal formulation gave rise to stable, nano-sized vesicles, able

Impact of body composition on pharmacokinetics of doxorubicin in children: A Glaser Pediatric Research Network study

USDA-ARS?s Scientific Manuscript database

We studied the relationship between doxorubicin pharmacokinetics and body composition in children with cancer. Children between 1 and 21 years of age, receiving doxorubicin as an infusion of any duration <24 h on either a 1-day or 2-day schedule, were eligible if they had no significant abnormality ...

Deracemization of bilirubin as the marker of the chirality of micellar aggregates.

PubMed

Sorrenti, Alessandro; Altieri, Barbara; Ceccacci, Francesca; Di Profio, Pietro; Germani, Raimondo; Giansanti, Luisa; Savelli, Gianfranco; Mancini, Giovanna

2012-01-01

The deracemization of bilirubin in micellar aggregates of structurally correlated chiral surfactants was studied by circular dichroism experiments and exploited as the marker of the expression of chirality of the aggregates. The obtained results suggest that the hydrophobic interactions control the transfer of chirality from the monomers to the aggregates, and that different regions of the same aggregate might feature opposite enantiorecognition capabilities. Copyright © 2011 Wiley-Liss, Inc.

CDK4 inhibition and doxorubicin mediate breast cancer cell apoptosis through Smad3 and survivin

PubMed Central

Tarasewicz, Elizabeth; Hamdan, Randala; Straehla, Joelle; Hardy, Ashley; Nunez, Omar; Zelivianski, Stanislav; Dokic, Danijela; Jeruss, Jacqueline S

2014-01-01

Cyclin D1/CDK4 activity is upregulated in up to 50% of breast cancers and CDK4-mediated phosphorylation negatively regulates the TGFβ superfamily member Smad3. We sought to determine if CDK4 inhibition and doxorubicin chemotherapy could impact Smad3-mediated cell/colony growth and apoptosis in breast cancer cells. Parental and cyclin D1-overexpressing MCF7 cells were treated with CDK4 inhibitor, doxorubicin, or combination therapy and cell proliferation, apoptosis, colony formation, and expression of apoptotic proteins were evaluated using an MTS assay, TUNEL staining, 3D Matrigel assay, and apoptosis array/immunoblotting. Study cells were also transduced with WT Smad3 or a Smad3 construct resistant to CDK4 phosphorylation (5M) and colony formation and expression of apoptotic proteins were assessed. Treatment with CDK4 inhibitor/doxorubicin combination therapy, or transduction with 5M Smad3, resulted in a similar decrease in colony formation. Treating cyclin D overexpressing breast cancer cells with combination therapy also resulted in the greatest increase in apoptosis, resulted in decreased expression of anti-apoptotic proteins survivin and XIAP, and impacted subcellular localization of pro-apoptotic Smac/DIABLO. Additionally, transduction of 5M Smad3 and doxorubicin treatment resulted in the greatest change in apoptotic protein expression. Collectively, this work showed the impact of CDK4 inhibitor-mediated, Smad3-regulated tumor suppression, which was augmented in doxorubicin-treated cyclin D-overexpressing study cells. PMID:25006666

Effect of infusion regime on doxorubicin pharmacokinetics in the cat.

PubMed

Hahn, K A; Frazier, D L; Cox, S K; Legendre, A M

1997-01-01

In the pharmacokinetic evaluation of a single doxorubicin dose calculated by body surface area (25 mg/m2) or body weight (1 mg/kg body weight) and given intravenously as a 10-, 15-, or 20-minute infusion, the rate of doxorubicin infusion (mg per minute per m2 or mg per minute per kg) correlated positively with clearance and the distribution rate constant alpha, and it inversely correlated with area under the plasma concentration versus time curve (AUC). These findings suggest that a slower infusion rate results in a greater AUC and longer distribution phase than a faster infusion rate and indicates the importance of normalizing dosage regimes by infusion rate rather than by infusion duration when considering dose-response phenomena in veterinary patients.

Nanospheres Encapsulating Anti-Leishmanial Drugs for Their Specific Macrophage Targeting, Reduced Toxicity, and Deliberate Intracellular Release

PubMed Central

Shukla, Anil Kumar; Patra, Sanjukta

2012-01-01

Abstract The current work focuses on the study of polymeric, biodegradable nanoparticles (NPs) for the encapsulation of doxorubicin and mitomycin C (anti-leishmanial drugs), and their efficient delivery to macrophages, the parasite's home. The biodegradable polymer methoxypoly-(ethylene glycol)-b-poly (lactic acid) (MPEG-PLA) was used to prepare polymeric NPs encapsulating doxorubicin and mitomycin C. The morphology, mean diameter, and surface area of spherical NPs were determined by transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), and BET surface area analysis. X-ray diffraction was performed to validate drug encapsulation. An in vitro release profile of the drugs suggested a fairly slow release. These polymeric NPs were efficiently capable of releasing drug inside macrophages at a slower pace than the free drug, which was monitored by epi-fluorescence microscopy. Encapsulation of doxorubicin and mitomycin C into NPs also decreases cellular toxicity in mouse macrophages (J774.1A). PMID:22925019

Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer

PubMed Central

Pisano, Carmela; Cecere, Sabrina Chiara; Di Napoli, Marilena; Cavaliere, Carla; Tambaro, Rosa; Facchini, Gaetano; Losito, Simona; Pizzolorusso, Antonio; Pignata, Sandro

2013-01-01

Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemonaïve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent. PMID:23577259

Treatment of advanced soft tissue sarcomas with ifosfamide and doxorubicin combination chemotherapy.

PubMed

Barişta, I; Tekuzman, G; Yalçin, S; Güllü, I; Güler, N; Ozişik, Y; Kars, A; Celik, I; Türker, A; Altundağ, K; Zengin, N; Uner, A; Baltali, E; Firat, D

2000-01-01

Our objective was to assess the efficacy of a standard dose ifosfamide and doxorubicin containing regimen in the treatment of advanced soft tissue sarcomas. Forty consecutive patients with a median age of 35.5 years were treated. Ifosfamide was administered at a dose of 2.5 g/m(2)/day as 72-hour continuous infusion with mesna at the same dosage and schedule. Doxorubicin was given at the dose of 60 mg/m(2)/day as 2-hour infusion on day 1. Six patients had a complete response (15%), and 9 (22.5%) had a partial response, fourteen patients (35%) stable disease, and 11 (27.5%) did not respond to chemotherapy. The median duration of response was 13 and 5 months for the complete and partial responders, respectively. The median survival was 37 months. Febrile neutropenia was encountered in 9 cases (22.5%). The present ifosfamide and doxorubicin combination is a moderately effective and well-tolerable regimen in the treatment of advanced soft tissue sarcomas. Copyright 2000 Wiley-Liss, Inc.

A Phase I Study of Triapine® in Combination with Doxorubicin in Patients with Advanced Solid Tumors

PubMed Central

Schelman, William R.; Morgan-Meadows, Sherry; Marnocha, Rebecca; Lee, Fred; Eickhoff, Jens; Huang, Wei; Pomplun, Marcia; Jiang, Zhisheng; Alberti, Dona; Kolesar, Jill M.; Ivy, Percy; Wilding, George; Traynor, Anne M.

2011-01-01

Purpose To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine® administered in combination with doxorubicin. Study Design Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine® IV on days 1-4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m2 and Triapine® 25 mg/m2. PK analysis was performed at various time-points before and after treatment. Results Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m2, Triapine® 45 mg/m2), 2 patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional 3 patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m2) with Triapine® 45 mg/m2. The 2 patients enrolled on this level had 2 DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine® were reduced to 45 mg/m2 and 25 mg/m2, respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Conclusions Pretreated patients with advanced malignancies can tolerate the combination of Triapine® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m2 on day 1 and Triapine® 25 mg/m2 on

Probes for the micellar cage effect. The magnetic 13c-isotope effect and a new cage product in the photolysis of dibenzyl ketone

NASA Astrophysics Data System (ADS)

Kraeutler, Bernhard; Turro, Nicholas J.

1980-03-01

An isotopic enrichment factor, α, is employed as a novel probe to study the effect of solute and of detergent concentration on micellar parameters. The formation of a new cage product is also found to follow monotonically the concentration of micelles in aqueous detergent solutions. It is shown by these probes that the average occupancy of the micelles by the solute does not significantly alter the dynamic micellar behavior with respect to reactions that occur in the micelle cage.

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

Baseline Immunoglobulin E Levels as a Marker of Doxorubicin and Trastuzumab-Associated Cardiac Dysfunction

PubMed Central

Beer, Lynn A.; Kossenkov, Andrew V.; Liu, Qin; Luning Prak, Eline; Domchek, Susan; Speicher, David W.; Ky, Bonnie

2016-01-01

Rationale There is a critical need to develop robust, mechanistic strategies to identify patients at increased risk of cancer therapeutics-related cardiac dysfunction (CTRCD). Objective We aimed to discover new biomarkers associated with doxorubicin and trastuzumab-induced CTRCD using high-throughput proteomic profiling. Methods and Results Plasma, echocardiograms, and clinical outcomes were collected at standardized intervals in breast cancer patients undergoing doxorubicin and trastuzumab cancer therapy. Thirty-one longitudinal plasma samples from three cases with CTRCD and four age- and cancer-matched controls without CTRCD were processed and analyzed using label-free liquid chromatography- mass spectrometry (LC-MS). From these analyses, 862 proteins were identified from case/control pairs 1 and 2, and 1,360 proteins from case/control pair 3. Proteins with a greater than 1.5-fold change in cases compared to controls with a p<0.05 either at the time of CTRCD diagnosis or across all timepoints were considered candidate diagnostic or predictive biomarkers, respectively. The protein that demonstrated the largest differences between cases and controls was immunoglobulin E (IgE), with higher levels detected at baseline and across all timepoints in controls without CTRCD as compared to matched CTRCD cases (p<0.05). Similarly, in a validation study of 35 participants treated with doxorubicin and trastuzumab, high baseline IgE levels were associated with a significantly lower risk of CTRCD (p=0.018). Conclusions In patients receiving doxorubicin and trastuzumab, high baseline IgE levels are associated with a lower risk of CTRCD. These novel findings suggest a new paradigm in cardio-oncology, implicating the immune system as a potential mediator of doxorubicin and trastuzumab-induced cardiac dysfunction. PMID:27582370

Fasting Reduces the Incidence of Delayed-Type Vomiting Associated with Doxorubicin Treatment in Dogs with Lymphoma.

PubMed

Withers, Sita S; Kass, Philip H; Rodriguez, Carlos O; Skorupski, Katherine A; O'Brien, Danielle; Guerrero, Teri A; Sein, Kristen D; Rebhun, Robert B

2014-05-12

Fasting reduces gastrointestinal cellular proliferation rates through G 1 cycle blockade and can promote cellular protection of normal but not cancer cells through altered cell signaling including down-regulation of insulin-like growth factor 1 (IGF-1). Consequently, the purpose of this study was to determine the effects of fasting on delayed-type chemotherapy-induced nausea and vomiting in dogs receiving doxorubicin. This prospective randomized crossover study involved intended administration of two doses of doxorubicin. Cancer-bearing dogs were randomized to be fasted for 24 hours beginning at 6 P.M. the night before the first or second doxorubicin administration, and all treatments were administered within an hour before or after 12 P.M. Dogs were fed normally before the alternate dose. Circulating IGF-1 concentrations were determined from serum samples obtained immediately before each doxorubicin treatment. Data from 35 doses were available from 20 dogs enrolled. Dogs that were fasted exhibited a significantly lower incidence of vomiting, when compared to fed dogs (10% compared to 67%, P = .020). Furthermore, among the 15 dogs that completed crossover dosing, vomiting was abrogated in four of five dogs that experienced doxorubicin-induced vomiting when fed normally (P = .050). No differences in other gastrointestinal, constitutional, or bone marrow toxicities or serum IGF-1 levels were observed. Copyright © 2014 Elsevier Inc. All rights reserved.

Oleic Acid Protects Against Oxidative Stress Exacerbated by Cytarabine and Doxorubicin in Rat Brain.

PubMed

Guzmán, David Calderón; Brizuela, Norma Osnaya; Herrera, Maribel Ortíz; Olguín, Hugo Juárez; García, Ernestina Hernández; Peraza, Armando Valenzuela; Mejía, Gerardo Barragán

2016-01-01

The objective of this study was to analyze the effect of doxorubicin and cytarabine on biogenic amines and oxidative biomarkers in the brain of rats treated with oleic acid. Thirty-six Wistar rats distributed in 6 groups, were treated as follows: group 1 (control), NaCl 0.9%; group 2 doxorubicin (1mg/kg); group 3 cytarabine (70mg /kg); group 4 oleic acid (1500μl/kg); group 5 doxorubicin + oleic acid; group 6 cytarabine + oleic acid. All compounds were administered intraperitoneally for 5 days. The Rats were sacrificed after receiving the last administration and their brains were dissected in cortex, hemispheres, and cerebellum/medulla oblongata. Blood samples were obtained on sacrifice to assess the levels of glucose and triglycerides. In each brain region, lipoperoxidation (TBARS), H2O2, Na+, K+ ATPase, glutathione (GSH), serotonin metabolites (5-HIAA) and dopamine were measured using validated methods. Cytarabine decreased the levels of dopamine, TBARS, GSH, H2O2 and ATPase in all regions. Doxorubicin combined with oleic acid increased the levels of GSH in cortex, and decreased ATPase in cerebellum/medulla oblongata. These results suggest that the reduction of dopamine and oxidant effect during cytarabine treatment could result in brain injury but could be prevented by oleic acid supplementation.

Interfacial instability of wormlike micellar solutions sheared in a Taylor-Couette cell

NASA Astrophysics Data System (ADS)

Mohammadigoushki, Hadi; Muller, Susan J.

2014-10-01

We report experiments on wormlike micellar solutions sheared in a custom-made Taylor-Couette (TC) cell. The computer controlled TC cell allows us to rotate both cylinders independently. Wormlike micellar solutions containing water, CTAB, and NaNo3 with different compositions are highly elastic and exhibit shear banding within a range of shear rate. We visualized the flow field in the θ-z as well as r-z planes, using multiple cameras. When subject to low shear rates, the flow is stable and azimuthal, but becomes unstable above a certain threshold shear rate. This shear rate coincides with the onset of shear banding. Visualizing the θ-z plane shows that this instability is characterized by stationary bands equally spaced in the z direction. Increasing the shear rate results to larger wave lengths. Above a critical shear rate, experiments reveal a chaotic behavior reminiscent of elastic turbulence. We also studied the effect of ramp speed on the onset of instability and report an acceleration below which the critical Weissenberg number for onset of instability is unaffected. Moreover, visualizations in the r-z direction reveals that the interface between the two bands undulates. The shear band evolves towards the outer cylinder upon increasing the shear rate, regardless of which cylinder is rotating.

Micellar and analytical implications of a new potentiometric PVC sensor based on neutral ion-pair complexes of dodecylmethylimidazolium bromide-sodium dodecylsulfate.

PubMed

Sanan, Reshu; Mahajan, Rakesh Kumar

2013-03-15

With an aim to characterize the micellar aggregates of imidazolium based ionic liquids, a new potentiometric PVC sensor based on neutral ion-pair complexes of dodecylmethylimidazolium bromide-sodium dodecylsulfate (C12MeIm(+)DS(-)) has been developed. The electrode exhibited a linear response for the concentration range of 7.9×10(-5)-9.8×10(-3) M with a super-Nernstian slope of 92.94 mV/decade, a response time of 5 s and critical micellar concentration (cmc) of 10.09 mM for C12MeImBr. The performance of the electrode in investigating the cmc of C12MeImBr in the presence of two drugs [promazine hydrochloride (PMZ) and promethazine hydrochloride (PMT)] and three triblock copolymers (P123, L64 and F68) has been found to be satisfactory on comparison with conductivity measurements. Various micellar parameters have been evaluated for the binary mixtures of C12MeImBr with drugs and triblock copolymers using Clint's, Rubingh's, and Motomura's approach. Thus the electrode offers a simple, straightforward and relatively fast technique for the characterization of micellar aggregates of C12MeImBr, complementing existing conventional techniques. Further, the analytical importance of proposed C12MeIm(+)-ISE as end point indicator in potentiometric titrations and for direct determination of cationic surfactants [cetylpyridinium chloride (CPC), tetradecyltrimethylammonium bromide (TTAB), benzalkonium chloride (BC)] in some commercial products was judged by comparing statistically with classical two-phase titration methods. Copyright © 2013 Elsevier Inc. All rights reserved.

Therapeutically blocking Interleukin-11 Receptor-α enhances doxorubicin cytotoxicity in high grade type I endometrioid tumours.

PubMed

Winship, Amy; Van Sinderen, Michelle; Rainczuk, Katarzyna; Dimitriadis, Evdokia

2017-04-04

High grade type I endometrial cancers have poor prognosis. Interleukin (IL)11 is elevated in tumours and uterine lavage with increasing tumour grade in women. IL11 regulates cell cycle, invasion and migration and we recently demonstrated that IL11 receptor (R)α inhibition impaired low and moderate grade endometrial tumourigenesis in vivo. In this report, we hypothesized that micro-RNA(miR)-1 regulates IL11 and that IL11 promotes high grade endometrial tumour growth. We aimed to determine whether combination treatment using an anti-human IL11Rα blocking antibody (Ab) and doxorubicin chemotherapeutic impairs high grade tumour growth. MiR-1 was absent in human endometrial tumours versus human benign endometrium (n = 10/group). Transfection with miR-1 mimic restored miR-1 expression, down-regulated IL11 mRNA and impaired cell viability in grade 3-derived AN3CA human endometrial epithelial cancer cells. AN3CA cell proliferation was reduced in response to Ab and doxorubicin combination treatment versus Ab, IgG control, or doxorubicin alone. Subcutaneous xenograft tumours were established in female Balb/c athymic nude mice using AN3CA cells expressing IL11 and IL11Rα. Administration of recombinant human IL11 to mice (n = 4/group) activated IL11 downstream target, signal transducers and activators of transcription (STAT3) and significantly increased tumour growth (p < 0.05), suggesting that IL11 promotes high grade tumour growth. IL11Rα blocking Ab reduced STAT3 phosphorylation and combination treatment with doxorubicin resulted in a significant reduction in tumour growth (p < 0.05) compared to Ab, doxorubicin, or IgG control. Our data suggest that therapeutically targeting IL11Rα in combination with doxorubicin chemotherapy could inhibit high grade type I endometrioid cancer growth.

Remission of orbital sarcoma in a dog, using doxorubicin therapy.

PubMed

Schoster, J V; Wyman, M

1978-05-01

A 7-year-old female mixed-breed dog with an undifferentiated sarcoma of the orbit was treated for 7 months with doxorubicin hydrochloride. Though remission was achieved, the dog died of acute heart failure.

Sildenafil citrate improves the delivery and anticancer activity of doxorubicin formulations in a mouse model of breast cancer.

PubMed

Greish, Khaled; Fateel, Maryam; Abdelghany, Sara; Rachel, Nanitha; Alimoradi, Houman; Bakhiet, Moiz; Alsaie, Ahmed

2017-11-21

Sildenafil is an approved drug for the treatment of erectile dysfunction. The drug exerts its action through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. In this work, we tested whether the aforementioned effects of sildenafil on tumour vasculatures could result in an improvement of anticancer drug concentration in tumour tissues and hence improves its anticancer effect. Sildenafil when added to doxorubicin showed synergistic anticancer activity against 4T1 breast cancer cells in vitro. Adding 1, 30 and 100 μM of Viagra to 1 μM of doxorubicin resulted in 1.8-fold, 6.2-fold and 21-fold statistically significant increases in its cytotoxic effect, respectively. As a result, 4T1 tumour-bearing mice showed up to 2.7-fold increase in drug concentrations of the fluorescent Dye DiI and doxorubicin in tumour tissues, as well as their nanoformulations. Animals treated with the combinations of both Sildenafil citrate and doxorubicin showed a statistically significant 4.7-fold reduction in tumour size compared to doxorubicin alone. This work highlights the effect of Sildenafil on tumour vasculatures and provides a rational for further testing the combination on breast cancer patients.

Jet A fuel recovery using micellar flooding: Design and implementation.

PubMed

Kostarelos, Konstantinos; Lenschow, Søren R; Stylianou, Marinos A; de Blanc, Phillip C; Mygind, Mette Marie; Christensen, Anders G

2016-09-01

Surfactants offer two mechanisms for recovering NAPLs: 1) to mobilize NAPL by reducing NAPL/water interfacial tension, and; 2) to increase the NAPL's aqueous solubility-called solubilization-as an enhancement to pump & treat. The second approach has been well-studied and applied successfully in several pilot-scale and a few full-scale tests within the last 15years, known as Surfactant Enhanced Aquifer Remediation (SEAR). A useful source of information for this second approach is the "Surfactant-enhanced aquifer remediation (SEAR) design manual" from the U.S. Navy Facilities Engineering Command. Few attempts, however, have been made at recovering NAPLs using the mobilization approach presented in this paper. Now, a full-scale field implementation of the mobilization approach is planned to recover an LNAPL (Jet A fuel) from a surficial sand aquifer located in Denmark using a smaller amount of surfactant solution and fewer PVs of throughput compared with the SEAR approach. The approach will rely on mobilizing the LNAPL so that it is recovered ahead of the surfactant microemulsion, also known as a micellar flood. This paper will review the laboratory work performed as part of the design for a full-scale implementation of a micellar flood. Completed lab work includes screening of surfactants, phase behavior and detailed salinity scans of the most promising formulations, and generating a ternary diagram to be used for the numerical simulations of the field application. The site owners and regulators were able to make crucial decisions such as the anticipated field results based on this work. Copyright © 2016 Elsevier B.V. All rights reserved.

Anticancer drug delivery with transferrin targeted polymeric chitosan vesicles.

PubMed

Dufes, Christine; Muller, Jean-Marc; Couet, William; Olivier, Jean-Christophe; Uchegbu, Ijeoma F; Schätzlein, Andreas G

2004-01-01

The study reports the initial biological evaluation of targeted polymeric glycol chitosan vesicles as carrier systems for doxorubicin (Dox). Transferrin (Tf) was covalently bound to the Dox-loaded palmitoylated glycol chitosan (GCP) vesicles using dimethylsuberimidate (DMSI). For comparison, glucose targeted niosomes were prepared using N-palmitoyl glucosamine. Biological properties were studied using confocal microscopy, flow cytometry, and cytotoxicity assays as well as a mouse xenograft model. Tf vesicles were taken up rapidly with a plateau after 1-2 h and Dox reached the nucleus after 60-90 min. Uptake was not increased with the use of glucose ligands, but higher uptake and increased cytotoxicity were observed for Tf targeted as compared to GCP Dox alone. In the drug-resistant A2780AD cells and in A431 cells, the relative increase in activity was significantly higher for the Tf-GCP vesicles than would have been expected from the uptake studies. All vesicle formulations had a superior in vivo safety profile compared to the free drug. The in vitro advantage of targeted Tf vesicles did not translate into a therapeutic advantage in vivo. All vesicles reduced tumor size on day 2 but were overall less active than the free drug.

Potentiation of apoptosis by histone deacetylase inhibitors and doxorubicin combination: cytoplasmic cathepsin B as a mediator of apoptosis in multiple myeloma.

PubMed

Cheriyath, V; Kuhns, M A; Kalaycio, M E; Borden, E C

2011-03-15

Although inhibitors of histone deacetylase inhibitors (HDACis) in combination with genotoxins potentiate apoptosis, the role of proteases other than caspases in this process remained elusive. Therefore, we examined the potentiation of apoptosis and related mechanisms of HDACis and doxorubicin combination in a panel of myeloma cell lines and in 25 primary myelomas. At IC(50) concentrations, sodium butyrate (an HDACi) or doxorubicin alone caused little apoptosis. However, their combination potentiated apoptosis and synergistically reduced the viability of myeloma cells independent of p53 and caspase 3-7 activation. Potentiated apoptosis correlated with nuclear translocation of apoptosis-inducing factor, suggesting the induction of caspase 3- and 7-independent pathways. Consistent with this, butyrate and doxorubicin combination significantly increased the activity of cytoplasmic cathepsin B. Inhibition of cathepsin B either with a small-molecule inhibitor or downregulation with a siRNA reversed butyrate- and doxorubicin-potentiated apoptosis. Finally, ex vivo, clinically relevant concentrations of butyrate or SAHA (suberoylanilide hydroxamic acid, vorinostat, an HDACi in clinical testing) in combination with doxorubicin significantly (P<0.0001) reduced the survival of primary myeloma cells. Cathepsin B has a prominent function in mediating apoptosis potentiated by HDACi and doxorubicin combinations in myeloma. Our results support a molecular model of lysosomal-mitochondrial crosstalk in HDACi- and doxorubicin-potentiated apoptosis through the activation of cathepsin B.

Modeling the Inhomogeneous Response of Steady and Transient Flows of Entangled Micellar Solutions

NASA Astrophysics Data System (ADS)

McKinley, Gareth

2008-03-01

Surfactant molecules can self-assemble in solution into long flexible structures known as wormlike micelles. These structures entangle, forming a viscoelastic network similar to those in entangled polymer melts and solutions. However, in contrast to `inert' polymeric networks, wormlike micelles continuously break and reform leading to an additional relaxation mechanism and the name `living polymers'. Observations in both classes of entangled fluids have shown that steady and transient shearing flows of these solutions exhibit spatial inhomogeneities such as `shear-bands' at sufficiently large applied strains. In the present work, we investigate the dynamical response of a class of two-species elastic network models which can capture, in a self-consistent manner, the creation and destruction of elastically-active network segments, as well as diffusive coupling between the microstructural conformations and the local state of stress in regions with large spatial gradients of local deformation. These models incorporate a discrete version of the micellar breakage and reforming dynamics originally proposed by Cates and capture, at least qualitatively, non-affine tube deformation and chain disentanglement. The `flow curves' of stress and apparent shear rate resulting from an assumption of homogeneous deformation is non-monotonic and linear stability analysis shows that the region of non-monotonic response is unstable. Calculation of the full inhomogeneous flow field results in localized shear bands that grow linearly in extent across the gap as the apparent shear rate increases. Time-dependent calculations in step strain, large amplitude oscillatory shear (LAOS) and in start up of steady shear flow show that the velocity profile in the gap and the total stress measured at the bounding surfaces are coupled and evolve in a complex non-monotonic manner as the shear bands develop and propagate.

TRACE ANALYSIS OF FLUORESCEIN-DERIVATIZED PHENOXY ACID HERBICIDES BY MICELLAR ELECTROKINETIC CHROMATOGRAPHY WITH LASER-INDUCTED FLUORESCENCE DETECTION

EPA Science Inventory

Micellar electrokinetic chromatography (MEKC) with laser-induced fluorescence (LIF) detection was used for the trace analysis of phenoxy acid herbicides. Capillary electrophoresis (CE) with LIF detection, which has not previously been used for pesticide analysis, overcomes the po...

Protolichesterinic acid enhances doxorubicin-induced apoptosis in HeLa cells in vitro.

PubMed

Brisdelli, Fabrizia; Perilli, Mariagrazia; Sellitri, Doriana; Bellio, Pierangelo; Bozzi, Argante; Amicosante, Gianfranco; Nicoletti, Marcello; Piovano, Marisa; Celenza, Giuseppe

2016-08-01

The aim of this study was to investigate the effect of protolichesterinic acid, a lichen secondary metabolite, on anti-proliferative activity of doxorubicin in three human cancer cell lines, HeLa, SH-SY5Y and K562 cells. The data obtained from MTT assays, performed on cells treated with protolichesterinic acid and doxorubicin alone and in combination, were analysed by the median-effect method as proposed by Chou and Talalay and the Bliss independence model. Apoptosis rate was evaluated by fluorescence microscopy, caspase-3, 8 and 9 activities were detected by spectrofluorimetric analysis and protein expression of Bim, Bid, Bax and Mcl-2 was analysed by Western blotting. The interaction of protolichesterinic acid with thioesterase domain of human fatty acid synthase (hFAS) was investigated by a molecular docking study. The in vitro activity of doxorubicin against HeLa cancer cell line, but not against SH-SY5Y and K562 cells, was synergically increased by protolichesterinic acid. The increased cytotoxicity caused by protolichesterinic acid in HeLa cells was due to a pro-apoptotic effect and was associated to caspase-3, 8 and 9 activation. The simultaneous treatment for 24h with protolichesterinic acid plus doxorubicin caused an increase of Bim protein expression and the appearance of cleaved form of Bid protein. The molecular modelling analysis showed that protolichesterinic acid seemed to behave as a competitive inhibitor of hFAS. These results suggest that protolichesterinic acid could be envisaged as an useful tool against certain types of tumor cells in combination with anticancer drugs. Copyright © 2016 Elsevier Inc. All rights reserved.

Involvement of HIF-1α activation in the doxorubicin resistance of human osteosarcoma cells.

PubMed

Roncuzzi, Laura; Pancotti, Fabia; Baldini, Nicola

2014-07-01

Osteosarcoma is the most common primary bone cancer in children and adolescents. Despite aggressive treatment regimens, survival outcomes remain unsatisfactory, particularly in patients with metastatic and/or recurrent disease. Unfortunately, treatment failure is commonly due to the development of chemoresistance, for which the underlying molecular mechanisms remain unclear. The aim of the present study was to investigate the role of hypoxia-inducible factor 1α (HIF‑1α) and its signalling pathways as mediators of drug-resistance in human osteosarcoma. Toward this aim, we established two osteosarcoma cell lines selected for resistance to doxorubicin, a drug of choice in the treatment of this tumour. Our results showed that the multidrug resistance (MDR) phenotype was also mediated by HIF-1α, the most important regulator of cell adaptation to hypoxia. Our data showed that this transcription factor promoted the outward transport of intracellular doxorubicin by activating the P-glycoprotein (P-gp) expression in osteosarcoma cells maintained in normoxic conditions. In addition, it hindered doxorubicin-induced apoptosis by regulating the expression of c-Myc and p21. Finally, we observed that the doxorubicin-resistant cells maintained for 2 months of continuous culture in a drug-free medium, lost their drug-resistance and this effect was associated with the absence of HIF-1α expression. The emerging role of HIF-1α in osteosarcoma biology indicates its use as a valuable therapeutic target.

Comments on some novel approaches for the determination of micellar aggregation numbers

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

Kratohvil, J.P.

1980-05-01

Micellar aggregation numbers of sodium dodecyl sulfates in water and at several concentrations of soidum chloride from several recent papers and from earlier literature have been critically evaluated. The data of D.A. Doughty (J. Phys. Chem. 83, 2621, 1979) based on sedimentation equilibrium and H.F. Huisman (Proc. Kon. Ned. Akad. Wetensch. B 67, 367, 376, 388, 407, 1964) from intensity light scattering are recommended as standared reference data for sodium dodecyl sulfate. 37 references.

Super-enhanced particle nucleation in styrene emulsion polymerization in the presence of sodium styrene sulfonate.

PubMed

Farias-Cepeda, Lorena; Herrera-Ordonez, Jorge; Hernandez-Martinez, Angel R; Estevez, Miriam; Rosales-Marines, Lucero

2017-08-15

The styrene (St) emulsion polymerization using Aerosol MA80 as surfactant and in the presence of sodium styrene sulfonate (NaSS) was studied. The effect of NaSS content was assessed using MA80 concentrations below and at the critical micellar concentration. It was found that at the higher NaSS and MA80 contents, the number of particles (N) reaches a maximum of the order of 10 17 particles/cm 3 water, a huge value that has never been reported. In this work an explanation for this super-enhanced particle nucleation phenomenon is proposed. Such hypothesis is based on the role of St-NaSS oligomers formed in the aqueous phase and their synergy with MA80 molecules to provide colloidal stability to the system. The proposal seems to be consistent with the experimental data obtained for the evolution of monomer conversion, N, particles size distribution and the wideness of this latter as well as with a theoretical estimation of the N. Copyright © 2017 Elsevier Inc. All rights reserved.

Precision synthesis of functional materials via RAFT polymerization and click-type chemical reactions

NASA Astrophysics Data System (ADS)

Flores, Joel Diez

2011-12-01

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

Biochemical indicators of nephrotoxicity in blood serum of rats treated with novel 4-thiazolidinone derivatives or their complexes with polyethylene glycol-containing nanoscale polymeric carrier

PubMed

Kоbyli nska, L I; Havrylyuk, D Ya; Mitina, N E; Zaichenko, A S; Lesyk, R B; Zіme nkovsky, B S; Stoika, R S

2016-01-01

The aim of this study was to compare the effect of new synthetic 4-thiazolidinone derivatives (potential anticancer compounds denoted as 3882, 3288 and 3833) and doxorubicin (positive control) in free form and in their complexes with synthetic polyethylene glycol-containing nanoscale polymeric carrier on the biochemical indicators of nephrotoxicity in blood serum of rats. The concentration of total protein, urea, creatinine, glucose, ions of sodium, potassium, calcium, iron and chloride was measured. It was found that after injection of the investigated compounds, the concentration of sodium cations and chloride anions in blood serum was increased compared with control (untreated animals). Doxorubicin’s injection was accompanied by a decrease in the concentration of iron cations. The concentration of total protein, urea and creatinine decreased under the influence of the studied compounds. Complexation of these аntineoplastic substances with a synthetic polymeric nanocarrier lowered the concentration of the investigated metabolites substantially compared to the effect of these compounds in free form. The normalization of concentration of total protein, urea and creatinine in blood serum of rats treated with complexes of the studied compounds with the polymeric carrier comparing with increased concentration of these indicators at the introduction of such compounds in free form was found.

Radical-Mediated Enzymatic Polymerizations

PubMed Central

Zavada, Scott R.; Battsengel, Tsatsral; Scott, Timothy F.

2016-01-01

Polymerization reactions are commonly effected by exposing monomer formulations to some initiation stimulus such as elevated temperature, light, or a chemical reactant. Increasingly, these polymerization reactions are mediated by enzymes―catalytic proteins―owing to their reaction efficiency under mild conditions as well as their environmental friendliness. The utilization of enzymes, particularly oxidases and peroxidases, for generating radicals via reduction-oxidation mechanisms is especially common for initiating radical-mediated polymerization reactions, including vinyl chain-growth polymerization, atom transfer radical polymerization, thiol–ene step-growth polymerization, and polymerization via oxidative coupling. While enzyme-mediated polymerization is useful for the production of materials intended for subsequent use, it is especially well-suited for in situ polymerizations, where the polymer is formed in the place where it will be utilized. Such polymerizations are especially useful for biomedical adhesives and for sensing applications. PMID:26848652

Photo-responsive polymeric micelles.

PubMed

Huang, Yu; Dong, Ruijiao; Zhu, Xinyuan; Yan, Deyue

2014-09-07

Photo-responsive polymeric micelles have received increasing attention in both academic and industrial fields due to their efficient photo-sensitive nature and unique nanostructure. In view of the photo-reaction mechanism, photo-responsive polymeric micelles can be divided into five major types: (1) photoisomerization polymeric micelles, (2) photo-induced rearrangement polymeric micelles, (3) photocleavage polymeric micelles, (4) photo-induced crosslinkable polymeric micelles, and (5) photo-induced energy conversion polymeric micelles. This review highlights the recent advances of photo-responsive polymeric micelles, including the design, synthesis and applications in various biomedical fields. Especially, the influence of different photo-reaction mechanisms on the morphology, structure and properties of the polymeric micelles is emphasized. Finally, the possible future directions and perspectives in this emerging area are briefly discussed.

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons.

PubMed

Manchon, Jose Felix Moruno; Dabaghian, Yuri; Uzor, Ndidi-Ese; Kesler, Shelli R; Wefel, Jeffrey S; Tsvetkov, Andrey S

2016-05-11

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors.

Levetiracetam mitigates doxorubicin-induced DNA and synaptic damage in neurons

PubMed Central

Manchon, Jose Felix Moruno; Dabaghian, Yuri; Uzor, Ndidi-Ese; Kesler, Shelli R.; Wefel, Jeffrey S.; Tsvetkov, Andrey S.

2016-01-01

Neurotoxicity may occur in cancer patients and survivors during or after chemotherapy. Cognitive deficits associated with neurotoxicity can be subtle or disabling and frequently include disturbances in memory, attention, executive function and processing speed. Searching for pathways altered by anti-cancer treatments in cultured primary neurons, we discovered that doxorubicin, a commonly used anti-neoplastic drug, significantly decreased neuronal survival. The drug promoted the formation of DNA double-strand breaks in primary neurons and reduced synaptic and neurite density. Pretreatment of neurons with levetiracetam, an FDA-approved anti-epileptic drug, enhanced survival of chemotherapy drug-treated neurons, reduced doxorubicin-induced formation of DNA double-strand breaks, and mitigated synaptic and neurite loss. Thus, levetiracetam might be part of a valuable new approach for mitigating synaptic damage and, perhaps, for treating cognitive disturbances in cancer patients and survivors. PMID:27168474

Effects of curcumin in pediatric epithelial liver tumors: inhibition of tumor growth and alpha-fetoprotein in vitro and in vivo involving the NFkappaB- and the beta-catenin pathways

PubMed Central

Bortel, Nicola; Armeanu-Ebinger, Sorin; Schmid, Evi; Kirchner, Bettina; Frank, Jan; Kocher, Alexa; Schiborr, Christina; Warmann, Steven; Fuchs, Jörg; Ellerkamp, Verena

2015-01-01

In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best-investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC. PMID:26515460

Synthesis of mesoporous silica nanoparticles and nanorods: Application to doxorubicin delivery

NASA Astrophysics Data System (ADS)

Rahmani, Saher; Durand, Jean-Olivier; Charnay, Clarence; Lichon, Laure; Férid, Mokhtar; Garcia, Marcel; Gary-Bobo, Magali

2017-06-01

The synthesis and application of mesoporous silica nanoparticles (MSN) and mesoporous silica nanorods (MSNR) for drug delivery were described. MSN or MSNR were obtained by adjusting the amount of added cosolvent to the sol-gel solution. Therefore, the addition of ethanol (EtOH) has contributed to the control of the particle shape and to the structure of the mesoporosity. MSN and MSNR particles were then loaded with doxorubicin and incubated with MCF-7 breast cancer cells. MSN and MSNR particles were efficient in killing cancer cells but their behavior in drug delivery was altered on account of the difference in their morphology. MSN showed a burst release of doxorubicin in cells whereas MSNR showed a sustained delivery of the anti-cancer drug.

Nuclear phospho-Akt increase predicts synergy of PI3K inhibition and doxorubicin in breast and ovarian cancer.

PubMed

Wallin, Jeffrey J; Guan, Jane; Prior, Wei Wei; Edgar, Kyle A; Kassees, Robert; Sampath, Deepak; Belvin, Marcia; Friedman, Lori S

2010-09-08

The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is frequently disrupted in cancer and implicated in multiple aspects of tumor growth and survival. In addition, increased activity of this pathway in cancer is associated with resistance to chemotherapeutic agents. Therefore, it has been hypothesized that PI3K inhibitors could help to overcome resistance to chemotherapies. We used preclinical cancer models to determine the effects of combining the DNA-damaging drug doxorubicin with GDC-0941, a class I PI3K inhibitor that is currently being tested in early-stage clinical trials. We found that PI3K inhibition significantly increased apoptosis and enhanced the antitumor effects of doxorubicin in a defined set of breast and ovarian cancer models. Doxorubicin treatment caused an increase in the amount of nuclear phospho-Akt(Ser473) in cancer cells that rely on the PI3K pathway for survival. This increased phospho-Akt(Ser473) response to doxorubicin correlates with the strength of GDC-0941's effect to augment doxorubicin action. These studies predict that clinical use of combination therapies with GDC-0941 in addition to DNA-damaging agents will be effective in tumors that rely on the PI3K pathway for survival.

Targeting PEPT1: a novel strategy to improve the antitumor efficacy of doxorubicin in human hepatocellular carcinoma therapy.

PubMed

Gong, Yanxia; Wu, Xiang; Wang, Tao; Zhao, Jia; Liu, Xi; Yao, Zhi; Zhang, Qingyu; Jian, Xu

2017-06-20

Proton coupled oligopeptide transporter 1 (PEPT1) is a member of the peptide transporter superfamily and plays important role in the absorption of oligopeptide and peptidomimetic drugs. Our previous research verified that PEPT1 expressed specifically in human Hepatocellular carcinoma (HCC) tissue and cell lines and showed potential transport activity to be a new candidate of the tumor therapeutic target. In this study, we aim to explore the feasibility of a novel tumor target therapeutic strategy: Targeting PEPT1 to improve the antitumor efficacy of Doxorubicin in human HCC therapy. First, Doxorubicin was conjugated with Glycylglycylglycine (Gly-Gly-Gly) - a tripeptide which was known as the substrate of PEPT1 and characterized by HPLC and MS successfully. Doxorubicin-tripeptide conjugate was then observed to clarify the target delivery by PEPT1 and the antitumor effect on human hepatocarcinoma in vivo and in vitro. Furthermore, the improvement of the toxic and side effect of Doxorubicin after conjugation was also evaluated by some biochemical tests. Our results reveal that targeting PEPT1 may contribute to the efficient delivery of Doxorubicin to hepatocarcinoma cells and the reduction of drug toxicity. PEPT1 has the prospect to be a novel target of HCC therapy.

Synthesis and characterization of a multifunctional gold-doxorubicin nanoparticle system for pH triggered intracellular anticancer drug release.

PubMed

Khutale, Ganesh V; Casey, Alan

2017-10-01

A nanoparticle drug carrier system has been developed to alter the cellular uptake and chemotherapeutic performance of an available chemotherapeutic drug. The system comprises of a multifunctional gold nanoparticle based drug delivery system (Au-PEG-PAMAM-DOX) as a novel platform for intracellular delivery of doxorubicin (DOX). Spherical gold nanoparticles were synthesized by a gold chloride reduction, stabilized with thiolated polyethylene glycol (PEG) and then covalently coupled with a polyamidoamine (PAMAM) G4 dendrimer. Further, conjugation of an anti-cancer drug doxorubicin to the dendrimer via amide bond resulted in Au-PEG-PAMAM-DOX drug delivery system. Acellular drug release studies proved that DOX released from Au-PEG-PAMAM-DOX at physiological pH was negligible but it was significantly increased at a weak acidic milieu. The intracellular drug release was monitored with confocal laser scanning microscopy analysis. In vitro viability studies showed an increase in the associated doxorubicin cytotoxicity not attributed to carrier components indicating the efficiency of the doxorubicin was improved, upon conjugation to the nano system. As such it is postulated that the developed pH triggered multifunctional doxorubicin-gold nanoparticle system, could lead to a promising platform for intracellular delivery of variety of anticancer drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

Sleep pattern and locomotor activity are impaired by doxorubicin in non-tumor-bearing rats.

PubMed

Lira, Fabio Santos; Esteves, Andrea Maculano; Pimentel, Gustavo Duarte; Rosa, José Cesar; Frank, Miriam Kannebley; Mariano, Melise Oliveira; Budni, Josiane; Quevedo, João; Santos, Ronaldo Vagner Dos; de Mello, Marco Túlio

2016-01-01

We sought explore the effects of doxorubicin on sleep patterns and locomotor activity. To investigate these effects, two groups were formed: a control group and a Doxorubicin (DOXO) group. Sixteen rats were randomly assigned to either the control or DOXO groups. The sleep patterns were examined by polysomnographic recording and locomotor activity was evaluated in an open-field test. In the light period, the total sleep time and slow wave sleep were decreased, while the wake after sleep onset and arousal were increased in the DOXO group compared with the control group (p<0.05). In the dark period, the total sleep time, arousal, and slow wave sleep were increased, while the wake after sleep onset was decreased in the DOXO group compared with the control group (p<0.05). Moreover, DOXO induced a decrease of crossing and rearing numbers when compared control group (p<0.05). Therefore, our results suggest that doxorubicin induces sleep pattern impairments and reduction of locomotor activity.

Separation and determination of peptide metabolite of Bacillus licheniformis in a microbial fuel cell by high-speed capillary micellar electrokinetic chromatography.

PubMed

Wang, Wei; Bai, Ruiguang; Cai, Xiaoyu; Lin, Ping; Ma, Lihong

2017-11-01

A method using high-speed capillary micellar electrokinetic chromatography and a microbial fuel cell was applied to determine the metabolite of the peptides released by Bacillus licheniformis. Two peptides, l-carnosine and l-alanyl-l-glutamine were used as the substrate to feed Bacillus licheniformis in a microbial fuel cell. The metabolism process of the bacterium was monitored by analyzing the voltage outputs of the microbial fuel cell. A home-made spontaneous injection device was applied to perform high-speed capillary micellar electrokinetic chromatography. Under the optimized conditions, tryptophan, glycine, valine, tyrosine and the two peptides could be rapidly separated within 2.5 min with micellar electrokinetic chromatography mode. Then the method was applied to analyze the solutions sampled from the microbial fuel cell. After 92 h running, valine, as the metabolite, was successfully detected with concentration 3.90 × 10 -5 M. The results demonstrated that Bacillus licheniformis could convert l-carnosine and l-alanyl-l-glutamine into valine. The method employed in this work was proved to have great potential in analysis of metabolites, such as amino acids, for microorganisms. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A cannabinoid anticancer quinone, HU-331, is more potent and less cardiotoxic than doxorubicin: a comparative in vivo study.

PubMed

Kogan, Natalya M; Schlesinger, Michael; Peters, Maximilian; Marincheva, Gergana; Beeri, Ronen; Mechoulam, Raphael

2007-08-01

Several quinones have been found to be effective in the treatment of some forms of cancer; however, their cumulative heart toxicity limits their use. The cannabinoid quinone HU-331 [3S,4R-p-benzoquinone-3-hydroxy-2-p-mentha-(1,8)-dien-3-yl-5-pentyl] is highly effective against tumor xenografts in nude mice. We report now a comparison of the anticancer activity of HU-331 and its cardiotoxicity with those of doxorubicin in vivo. General toxicity was assayed in Sabra, nude and SCID-NOD mice. The anticancer activity in vivo was assessed by measurement of the tumors with an external caliper in HT-29 and Raji tumor-bearing mice and by weighing the excised tumors. Left ventricular function was evaluated with transthoracic echocardiography. Myelotoxicity was evaluated by blood cell count. Cardiac troponin T (cTnT) plasma levels were determined by immunoassay. HU-331 was found to be much less cardiotoxic than doxorubicin. The control and the HU-331-treated groups gained weight, whereas the doxorubicin-treated group lost weight during the study. In HT-29 colon carcinoma, the tumor weight in the HU-331-treated group was 54% smaller than in the control group and 30% smaller than in the doxorubicin-treated group. In Raji lymphoma, the tumor weight in the HU-331-treated group was 65% smaller than in the control group and 33% smaller than in the doxorubicin-treated group. In contrast to doxorubicin, HU-331 did not generate reactive oxygen species in mice hearts (measured by protein carbonylation levels and malondialdehyde levels). In vivo, HU-331 was more active and less toxic than doxorubicin and thus it has a high potential for development as a new anticancer drug.

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.

Tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity: Potential role of tannins in cancer chemotherapy

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

Tikoo, Kulbhushan, E-mail: tikoo.k@gmail.com; Sane, Mukta Subhash; Gupta, Chanchal

2011-03-15

Doxorubicin, an anthracycline antibiotic, is widely used in the treatment of various solid tumors including breast cancer. However, its use is limited due to a variety of toxicities including cardiotoxicity. The present study aimed to evaluate the effect of tannic acid, a PARG/PARP inhibitor and an antioxidant, on doxorubicin-induced cardiotoxicity in H9c2 embryonic rat heart myoblasts and its anti-cancer activity in MDA-MB-231 human breast cancer cells as well as in DMBA-induced mammary tumor animals. Doxorubicin-induced cardiotoxicity was assessed by measurement of heart weight, plasma LDH level and histopathology. Bcl-2, Bax, PARP-1 and p53 expression were examined by western blotting. Ourmore » results show that tannic acid prevents activation of PARP-1, reduces Bax and increases Bcl-2 expression in H9c2 cells, thus, preventing doxorubicin-induced cell death. Further, it reduces the cell viability of MDA-MB-231 breast cancer cells, increases p53 expression in mammary tumors and shows maximum tumor volume reduction, suggesting that tannic acid potentiates the anti-cancer activity of doxorubicin. To the best of our knowledge, this is the first report which shows that tannic acid ameliorates doxorubicin-induced cardiotoxicity and potentiates its anti-cancer activity both in vitro (H9c2 and MDA-MB-231 cells) as well as in in vivo model of DMBA-induced mammary tumor animals.« less

Synergistic effect of pyrazoles derivatives and doxorubicin in claudin-low breast cancer subtype.

PubMed

Saueressig, Silvia; Tessmann, Josiane; Mastelari, Rosiane; da Silva, Liziane Pereira; Buss, Julieti; Segatto, Natalia Vieira; Begnini, Karine Rech; Pacheco, Bruna; de Pereira, Cláudio Martin Pereira; Collares, Tiago; Seixas, Fabiana Kömmling

2018-02-01

Breast cancer is a global public health problem. For some subtypes, such as Claudin-low, the prognosis is poorer and the treatment is still a challenge. Pyrazoles are an important class of heterocyclic compounds and are promising anticancer agents based on their chemical properties. The present study was aimed not only at testing pyrazoles previously prepared by our research group in two breast cancer cell lines characterized by intermediated response to conventional chemotherapy but also at analyzing the possible synergistic effect of these pyrazoles associated with doxorubicin. Four 1-thiocarbamoyl-3,5-diaryl-4,5-dihydro-1H pyrazoles were tested for the first time in MCF-7 and MDA-MB-231 culture cells. The pyrazoles with best results in cytotoxicity were used in combination with doxorubicin and compared with this drug alone as standard. The synergic effect was analyzed using Combination Index method. In addition, cell death and apoptosis assays were carried out. Two pyrazoles with cytotoxic effect in MCF-7 and especially in MDA-MB-231 were identified. This activity was markedly higher in pyrazoles containing bromine and chlorine substituents. The combination of these pyrazoles with doxorubicin had a significant synergic effect in both cells tested and mainly in MDA-MB-231. These data were confirmed with apoptosis and cell death analysis. The synergic effect observed with combination of these pyrazoles and doxorubicin deserves special attention in Claudin-low breast cancer subtype. This should be explored in order to improve treatment results and minimize side effects. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Effect of cationic side-chains on intracellular delivery and cytotoxicity of pH sensitive polymer-doxorubicin nanocarriers.

PubMed

Fang, Chen; Kievit, Forrest M; Cho, Yong-Chan; Mok, Hyejung; Press, Oliver W; Zhang, Miqin

2012-11-21

Fine-tuning the design of polymer-doxorubicin conjugates permits optimization of an efficient nanocarrier to greatly increase intracellular uptake and cytotoxicity. Here, we report synthesis of a family of self-assembled polymer-doxorubicin nanoparticles and an evaluation of the effects of various types of side-chains on intracellular uptake and cytotoxicity of the nanocarriers for lymphoma cells. Monomers with three different cationic side-chains (CA) and pK(a)'s, i.e., a guanidinium group (Ag), an imidazole group (Im), and a tertiary amine group (Dm), were comparatively investigated. The cationic monomer, poly(ethylene glycol) (PEG), and doxorubicin (Dox) were reacted with 1,4-(butanediol) diacrylate (BUDA) to prepare a poly(β-amino ester) (PBAE) polymer via Michael addition. All three polymer-Dox conjugates spontaneously formed nanoparticles (NP) through hydrophobic interactions between doxorubicin in aqueous solution, resulting in NP-Im/Dox, NP-Ag/Dox, and NP-Dm/Dox, with hydrodynamic sizes below 80 nm. Doxorubicin was linked to all 3 types of NPs with a hydrazone bond to assure selective release of doxorubicin only at acidic pH, as it occurs in the tumor microenvironment. Both NP-Im/Dox and NP-Ag/Dox exhibited much higher intracellular uptake by Ramos cells (Burkitt's lymphoma) than NP-Dm/Dox, suggesting that the type of side chain in the NPs determines the extent of intracellular uptake. As a result, NP-Im/Dox and NP-Ag/Dox showed cytotoxicity that was comparable to free Dox in vitro. Our findings suggest that the nature of surface cationic group on nanocarriers may profoundly influence their intracellular trafficking and resulting therapeutic efficacy. Thus, it is a crucial factor to be considered in the design of novel carriers for intracellular drug delivery.

Doxorubicin-conjugated bacteriophages carrying anti-MHC class I chain-related A for targeted cancer therapy in vitro.

PubMed

Phumyen, Achara; Jantasorn, Siriporn; Jumnainsong, Amonrat; Leelayuwat, Chanvit

2014-01-01

Cancer therapy by systemic administration of anticancer drugs, besides the effectiveness shown on cancer cells, demonstrated the side effects and cytotoxicity on normal cells. The targeted drug-carrying nanoparticles may decrease the required drug concentration at the site and the distribution of drugs to normal tissues. Overexpression of major histocompatibility complex class I chain-related A (MICA) in cancer is useful as a targeted molecule for the delivery of doxorubicin to MICA-expressing cell lines. The application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide (EDC) chemistry was employed to conjugate the major coat protein of bacteriophages carrying anti-MICA and doxorubicin in a mildly acid condition. Doxorubicin (Dox) on phages was determined by double fluorescence of phage particles stained by M13-fluorescein isothiocyanate (FITC) and drug autofluorescence by flow cytometry. The ability of anti-MICA on phages to bind MICA after doxorubicin conjugation was evaluated by indirect enzyme-linked immunosorbent assay. One cervical cancer and four cholangiocarcinoma cell lines expressing MICA were used as models to evaluate targeting activity by cell cytotoxicity test. Flow cytometry and indirect enzyme-linked immunosorbent assay demonstrated that most of the phages (82%) could be conjugated with doxorubicin, and the Dox-carrying phage-displaying anti-MICA (Dox-phage) remained the binding activity against MICA. Dox-phage was more efficient than free drugs in killing all the cell lines tested. The half maximal inhibitory concentration (IC50) values of Dox-phage were lower than those of free drugs at approximately 1.6-6 times depending on MICA expressions and the cell lines tested. Evidently, the application of 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide chemistry is effective to conjugate doxorubicin and major coat protein of bacteriophages without destroying binding activity of MICA antibodies. Dox-carrying bacteriophages targeting MICA have been

Effect of cationic side-chains on intracellular delivery and cytotoxicity of pH sensitive polymer-doxorubicin nanocarriers

NASA Astrophysics Data System (ADS)

Fang, Chen; Kievit, Forrest M.; Cho, Yong-Chan; Mok, Hyejung; Press, Oliver W.; Zhang, Miqin

2012-10-01

Fine-tuning the design of polymer-doxorubicin conjugates permits optimization of an efficient nanocarrier to greatly increase intracellular uptake and cytotoxicity. Here, we report synthesis of a family of self-assembled polymer-doxorubicin nanoparticles and an evaluation of the effects of various types of side-chains on intracellular uptake and cytotoxicity of the nanocarriers for lymphoma cells. Monomers with three different cationic side-chains (CA) and pKa's, i.e., a guanidinium group (Ag), an imidazole group (Im), and a tertiary amine group (Dm), were comparatively investigated. The cationic monomer, poly(ethylene glycol) (PEG), and doxorubicin (Dox) were reacted with 1,4-(butanediol) diacrylate (BUDA) to prepare a poly(β-amino ester) (PBAE) polymer via Michael addition. All three polymer-Dox conjugates spontaneously formed nanoparticles (NP) through hydrophobic interactions between doxorubicin in aqueous solution, resulting in NP-Im/Dox, NP-Ag/Dox, and NP-Dm/Dox, with hydrodynamic sizes below 80 nm. Doxorubicin was linked to all 3 types of NPs with a hydrazone bond to assure selective release of doxorubicin only at acidic pH, as it occurs in the tumor microenvironment. Both NP-Im/Dox and NP-Ag/Dox exhibited much higher intracellular uptake by Ramos cells (Burkitt's lymphoma) than NP-Dm/Dox, suggesting that the type of side chain in the NPs determines the extent of intracellular uptake. As a result, NP-Im/Dox and NP-Ag/Dox showed cytotoxicity that was comparable to free Dox in vitro. Our findings suggest that the nature of surface cationic group on nanocarriers may profoundly influence their intracellular trafficking and resulting therapeutic efficacy. Thus, it is a crucial factor to be considered in the design of novel carriers for intracellular drug delivery.

Cordycepin enhances Epstein-Barr virus lytic infection and Epstein-Barr virus-positive tumor treatment efficacy by doxorubicin.

PubMed

Du, Yinping; Yu, Jieshi; Du, Li; Tang, Jun; Feng, Wen-Hai

2016-07-01

The consistent latent presence of Epstein-Barr virus (EBV) in tumor cells offers potential for virus-targeted therapies. The switch from the latent form of EBV to the lytic form in tumor cells can lead to tumor cell lysis. In this study, we report that a natural small molecule compound, cordycepin, can induce lytic EBV infection in tumor cells. Subsequently, we demonstrate that cordycepin can enhance EBV reactivating capacity and EBV-positive tumor cell killing ability of low dose doxorubicin. The combination of cordycepin and doxorubicin phosphorylates CCAAT/enhancer binding protein β (C/EBPβ) through protein kinase C (PKC)-p38 mitogen activated protein kinases (p38 MAPK) signaling pathway, and C/EBPβ is required for the activation of lytic EBV infection. Most importantly, an in vivo experiment demonstrates that the combination of cordycepin and doxorubicin is more effective in inhibiting tumor growth in SCID mice than is doxorubicin alone. Our findings establish that cordycepin can enhance the efficacy of conventional chemotherapy for treatment of EBV-positive tumors. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chiral separation of amino acids in biological fluids by micellar electrokinetic chromatography with laser-induced fluorescence detection.

PubMed

Thorsén, G; Bergquist, J

2000-08-18

A method is presented for the chiral analysis of amino acids in biological fluids using micellar electrokinetic chromatography (MEKC) and laser-induced fluorescence (LIF). The amino acids are derivatized with the chiral reagent (+/-)-1-(9-anthryl)-2-propyl chloroformate (APOC) and separated using a mixed micellar separation system. No tedious pre-purification of samples is required. The excellent separation efficiency and good detection capabilities of the MEKC-LIF system are exemplified in the analysis of urine and cerebrospinal fluid. This is the first time MEKC has been reported for chiral analysis of amino acids in biological fluids. The amino acids D-alanine, D-glutamine, and D-aspartic acid have been observed in cerebrospinal fluid, and D-alanine and D-glutamic acid in urine. To the best of our knowledge no measurements of either D-alanine in cerebrospinal fluid or D-glutamic acid in urine have been presented in the literature before.

Interactions of doxorubicin with self-assembled monolayer-modified electrodes: electrochemical, surface plasmon resonance (SPR), and gravimetric studies.

PubMed

Nieciecka, Dorota; Krysinski, Pawel

2011-02-01

We present the results on the partitioning of doxorubicin (DOX), a potent anticancer drug, through the model membrane system, self-assembled monolayers (SAMs) on gold electrodes. The monolayers were formed from alkanethiols of comparable length with different ω-terminal groups facing the aqueous electrolyte: the hydrophobic -CH(3) groups for the case of dodecanethiol SAMs or hydrophilic -OH groups of mercaptoundecanol SAMs. The electrochemical experiments combined with the surface plasmon resonance (SPR) and gravimetric studies show that doxorubicin is likely adsorbed onto the surface of hydrophilic monolayer, while for the case of the hydrophobic one the drug mostly penetrates the monolayer moiety. The adsorption of the drug hinders further penetration of doxorubicin into the monolayer moiety.

Intramyocardial injection of SERCA2a-expressing lentivirus improves myocardial function in doxorubicin-induced heart failure.

PubMed

Mattila, Minttu; Koskenvuo, Juha; Söderström, Mirva; Eerola, Kim; Savontaus, Mikko

2016-07-01

Doxorubicin is an effective anticancer drug. The major limitation to its use is the induction of dose-dependent cardiomyopathy. No specific treatment exists for doxorubicin-induced cardiomyopathy and treatments used for other forms of heart failure have only limited beneficial effects. The contraction-relaxation cycle of the heart is controlled by cytosolic calcium concentrations, which, in turn, are critically regulated by the activity of the sarcoplasmic reticulum Ca(2) (+) ATPase (SERCA2a) pump. We hypothesized that SERCA2a gene transfer would ameliorate doxorubicin-induced cardiomyopathy. Lentiviral vectors LV-SERCA2a-GFP and LV-GFP were constructed and in vitro gene transfer of LV-SERCA2a-GFP confirmed SERCA2a expression by western blot analysis. Heart failure was induced by giving a single intraperitoneal injection of doxorubicin. LV-SERCA2a-GFP, LV-GFP vectors and phosphate-buffered saline (PBS) were injected under echocardiographic control to the anterior wall of the left ventricle. Echocardiography analyses were performed on the injection day and 28 days postinjection. On the injection day, there were no significant differences in the average ejection fractions (EFs) among SERCA2a (40.0%), GFP (41.1%) and PBS (39.4%) injected animals. On day 28, EF in the SERCA2a group had increased by 16.6 ± 6.7% to 46.4 ± 2.1%. By contrast, EFs in the GFP (40.2 ± 1.3%) and PBS (40.6 ± 1.4%) groups remained at pre-injection levels. In addition, end systolic and end diastolic left ventricle volumes were significantly smaller in the SERCA2a group compared to controls. SERCA2a gene transfer significantly improves left ventricle function and dimensions in doxorubicin-induced cardiomyopathy, thus making LV-SERCA2a gene transfer an attractive treatment modality for doxorubicin-induced heart failure. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Glucosamine-anchored doxorubicin-loaded targeted nano-niosomes: pharmacokinetic, toxicity and pharmacodynamic evaluation.

PubMed

Pawar, Smita; Shevalkar, Ganesh; Vavia, Pradeep

2016-09-01

Efficacy of anticancer drug is limited due to non-selectivity and toxicities allied with the drug; therefore the heart of the present work is to formulate drug delivery systems targeted selectively towards cancer cells with minimal toxicity to normal cells. Targeted drug delivery system of doxorubicin (DOX)-loaded niosomes using synthesized N-lauryl glucosamine (NLG) as a targeting ligand. NLG-anchored DOX niosomes were developed using ethanol injection method. Developed niosomes had particle size <150 nm and high entrapment efficiency ∼90%. In vivo pharmacokinetics exhibited long circulating nature of targeted niosomes with improved bioavailability, which significantly reduced CL and Vd than DOX solution and non-targeted niosomes (35 fold and 2.5 fold, respectively). Tissue-distribution study and enzymatic assays revealed higher concentration of DOX solution in heart while no toxicity to major organs with developed targeted niosomes was observed. Solid skin melanoma tumor model in mice manifested the commendable targeting potential of targeted niosomes with significant reduction in tumor volume and high % survival rate without drop in body weight in comparison with DOX solution and non-targeted niosomes of DOX. The glucosamine-anchored DOX-loaded targeted niosomes showed its potential in cancer targeted drug therapy with reduced toxicity. Abbreviations ALT alanine transaminase CL clearance CPK creatinine phosphokinase DOX doxorubicin EDC.HCL ethyl carbidimide hydrochloride GLUT glucose transporter GSH glutathione S-transferase LDH lactate dehydrogenase LHRH luteinizing hormone-releasing hormone MDA malonaldehyde NHS N-hydroxy succinimide NLG N-lauryl glucosamine NTAR DoxNio non-targeted doxorubicin niosomes PBS phosphate buffer saline RGD argynyl glycyl aspartic acid SGOT serum glutamate oxaloacetate transaminase SGPT serum glutamate pyruvate transaminase SOD superoxide dismutase TAR DoxNio targeted doxorubicin niosomes Vd volume of distribution.

Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats.

PubMed

Wang, Yu; Mei, Xueting; Yuan, Jingquan; Lu, Wenping; Li, Binglong; Xu, Donghui

2015-11-15

The clinical efficacy of anthracycline anti-neoplastic agents is limited by cardiac and hepatic toxicities. The aim of this study was to assess the hepatoprotective and cardioprotective effects of taurine zinc solid dispersions, which is a newly-synthesized taurine zinc compound, against doxorubicin-induced toxicity in Sprague-Dawley rats intraperitoneally injected with doxorubicin hydrochloride (3mg/kg) three times a week (seven injections) over 28 days. Hemodynamic parameters, levels of liver toxicity markers and oxidative stress were assessed. Taurine zinc significantly attenuated the reductions in blood pressure, left ventricular pressure and ± dp/dtmax, increases in serum alanine aminotransferase and aspartate aminotransferase activities, and reductions in serum Zn(2+) and albumin levels (P<0.05 or 0.01) induced by doxorubicin. In rats treated with doxorubicin, taurine zinc dose-dependently increased liver superoxide dismutase activity and glutathione concentration, and decreased malondialdehyde level (P<0.01). qBase(+) was used to evaluate the stability of eight candidate reference genes for real-time quantitative reverse-transcription PCR. Taurine zinc dose-dependently increased liver heme oxygenase-1 and UDP-glucuronyl transferase mRNA and protein expression (P<0.01). Western blotting demonstrated that taurine zinc inhibited c-Jun N-terminal kinase phosphorylation by upregulating dual-specificity phosphoprotein phosphatase-1. Additionally, taurine zinc inhibited cardiomyocyte apoptosis as there was decreased TUNEL/DAPI positivity and protein expression of caspase-3. These results indicate that taurine zinc solid dispersions prevent the side-effects of anthracycline-based anticancer therapy. The mechanisms might be associated with the enhancement of antioxidant defense system partly through activating transcription to synthesize endogenous phase II medicine enzymes and anti-apoptosis through inhibiting JNK phosphorylation. Copyright © 2015 Elsevier Inc

Engineering novel targeted nanoparticle formulations to increase the therapeutic efficacy of conventional chemotherapeutics against multiple myeloma

NASA Astrophysics Data System (ADS)

Ashley, Jonathan D.

Multiple myeloma (MM) is a hematological malignancy which results from the uncontrolled clonal expansion of plasma cells within the body. Despite recent medical advances, this disease remains largely incurable, with a median survival of ˜7 years, owing to the development of drug resistance. This dissertation will explore new advances in nanotechnology that will combine the cytotoxic effects of small molecule chemotherapeutics with the tumor targeting capabilities of nanoparticles to create novel nanoparticle formulations that exhibit enhanced therapeutic indices in the treatment of MM. First, doxorubicin was surfaced conjugated onto micellar nanoparticles via an acid labile hydrazone bond to increase the drug accumulation at the tumor. The cell surface receptor Very Late Antigen-4 (VLA-4; alpha4beta1) is expressed on cancers of hematopoietic origin and plays a vital role in the cell adhesion mediated drug resistance (CAM-DR) in MM. Therefore, VLA-4 antagonist peptides were conjugated onto the nanoparticles via a multifaceted procedure to actively target MM cells and simultaneously inhibit CAM-DR. The micellar doxorubicin nanoparticles were able to overcome CAM-DR and demonstrated improved therapeutic index relative to free doxorubicin. In addition to doxorubicin, other classes of therapeutic agents, such as proteasome inhibitors, can be incorporated in nanoparticles for improved therapeutic outcomes. Utilizing boronic acid chemistry, bortezomib prodrugs were synthesized using a reversible boronic ester bond and then incorporated into liposomes. The different boronic ester bonds that could be potentially used in the synthesis of bortezomib prodrugs were screened based on stability using isobutylboronic acid. The liposomal bortezomib nanoparticles demonstrated significant proteasome inhibition and cytotoxicity in MM cells in vitro, and dramatically reduced the non-specific toxicities associated with free bortezomib while maintaining significant tumor growth

Novel synthesizing method of pH-dependent doxorubicin-loaded anti-CD22-labelled drug delivery nanosystem.

PubMed

Sun, Mengjiao; Wang, Jun; Lu, Qin; Xia, Guohua; Zhang, Yu; Song, Lina; Fang, Yongjun

2015-01-01

The objective of this study was to investigate the anticancer efficacy of dimercaptosuccinic acid-modified iron oxide magnetic nanoparticles coloaded with anti-CD22 antibodies and doxorubicin (anti-CD22-MNPs-DOX) on non-Hodgkin's lymphoma cells. The physical properties of anti-CD22-MNPs-DOX were studied and its antitumor effect on Raji cells in vitro was evaluated using the Cell Counting Kit-8 assay. Furthermore, cell apoptosis and intracellular accumulation of doxorubicin were determined by flow cytometry. The results revealed that anti-CD22-MNPs-DOX inhibited the proliferation of Raji cells, significantly increased the uptake of doxorubicin, and induced apoptosis. Therefore, it was concluded that a coloaded antibody and chemotherapeutic drug with magnetic nanoparticles might be an efficient targeted treatment strategy for non-Hodgkin's lymphoma.

Novel synthesizing method of pH-dependent doxorubicin-loaded anti-CD22-labelled drug delivery nanosystem

PubMed Central

Sun, Mengjiao; Wang, Jun; Lu, Qin; Xia, Guohua; Zhang, Yu; Song, Lina; Fang, Yongjun

2015-01-01

The objective of this study was to investigate the anticancer efficacy of dimercaptosuccinic acid-modified iron oxide magnetic nanoparticles coloaded with anti-CD22 antibodies and doxorubicin (anti-CD22-MNPs-DOX) on non-Hodgkin’s lymphoma cells. The physical properties of anti-CD22-MNPs-DOX were studied and its antitumor effect on Raji cells in vitro was evaluated using the Cell Counting Kit-8 assay. Furthermore, cell apoptosis and intracellular accumulation of doxorubicin were determined by flow cytometry. The results revealed that anti-CD22-MNPs-DOX inhibited the proliferation of Raji cells, significantly increased the uptake of doxorubicin, and induced apoptosis. Therefore, it was concluded that a coloaded antibody and chemotherapeutic drug with magnetic nanoparticles might be an efficient targeted treatment strategy for non-Hodgkin’s lymphoma. PMID:26379425

Surface dynamics of micellar diblock copolymer films

NASA Astrophysics Data System (ADS)

Song, Sanghoon; Cha, Wonsuk; Kim, Hyunjung; Jiang, Zhang; Narayanan, Suresh

2011-03-01

We studied the structure and surface dynamics of poly(styrene)-b-poly(dimethylsiloxane) (PS-b-PDMS) diblock copolymer films with micellar PDMS surrounded by PS shells. By `in-situ' high resolution synchrotron x-ray reflectivity and diffuse scattering, we obtained exact thickness, electron density and surface tension. A segregation layer near the top surface was appeared with increasing temperature Surface dynamics were measured as a function of film thickness and temperature by x-ray photon correlation spectroscopy. The best fit to relaxation time constants as a function of in-plane wavevectors were analyzed with a theory based on capillary waves with hydrodynamics with bilayer model Finally the viscosities for the top segregated layer as well as for the bottom layer are obtained at given temperatures This work was supported by National Research Foundation of Korea (R15-2008-006-01001-0), Seoul Research and Business Development Program (10816), and Sogang University Research Grant (2010).

Gingerol Synergizes the Cytotoxic Effects of Doxorubicin against Liver Cancer Cells and Protects from Its Vascular Toxicity.

PubMed

Al-Abbasi, Fahad A; Alghamdi, Eman A; Baghdadi, Mohammed A; Alamoudi, Abdulmohsin J; El-Halawany, Ali M; El-Bassossy, Hany M; Aseeri, Ali H; Al-Abd, Ahmed M

2016-07-08

Hydroxyphenylalkanes and diarylheptanoids possess potential therapeutic value in different pathophysiological conditions, such as malignancy. In the current study, naturally isolated hydroxyphenylalkane and diarylheptanoid compounds were investigated for potential chemo-modulatory effects in addition to potential vascular protective roles with doxorubicin. Diarylheptanoids showed stronger antioxidant effects, in comparison to hydroxyphenylalkanes, as demonstrated by DPPH assay and amelioration of CCl₄-induced disturbed intracellular GSH/GSSG balance. Shogaol and 4'-methoxygingerol showed considerable cytotoxic effects against HCT116, HeLa, HepG2 and MCF7 cells, with IC50 values ranging from 3.1 to 19.4 µM. Gingerol significantly enhanced the cytotoxic profile of doxorubicin against HepG₂ and Huh7, cells decreasing its IC50s by 10- and 4-fold, respectively. Cell cycle distribution was studied using DNA cytometry. Doxorubicin alone induced cell accumulation at S-phase and G₂/M-phase, while in combination with gingerol it significantly induced cell cycle arrest at the G₂/M-phase. Additionally, the vascular protective effect of gingerol against doxorubicin (10 µM) was examined on isolated aortic rings. Co-incubation with 6-gingerol (30 µM) completely blocked the exaggerated vasoconstriction and impaired vascular relaxation induced by doxorubicin. In conclusion, despite its relatively weak antioxidant properties, gingerol protected from DOX-induced vascular damage, apparently not through a ROS scavenging mechanism. Besides, gingerol synergized the cytotoxic effects of DOX against liver cancer cells without influencing the cellular pharmacokinetics.

Early biomarkers of doxorubicin-induced heart injury in a mouse model

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

Desai, Varsha G., E-mail: varsha.desai@fda.hhs.gov; Kwekel, Joshua C.; Vijay, Vikrant

Cardiac troponins, which are used as myocardial injury markers, are released in plasma only after tissue damage has occurred. Therefore, there is a need for identification of biomarkers of earlier events in cardiac injury to limit the extent of damage. To accomplish this, expression profiling of 1179 unique microRNAs (miRNAs) was performed in a chronic cardiotoxicity mouse model developed in our laboratory. Male B6C3F{sub 1} mice were injected intravenously with 3 mg/kg doxorubicin (DOX; an anti-cancer drug), or saline once a week for 2, 3, 4, 6, and 8 weeks, resulting in cumulative DOX doses of 6, 9, 12, 18,more » and 24 mg/kg, respectively. Mice were euthanized a week after the last dose. Cardiac injury was evidenced in mice exposed to 18 mg/kg and higher cumulative DOX dose whereas examination of hearts by light microscopy revealed cardiac lesions at 24 mg/kg DOX. Also, 24 miRNAs were differentially expressed in mouse hearts, with the expression of 1, 1, 2, 8, and 21 miRNAs altered at 6, 9, 12, 18, and 24 mg/kg DOX, respectively. A pro-apoptotic miR-34a was the only miRNA that was up-regulated at all cumulative DOX doses and showed a significant dose-related response. Up-regulation of miR-34a at 6 mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice. At 12 mg/kg DOX, up-regulation of miR-34a was associated with down-regulation of hypertrophy-related miR-150; changes observed before cardiac injury. These findings may lead to the development of biomarkers of earlier events in DOX-induced cardiotoxicity that occur before the release of cardiac troponins. - Highlights: • Upregulation of miR-34a before doxorubicin-induced cardiac tissue injury • Apoptosis might be an early event in mouse heart during doxorubicin treatment. • Expression of miR-150 declined before doxorubicin-induced cardiac tissue injury.« less

Multimodal doxorubicin loaded magnetic nanoparticles for VEGF targeted theranostics of breast cancer.

PubMed

Semkina, Alevtina S; Abakumov, Maxim A; Skorikov, Alexander S; Abakumova, Tatiana O; Melnikov, Pavel A; Grinenko, Nadejda F; Cherepanov, Sergey A; Vishnevskiy, Daniil A; Naumenko, Victor A; Ionova, Klavdiya P; Majouga, Alexander G; Chekhonin, Vladimir P

2018-05-03

In presented paper we have developed new system for cancer theranostics based on vascular endothelial growth factor (VEGF) targeted magnetic nanoparticles. Conjugation of anti-VEGF antibodies with bovine serum albumin coated PEGylated magnetic nanoparticles allows for improved binding with murine breast adenocarcinoma 4T1 cell line and facilitates doxorubicin delivery to tumor cells. It was shown that intravenous injection of doxorubicin loaded VEGF targeted nanoparticles increases median survival rate of mice bearing 4T1 tumors up to 50%. On the other hand magnetic resonance imaging (MRI) of 4T1 tumors 24 h after intravenous injection showed accumulation of nanoparticles in tumors, thus allowing simultaneous cancer therapy and diagnostics. Copyright © 2018. Published by Elsevier Inc.

Hydrophobic drug-triggered self-assembly of nanoparticles from silk-elastin-like protein polymers for drug delivery.

PubMed

Xia, Xiao-Xia; Wang, Ming; Lin, Yinan; Xu, Qiaobing; Kaplan, David L

2014-03-10

Silk-elastin-like protein polymers (SELPs) combine the mechanical and biological properties of silk and elastin. These properties have led to the development of various SELP-based materials for drug delivery. However, SELPs have rarely been developed into nanoparticles, partially due to the complicated fabrication procedures, nor assessed for potential as an anticancer drug delivery system. We have recently constructed a series of SELPs (SE8Y, S2E8Y, and S4E8Y) with various ratios of silk to elastin blocks and described their capacity to form micellar-like nanoparticles upon thermal triggering. In this study, we demonstrate that doxorubicin, a hydrophobic antitumor drug, can efficiently trigger the self-assembly of SE8Y (SELPs with silk to elastin ratio of 1:8) into uniform micellar-like nanoparticles. The drug can be loaded in the SE8Y nanoparticles with an efficiency around 6.5% (65 ng doxorubicin/μg SE8Y), S2E8Y with 6%, and S4E8Y with 4%, respectively. In vitro studies with HeLa cell lines demonstrate that the protein polymers are not cytotoxic (IC50 > 200 μg/mL), while the doxorubicin-loaded SE8Y nanoparticles showed a 1.8-fold higher cytotoxicity than the free drug. Confocal laser scanning microscopy (CLSM) and flow cytometry indicate significant uptake of the SE8Y nanoparticles by the cells and suggest internalization of the nanoparticles through endocytosis. This study provides an all-aqueous, facile method to prepare nanoscale, drug-loaded SELPs packages with potential for tumor cell treatments.

Chemiluminescence from an oxidation reaction of rhodamine B with cerium(IV) in a reversed micellar medium of cetyltrimethylammonium chloride in 1-hexanol-cyclohexane/water.

PubMed

Hasanin, Tamer H A; Tsunemine, Yusuke; Tsukahara, Satoshi; Okamoto, Yasuaki; Fujiwara, Terufumi

2011-01-01

The chemiluminescence (CL) emission, observed when rhodamine B (RB) in 1-hexanol-cyclohexane was mixed with cerium(IV) sulfate in sulfuric acid dispersed in a reversed micellar medium of cetyltrimethylammonium chloride (CTAC) in 1-hexanol-cyclohexane/water, was investigated using a flow-injection system. The CL emission from the oxidation reaction of RB with Ce(IV) was found to be stronger in the CTAC reversed micellar solution compared with an aqueous solution. Bearing on the enhancement effect of the CTAC reverse micelles on the RB-Ce(IV) CL, several studies including stopped-flow, fluorescence and electron spin resonance (ESR) spectrometries were performed. Rapid spectral changes of an intermediate in the RB-Ce(IV) reaction in the aqueous and reversed micellar solutions were successfully observed using a stopped-flow method. The effect of the experimental variables, i.e., oxidant concentration, sulfuric acid concentration, the mole fraction of 1-hexanol, water-to-surfactant molar concentration ratio, flow rate, upon the CL intensity was evaluated. Under the experimental conditions optimized for a flow-injection determination of RB based on the new reversed micellar-mediated CL reaction with Ce(IV), a detection limit of 0.08 µmol dm(-3) RB was achieved, and a linear calibration graph was obtained with a dynamic range from 0.5 to 20 µmol dm(-3). The relative standard deviation (n = 6) obtained at an RB concentration of 3 µmol dm(-3) was 3%.

Development and characterization of CD22-targeted pegylated-liposomal doxorubicin (IL-PLD).

PubMed

O'Donnell, Robert T; Martin, Shiloh M; Ma, Yunpeng; Zamboni, William C; Tuscano, Joseph M

2010-06-01

Non-Hodgkin's lymphoma (NHL) is the sixth most common cause of cancer deaths in the U.S. Most NHLs initially respond well to chemotherapy, but relapse is common and treatment is often limited due to the toxicity of chemotherapeutic agents. Pegylated-liposomal doxorubicin (PLD, Ben Venue Laboratories, Inc), a produces less myelotoxicity than non-liposomal (NL) doxorubicin. To further enhance efficacy and NHL targeting and to decrease toxicity, we conjugated an anti-CD22 monoclonal antibody (HB22.7) to the surface of PLD, thereby creating CD22-targeted immunoliposomal PLD (IL-PLD). HB22.7 was successfully conjugated to PLD and the resulting IL-PLD exhibits specific binding to CD22-expressing cells as assessed by immunofluorescence staining. IL-PLD exhibits more cytotoxicity than PLD in CD22 positive cell lines but does not increase killing of CD22 negative cells. The IC(50) of IL-PLD is 3.1 to 5.4 times lower than that of PLD in CD22+ cell lines while the IC(50) of IL-PLD is equal to that of PLD in CD22- cells. Furthermore, IL-PLD remained bound to the CD22+ cells after washing and continued to exert cytotoxic effects, while PLD and NL- doxorubicin could easily be washed from these cells.

Ventricular fractional shortening in 108 dogs with malignant lymphoma undergoing chemotherapy with a cyclic combination protocol including doxorubicin.

PubMed

Tater, G; Eberle, N; Hungerbuehler, S; Joetzke, A; Nolte, I; Wess, G; Betz, D

2012-01-01

The aim of this study was to evaluate whether changes in the left ventricular fractional shortening (LVFS) can be detected in dogs with malignant lymphoma undergoing a cyclic combination chemotherapy protocol including doxorubicin. Left ventricular fractional shortening as a stand-alone measurement will not show a significant change during the cyclic combination protocol. In this retrospective study, the records of dogs with malignant lymphoma treated between April 2001 and October 2010 were reviewed. Inclusion criteria comprised: a diagnosis of malignant lymphoma, a cyclic combination chemotherapy (including L-asparaginase, vincristine, cyclophosphamide, doxorubicin and prednisolone), and an echocardiographic examination by an experienced examiner before treatment and after each doxorubicin administration. One hundred and eight dogs were included and a total of 446 LVFS measurements had been performed. Patients were divided into four groups according to the number of doxorubicin administrations. Median LVFS did not change significantly during the cyclic combination protocol in all groups. All median LVFS values remained above the lower reference value of 25%. The measurement of LVFS did not show a significant change during the cyclic combination protocol treatment including doxorubicin in this population of dogs. Therefore either this cyclic combination protocol does not cause a systolic dysfunction or LVFS is not sensitive enough to detect early changes. Newer methods that are more sensitive then LVFS might be necessary to detect such changes.

Conductivity, A Simple Method to Probe Micellar Solutions

NASA Astrophysics Data System (ADS)

Bachofer, Steven J.

1996-09-01

A conductivity experiment on the tetradecyltrimethylammonium X-benzoate surfactants and the corresponding sodium X-benzoate salts demonstrates how this physical property can be applied to the study of the complex equilibria of ionic micellar aggregates. The surfactant CMC and fractional ionization constant (alpha) values are determined from the conductivity measurements. A student class studies the surfactants, in which a number of substituted benzoate counterions are utilized, and can be introduced to Quantitative Structure-Activity Relationships (QSAR) to explain the resulting CMC values. High quality data can be recorded with ease. The data from a student class illustrate that CMC values are sensitive to the hydrophobicity of the X-benzoate anion. However, hydrophobicity is not the only important parameter to be considered. The student class can propose other important factors with some additional reading of the colloidal literature.

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model.

PubMed

MacDiarmid, Jennifer A; Langova, Veronika; Bailey, Dale; Pattison, Scott T; Pattison, Stacey L; Christensen, Neil; Armstrong, Luke R; Brahmbhatt, Vatsala N; Smolarczyk, Katarzyna; Harrison, Matthew T; Costa, Marylia; Mugridge, Nancy B; Sedliarou, Ilya; Grimes, Nicholas A; Kiss, Debra L; Stillman, Bruce; Hann, Christine L; Gallia, Gary L; Graham, Robert M; Brahmbhatt, Himanshu

2016-01-01

Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

PubMed Central

MacDiarmid, Jennifer A.; Langova, Veronika; Bailey, Dale; Pattison, Scott T.; Pattison, Stacey L.; Christensen, Neil; Armstrong, Luke R.; Brahmbhatt, Vatsala N.; Smolarczyk, Katarzyna; Harrison, Matthew T.; Costa, Marylia; Mugridge, Nancy B.; Sedliarou, Ilya; Grimes, Nicholas A.; Kiss, Debra L.; Stillman, Bruce; Hann, Christine L.; Gallia, Gary L.; Graham, Robert M.; Brahmbhatt, Himanshu

2016-01-01

Background Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. Methodology/Principle Findings EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). Conclusions/Significance Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On

RITA enhances chemosensivity of pre-B ALL cells to doxorubicin by inducing p53-dependent apoptosis.

PubMed

Kazemi, Ahmad; Safa, Majid; Shahbazi, Atefeh

2011-07-01

The use of low-molecular-weight, non-peptidic molecules that disrupt the interaction between the p53 tumor suppressor and its negative regulator MDM2 has provided a promising alternative for the treatment of different types of cancer. Here, we used small-molecule reactivation of p53 and induction of tumor cell apoptosis (RITA) to sensitize leukemic NALM-6 cells to doxorubicin by upregulating p53 protein. RITA alone effectively inhibited NALM-6 cells viability in dose-dependent manner as measured by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay and induced apoptosis as evaluated by flow cytometry, whereas RITA in combination with doxorubicin enhanced NALM-6 cells to doxorubicin-sensitivity and promoted doxorubicin induced apoptosis. Levels of p53 protein and its proapoptotic target genes, quantified by western blot and real-time PCR respectively, showed that expression of p53 was significantly increased after RITA treatment. Using p53 inhibitors PFT-alpha and PFT-mu it was shown that p53-mediated apoptosis induced by RITA can be regulated by both p53-transcription-dependent and -independent pathways. Moreover, RITA-induced apoptosis was accompanied by the activation of caspase-3 and PARP cleavage. Therefore, exploiting synergistic effects between RITA and chemotherapeutics might be an effective clinical strategy for leukemia chemotherapy.

Polymeric microspheres

DOEpatents

Walt, David R.; Mandal, Tarun K.; Fleming, Michael S.

2004-04-13

The invention features core-shell microsphere compositions, hollow polymeric microspheres, and methods for making the microspheres. The microspheres are characterized as having a polymeric shell with consistent shell thickness.

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.

Recovery of intrinsic fluorescence from single-point interstitial measurements for quantification of doxorubicin concentration.

PubMed

Baran, Timothy M; Foster, Thomas H

2013-10-01

We developed a method for the recovery of intrinsic fluorescence from single-point measurements in highly scattering and absorbing samples without a priori knowledge of the sample optical properties. The goal of the study was to demonstrate accurate recovery of fluorophore concentration in samples with widely varying background optical properties, while simultaneously recovering the optical properties. Tissue-simulating phantoms containing doxorubicin, MnTPPS, and Intralipid-20% were created, and fluorescence measurements were performed using a single isotropic probe. The resulting spectra were analyzed using a forward-adjoint fluorescence model in order to recover the fluorophore concentration and background optical properties. We demonstrated recovery of doxorubicin concentration with a mean error of 11.8%. The concentration of the background absorber was recovered with an average error of 23.2% and the scattering spectrum was recovered with a mean error of 19.8%. This method will allow for the determination of local concentrations of fluorescent drugs, such as doxorubicin, from minimally invasive fluorescence measurements. This is particularly interesting in the context of transarterial chemoembolization (TACE) treatment of liver cancer. © 2013 Wiley Periodicals, Inc.

A facile doxorubicin-dichloroacetate conjugate nanomedicine with high drug loading for safe drug delivery.

PubMed

Yang, Conglian; Wu, Tingting; Qin, Yuting; Qi, Yan; Sun, Yu; Kong, Miao; Jiang, Xue; Qin, Xianya; Shen, Yaqi; Zhang, Zhiping

2018-01-01

Doxorubicin (DOX) is an effective chemotherapeutic agent but severe side effects limit its clinical application. Nanoformulations can reduce the toxicity while still have various limitations, such as complexity, low drug loading capability and excipient related concerns. An amphiphilic conjugate, doxorubicin-dichloroacetate, was synthesized and the corresponding nanoparticles were prepared. The in vitro cytotoxicity and intracellular uptake, in vivo imaging, antitumor effects and systemic toxicities of nanoparticles were carried out to evaluate the therapeutic efficiency of tumor. Doxorubicin-dichloroacetate conjugate can self-assemble into nanoparticles with small amount of DSPE-PEG 2000 , leading to high drug loading (71.8%, w/w) and diminished excipient associated concerns. The nanoparticles exhibited invisible systemic toxicity and high maximum tolerated dose of 75 mg DOX equiv./kg, which was 15-fold higher than that of free DOX. It also showed good tumor targeting capability and enhanced antitumor efficacy in murine melanoma model. This work provides a promising strategy to simplify the drug preparation process, increase drug loading content, reduce systemic toxicity as well as enhance antitumor efficiency.

Comparative cytotoxicity of gold-doxorubicin and InP-doxorubicin conjugates.

PubMed

Zhang, Xuan; Chibli, Hicham; Kong, Dekun; Nadeau, Jay

2012-07-11

Direct comparisons of different types of nanoparticles for drug delivery have seldom been performed. In this study we compare the physical properties and cellular activity of doxorubicin (Dox) conjugates to gold nanoparticles (Au) and InP quantum dots of comparable diameter. Although the Au particles alone are non-toxic and InP is moderately toxic, Au-Dox is more effective than InP-Dox against the Dox-resistant B16 melanoma cell line. Light exposure does not augment the efficacy of InP-Dox, suggesting that conjugates are breaking down. Electron and confocal microscopy and atomic absorption spectroscopy reveal that over 60% of the Au-Dox conjugates reach the cell nucleus. In contrast, InP-Dox enters cell nuclei to a very limited extent, although liberated Dox from the conjugates does eventually reach the nucleus. These observations are attributed to faster Dox release from Au conjugates under endosomal conditions, greater aggregation of InP-Dox with cytoplasmic proteins, and adherence of InP to membranes. These findings have important implications for design of active drug-nanoparticle conjugates.

Integration of CuAAC Polymerization and Controlled Radical Polymerization into Electron Transfer Mediated "Click-Radical" Concurrent Polymerization.

PubMed

Xue, Wentao; Wang, Jie; Wen, Ming; Chen, Gaojian; Zhang, Weidong

2017-03-01

The successful chain-growth copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) polymerization employing Cu(0)/pentamethyldiethylenetriamine (PMDETA) and alkyl halide as catalyst is first investigated by a combination of nuclear magnetic resonance, gel-permeation chromatography, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In addition, the electron transfer mediated "click-radical" concurrent polymerization utilizing Cu(0)/PMDETA as catalyst is successfully employed to generate well-defined copolymers, where controlled CuAAC polymerization of clickable ester monomer is progressed in the main chain acting as the polymer backbone, the controlled radical polymerization (CRP) of acrylic monomer is carried out in the side chain. Furthermore, it is found that there is strong collaborative effect and compatibility between CRP and CuAAC polymerization to improve the controllability. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

TVP1022 and propargylamine protect neonatal rat ventricular myocytes against doxorubicin-induced and serum starvation-induced cardiotoxicity.

PubMed

Kleiner, Yana; Bar-Am, Orit; Amit, Tamar; Berdichevski, Alexandra; Liani, Esti; Maor, Gila; Reiter, Irina; Youdim, Moussa B H; Binah, Ofer

2008-09-01

We recently reported that propargylamine derivatives such as rasagiline (Azilect) and its S-isomer TVP1022 are neuroprotective. The aim of this study was to test the hypothesis that the neuroprotective agents TVP1022 and propargylamine (the active moiety of propargylamine derivatives) are also cardioprotective. We specifically investigated the protective efficacy of TVP1022 and propargylamine in neonatal rat ventricular myocytes (NRVM) against apoptosis induced by the anthracycline chemotherapeutic agent doxorubicin and by serum starvation. We demonstrated that pretreatment of NRVM cultures with TVP1022 or propargylamine attenuated doxorubicin-induced and serum starvation-induced apoptosis, inhibited the increase in cleaved caspase 3 levels, and reversed the decline in Bcl-2/Bax ratio. These cytoprotective effects were shown to reside in the propargylamine moiety. Finally, we showed that TVP1022 neither caused proliferation of the human cancer cell lines HeLa and MDA-231 nor interfered with the anti-cancer efficacy of doxorubicin. These results suggest that TVP1022 should be considered as a novel cardioprotective agent against ischemic insults and against anthracycline cardiotoxicity and can be coadministered with doxorubicin in the treatment of human malignancies.

Omission of doxorubicin from the treatment of stage II-III, intermediate-risk Wilms' tumour (SIOP WT 2001): an open-label, non-inferiority, randomised controlled trial.

PubMed

Pritchard-Jones, Kathy; Bergeron, Christophe; de Camargo, Beatriz; van den Heuvel-Eibrink, Marry M; Acha, Tomas; Godzinski, Jan; Oldenburger, Foppe; Boccon-Gibod, Liliane; Leuschner, Ivo; Vujanic, Gordan; Sandstedt, Bengt; de Kraker, Jan; van Tinteren, Harm; Graf, Norbert

2015-09-19

Before this study started, the standard postoperative chemotherapy regimen for stage II-III Wilms' tumour pretreated with chemotherapy was to include doxorubicin. However, avoidance of doxorubicin-related cardiotoxicity effects is important to improve long-term outcomes for childhood cancers that have excellent prognosis. We aimed to assess whether doxorubicin can be omitted safely from chemotherapy for stage II-III, histological intermediate-risk Wilms' tumour when a newly defined high-risk blastemal subtype was excluded from randomisation. For this international, multicentre, open-label, non-inferiority, phase 3, randomised SIOP WT 2001 trial, we recruited children aged 6 months to 18 years at the time of diagnosis of a primary renal tumour from 251 hospitals in 26 countries who had received 4 weeks of preoperative chemotherapy with vincristine and actinomycin D. Children with stage II-III intermediate-risk Wilms' tumours assessed after delayed nephrectomy were randomly assigned (1:1) by a minimisation technique to receive vincristine 1·5 mg/m(2) at weeks 1-8, 11, 12, 14, 15, 17, 18, 20, 21, 23, 24, 26, and 27, plus actinomycin D 45 μg/kg every 3 weeks from week 2, either with five doses of doxorubicin 50 mg/m(2) given every 6 weeks from week 2 (standard treatment) or without doxorubicin (experimental treatment). The primary endpoint was non-inferiority of event-free survival at 2 years, analysed by intention to treat and a margin of 10%. Assessment of safety and adverse events included systematic monitoring of hepatic toxicity and cardiotoxicity. This trial is registered with EudraCT, number 2007-004591-39, and is closed to new participants. Between Nov 1, 2001, and Dec 16, 2009, we recruited 583 patients, 341 with stage II and 242 with stage III tumours, and randomly assigned 291 children to treatment including doxorubicin, and 292 children to treatment excluding doxorubicin. Median follow-up was 60·8 months (IQR 40·8-79·8). 2 year event-free survival was

Acridine Orange Conjugated Polymersomes for Simultaneous Nuclear Delivery of Gemcitabine and Doxorubicin to Pancreatic Cancer Cells.

PubMed

Anajafi, Tayebeh; Scott, Michael D; You, Seungyong; Yang, Xiaoyu; Choi, Yongki; Qian, Steven Y; Mallik, Sanku

2016-03-16

Considering the systemic toxicity of chemotherapeutic agents, there is an urgent need to develop new targeted drug delivery systems. Herein, we have developed a new nuclear targeted, redox sensitive, drug delivery vehicle to simultaneously deliver the anticancer drugs gemcitabine and doxorubicin to the nuclei of pancreatic cancer cells. We prepared polymeric bilayer vesicles (polymersomes), and actively encapsulated the drug combination by the pH gradient method. A redox-sensitive polymer (PEG-S-S-PLA) was incorporated to sensitize the formulation to reducing agent concentration. Acridine orange (AO) was conjugated to the surface of the polymersomes imparting nuclear localizing property. The polymersomes' toxicity and efficacy were compared with those of a free drug combination using monolayer and three-dimensional spheroid cultures of pancreatic cancer cells. We observed that the redox sensitive, nuclear-targeted polymersomes released more than 60% of their encapsulated contents in response to 50 mM glutathione. The nanoparticles are nontoxic; however, the drug encapsulated vesicles have significant toxicity. The prepared formulation can increase the drug's therapeutic index by delivering the drugs directly to the cells' nuclei, one of the key organelles in the cells. This study is likely to initiate research in targeted nuclear delivery using other drug formulations in other types of cancers.

Polymerization Reactor Engineering.

ERIC Educational Resources Information Center

Skaates, J. Michael

1987-01-01

Describes a polymerization reactor engineering course offered at Michigan Technological University which focuses on the design and operation of industrial polymerization reactors to achieve a desired degree of polymerization and molecular weight distribution. Provides a list of the course topics and assigned readings. (TW)

Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98.

PubMed

Loi, Sherene; Sirtaine, Nicolas; Piette, Fanny; Salgado, Roberto; Viale, Giuseppe; Van Eenoo, Françoise; Rouas, Ghizlane; Francis, Prudence; Crown, John P A; Hitre, Erika; de Azambuja, Evandro; Quinaux, Emmanuel; Di Leo, Angelo; Michiels, Stefan; Piccart, Martine J; Sotiriou, Christos

2013-03-01

Previous preclinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy (CT); however, clinical relevance has yet to be established in breast cancer (BC). We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case, anthracycline-only CT-in selected BC subtypes. We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC samples from the BIG 02-98 adjuvant phase III trial comparing anthracycline-only CT (doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil [CMF] or doxorubicin plus cyclophosphamide followed by CMF) versus CT combining doxorubicin and docetaxel (doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF). Readings were independently performed by two pathologists. Disease-free survival (DFS), overall survival (OS), and interaction with type of CT associations were studied. Median follow-up was 8 years. There was no significant prognostic association in the global nor estrogen receptor (ER) -positive/human epidermal growth factor receptor 2 (HER2) -negative population. However, each 10% increase in intratumoral and stromal lymphocytic infiltrations was associated with 17% and 15% reduced risk of relapse (adjusted P = .1 and P = .025), respectively, and 27% and 17% reduced risk of death in ER-negative/HER2-negative BC regardless of CT type (adjusted P = .035 and P = .023), respectively. In HER2-positive BC, there was a significant interaction between increasing stromal lymphocytic infiltration (10% increments) and benefit with anthracycline-only CT (DFS, interaction P = .042; OS, P = .018). In node-positive, ER-negative/HER2-negative BC, increasing lymphocytic infiltration was associated with excellent prognosis. Further validation of the clinical utility of tumor

An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice.

PubMed

Montgomery, Megan D; Chan, Trevor; Swigart, Philip M; Myagmar, Bat-Erdene; Dash, Rajesh; Simpson, Paul C

2017-01-01

Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35-40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies.

The effects of doxorubicin (adriamycin) on spinal fusion: an experimental model of posterolateral lumbar spinal arthrodesis.

PubMed

Tortolani, P Justin; Park, Andrew E; Louis-Ugbo, John; Attallah-Wasef, Emad S; Kraiwattanapong, Chaiwat; Heller, John G; Boden, Scott D; Yoon, S Tim

2004-01-01

Malignant spinal lesions may require surgical excision and segmental stabilization. The decision to perform a concomitant fusion procedure is influenced in part by the need for adjunctive chemotherapy as well as the patient's anticipated survival. Although some evidence exists that suggests that chemotherapy may inhibit bony healing, no information exists regarding the effect of chemotherapy on spinal fusion healing. To determine the effect of a frequently used chemotherapeutic agent, doxorubicin, on posterolateral spinal fusion rates. Prospective animal model of posterolateral lumbar fusion. Determination of spinal fusion by manual palpation of excised spines. Plain radiographic evaluation of denuded spines to evaluate intertransverse bone formation. Thirty-two New Zealand White rabbits underwent posterior intertransverse process fusion at L5-L6 with the use of iliac autograft bone. Rabbits randomly received either intravenous doxorubicin (2.5 mg/kg) by means of the central vein of the ear at the time of surgery (16 animals) or no treatment (16 animals; the control group). The animals were euthanized at 5 weeks, and the lumbar spines were excised. Spine fusion was assessed by manually palpating (by observers blinded to the treatment group) at the level of arthrodesis, and at the adjacent levels proximal and distal. This provided similar information to surgical fusion assessment by palpation in humans. Fusion was defined as the absence of palpable motion. Posteroanterior radiographs of the excised spines were graded in a blinded fashion using a five-point scoring system (0 to 4) devised to describe the amount of bone observed between the L5-L6 transverse processes. Power analysis conducted before initiation of the study indicated that an allocation of 16 animals to each group would permit detection of at least a 20% difference in fusion rates with statistical significance at p=.05. Eleven of the 16 spines (69%) in the control group and 6 of the 16 spines (38%) in

The Oral Bioavailability of Trans-Resveratrol from a Grapevine-Shoot Extract in Healthy Humans is Significantly Increased by Micellar Solubilization.

PubMed

Calvo-Castro, Laura A; Schiborr, Christina; David, Franziska; Ehrt, Heidi; Voggel, Jenny; Sus, Nadine; Behnam, Dariush; Bosy-Westphal, Anja; Frank, Jan

2018-05-01

Grapevine-shoot extract Vineatrol30 contains abundant resveratrol monomers and oligomers with health-promoting potential. However, the oral bioavailability of these compounds in humans is low (˂1-2%). The aim of this study was to improve the oral bioavailability of resveratrol from vineatrol by micellar solubilization. Twelve healthy volunteers (six women, six men) randomly ingested a single dose of 500 mg vineatrol (30 mg trans-resveratrol, 75 mg trans-ε-viniferin) as native powder or liquid micelles. Plasma and urine were collected at baseline and over 24 h after intake. Resveratrol and viniferin were analyzed by HPLC. The area under the plasma concentration-time curve (AUC) and mean maximum plasma trans-resveratrol concentrations were 5.0-fold and 10.6-fold higher, respectively, after micellar supplementation relative to the native powder. However, no detectable amounts of trans-ε-viniferin were found in either plasma or urine. The transepithelial permeability of trans-resveratrol and trans-ε-viniferin across differentiated Caco-2 monolayers was consistent to the absorbed fractions in vivo. The oral bioavailability of trans-resveratrol from the grapevine-shoot extract Vineatrol30 was significantly increased using a liquid micellar formulation, without any treatment-related adverse effects, making it a suitable system for improved supplementation of trans-resveratrol. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optimisation of resolution in micellar electrokinetic chromatography by multivariate evaluation of electrolytes.

PubMed

Mikaeli, S; Thorsén, G; Karlberg, B

2001-01-12

A novel approach to multivariate evaluation of separation electrolytes for micellar electrokinetic chromatography is presented. An initial screening of the experimental parameters is performed using a Plackett-Burman design. Significant parameters are further evaluated using full factorial designs. The total resolution of the separation is calculated and used as response. The proposed scheme has been applied to the optimisation of the separation of phenols and the chiral separation of (+)-1-(9-anthryl)-2-propyl chloroformate-derivatized amino acids. A total of eight experimental parameters were evaluated and optimal conditions found in less than 48 experiments.

Improved Micellar Formulation for Enhanced Delivery for Paclitaxel.

PubMed

Xu, Jieni; Zhang, Xiaolan; Chen, Yichao; Huang, Yixian; Wang, Pengcheng; Wei, Yuan; Ma, Xiaochao; Li, Song

2017-01-03

We have previously improved the bioactivity of PEG 5k -FTS 2 system by incorporating disulfide bond (PEG 5k -S-S-FTS 2 ) to facilitate the release of farnesyl thiosalicylic acid (FTS).1 Later, fluorenylmethyloxycarbonyl (Fmoc) moiety has been introduced to PEG 5k -FTS 2 system (PEG 5k -Fmoc-FTS 2 ) in order to enhance drug loading capacity (DLC) and formulation stability.2 In this study, we have brought in both disulfide linkage and Fmoc group to PEG 5k -FTS 2 to form a simple PEG 5k -Fmoc-S-S-FTS 2 micellar system. PEG 5k -Fmoc-S-S-FTS 2 conjugate formed filamentous micelles with a ∼10-fold decrease in critical micellar concentration (CMC). Compared with PEG 5k -Fmoc-FTS 2 , our novel system exhibited further strengthened DLC and colloidal stability. More FTS was freed from PEG 5k -Fmoc-S-S-FTS 2 in treated tumor cells compared to PEG 5k -Fmoc-FTS 2 , which was correlated to an increased cytotoxicity of our new carrier in these cancer cells. After loading Paclitaxel (PTX) into PEG 5k -Fmoc-S-S-FTS 2 micelles, it showed more potent efficiency in inhibition of tumor cell proliferation than Taxol and PTX-loaded PEG 5k -Fmoc-FTS 2 . PTX release kinetics of PTX/PEG 5k -Fmoc-S-S-FTS 2 was much slower than that of Taxol and PTX/PEG 5k -Fmoc-FTS 2 in normal release medium. In contrast, in glutathione (GSH)-containing medium, PTX in PEG 5k -Fmoc-S-S-FTS 2 micelles revealed faster and more complete release. Pharmacokinetics and tissue distribution study showed that our PEG 5k -Fmoc-S-S-FTS 2 system maintained PTX in circulation for a longer time and delivered more PTX to tumor sites with less accumulation in major organs. Finally, PTX-loaded PEG 5k -Fmoc-S-S-FTS 2 micelles resulted in a superior therapeutic effect in vivo compared to Taxol and PTX formulated in PEG 5k -Fmoc-FTS 2 micelles.

Development of a Singlet Oxygen Absorption Capacity (SOAC) Assay Method. Measurements of the SOAC Values for Carotenoids and α-Tocopherol in an Aqueous Triton X-100 Micellar Solution.

PubMed

Mukai, Kazuo; Ouchi, Aya; Azuma, Nagao; Takahashi, Shingo; Aizawa, Koichi; Nagaoka, Shin-Ichi

2017-02-01

Recently, a new assay method for the quantification of the singlet oxygen absorption capacity (SOAC) of antioxidants (AOs) and food extracts in homogeneous organic solvents was proposed. In this study, second-order rate constants (k Q ) for the reaction of singlet oxygen ( 1 O 2 ) with eight different carotenoids (Cars) and α-tocopherol (α-Toc) were measured in an aqueous Triton X-100 (5.0 wt %) micellar solution (pH 7.4, 35 °C), which was used as a simple model of biomembranes. The k Q and relative SOAC values were measured using ultraviolet-visible (UV-vis) spectroscopy. The UV-vis absorption spectra of Cars and α-Toc were measured in both a micellar solution and chloroform, to investigate the effect of solvent on the k Q and SOAC values. Furthermore, decay rates (k d ) of 1 O 2 were measured in 0.0, 1.0, 3.0, and 5.0 wt % micellar solutions (pH 7.4), using time-resolved near-infrared fluorescence spectroscopy, to determine the absolute k Q values of the AOs. The results obtained demonstrate that the k Q values of AOs in homogeneous and heterogeneous solutions vary notably depending on (i) the polarity [dielectric constant (ε)] of the reaction field between AOs and 1 O 2 , (ii) the local concentration of AOs, and (iii) the mobility of AOs in solution. In addition, the k Q and relative SOAC values obtained for the Cars in a heterogeneous micellar solution differ remarkably from those in homogeneous organic solvents. Measurements of k Q and SOAC values in a micellar solution may be useful for evaluating the 1 O 2 quenching activity of AOs in biological systems.

Effects of anti-cancer drug doxorubicin on endogenous biomarkers NAD(P)H, FAD and Trp in prostate cancer cells: a FLIM Study

NASA Astrophysics Data System (ADS)

Rehman Alam, Shagufta; Wallrabe, Horst; Svindrych, Zdenek; Christopher, Kathryn G.; Chandra, Dhyan; Periasamy, Ammasi

2017-02-01

Fluorescence Lifetime Imaging Microscopy (FLIM) can be used to identify changes in metabolic activity during cancer progression and upon anti-cancer drug treatment. Prostate cancer (PCa) is one of the leading cancers in men in the USA. This research focusses on understanding the lifetime changes of endogenous biomarkers: NAD(P)H, FAD and Trp in LNCaP cells upon treatment with doxorubicin using our 3-channel FLIM approach. The LNCaP cells were treated with doxorubicin for 24hr. Images using FLIM of LNCaP control and treated cells were acquired on Zeiss 780 multiphoton confocal microscope coupled with B and H TCSPC FLIM board. After FLIM data fitting and processing we observed increase in the mean fluorescence lifetime of Trp, NAD(P)H and FAD with doxorubicin treatment. Additionally, we saw reduction in the NAD(P)H/FAD redox ratio with doxorubicin treatment. Our results identify the changes in the lifetime of these endogenous biomarkers and in the cellular redox state as a metabolic response with doxorubicin treatment in prostate cancer cells.

Zoledronic acid enhances antitumor efficacy of liposomal doxorubicin.

PubMed

Hattori, Yoshiyuki; Shibuya, Kazuhiko; Kojima, Kaori; Miatmoko, Andang; Kawano, Kumi; Ozaki, Kei-Ichi; Yonemochi, Etsuo

2015-07-01

Previously, we found that the injection of zoledronic acid (ZOL) into mice bearing tumor induced changes of the vascular structure in the tumor. In this study, we examined whether ZOL treatment could decrease interstitial fluid pressure (IFP) via change of tumor vasculature, and enhance the antitumor efficacy of liposomal doxorubicin (Doxil®). When ZOL solution was injected at 40 µg/mouse per day for three consecutive days into mice bearing murine Lewis lung carcinoma LLC tumor, depletion of macrophages in tumor tissue and decreased density of tumor vasculature were observed. Furthermore, ZOL treatments induced inflammatory cytokines such as interleukin (IL)-10 and -12, granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF)-α in serum of LLC tumor-bearing mice, but not in normal mice, indicating that ZOL treatments might induce an inflammatory response in tumor tissue. Furthermore, ZOL treatments increased antitumor activity by Doxil in mice bearing a subcutaneous LLC tumor, although they did not significantly increase the tumor accumulation of doxorubicin (DXR). These results suggest that ZOL treatments might increase the therapeutic efficacy of Doxil via improvement of DXR distribution in a tumor by changing the tumor vasculature. ZOL treatment can be an alternative approach to increase the antitumor effect of liposomal drugs.

Self-organization of dendritic supermolecules, based on isocyanide-gold(I), -copper(I), -palladium(II), and -platinum(II) complexes, into micellar cubic mesophases.

PubMed

Coco, Silverio; Cordovilla, Carlos; Donnio, Bertrand; Espinet, Pablo; García-Casas, María Jesús; Guillon, Daniel

2008-01-01

First- and second-generation dendrimers with an isocyanide group as the focal functional point (CN-G(n); n: 1,2) and their corresponding organometallic complexes [MCl(CN-G(n))] (M: Au, Cu), [{CuCl(CN-G(n))2}2], and trans-[MI2(CN-G(n))2] (M: Pd, Pt) have been synthesized. The free ligands and the first-generation complexes do not show mesogenic behavior, but all of the second-generation complexes display a thermotropic micellar cubic mesophase, over a large temperature range, and some of them directly at room temperature. The structure of the mesophase consists of the packing of two, discrete polyhedral micellar aggregates in a three-dimensional cubic Im$\\bar 3$m lattice.

Suitable combination of promoter and micellar catalyst for kilo fold rate acceleration on benzaldehyde to benzoic acid conversion in aqueous media at room temperature: a kinetic approach.

PubMed

Ghosh, Aniruddha; Saha, Rumpa; Ghosh, Sumanta K; Mukherjee, Kakali; Saha, Bidyut

2013-05-15

The kinetics of oxidation of benzaldehyde by chromic acid in aqueous and aqueous surfactant (sodium dodecyl sulfate, SDS, alkyl phenyl polyethylene glycol, Triton X-100 and N-cetylpyridinium chloride, CPC) media have been investigated in the presence of promoter at 303 K. The pseudo-first-order rate constants (kobs) were determined from a logarithmic plot of absorbance as a function time. The rate constants were found to increase with introduction of heteroaromatic nitrogen base promoters such as Picolinic acid (PA), 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen). The product benzoic acid has been characterized by conventional melting point experiment, NMR, HRMS and FTIR spectral analysis. The mechanism of both unpromoted and promoted reaction path has been proposed for the reaction. In presence of the anionic surfactant SDS, cationic surfactant CPC and neutral surfactant TX-100 the reaction can undergo simultaneously in both aqueous and micellar phase with an enhanced rate of oxidation in the micellar phase. Both SDS and TX-100 produce normal micellar effect whereas CPC produce reverse micellar effect in the presence of benzaldehyde. The observed net enhancement of rate effects has been explained by considering the hydrophobic and electrostatic interaction between the surfactants and reactants. SDS and bipy combination is the suitable one for benzaldehyde oxidation. Copyright © 2013 Elsevier B.V. All rights reserved.

Hybrid ZnPc@TiO2 nanostructures for targeted photodynamic therapy, bioimaging and doxorubicin delivery.

PubMed

Flak, Dorota; Yate, Luis; Nowaczyk, Grzegorz; Jurga, Stefan

2017-09-01

In this study ZnPc@TiO 2 hybrid nanostructures, both nanoparticles and nanotubes, as potential photosensitizers for the photodynamic therapy, fluorescent bioimaging agents, as well as anti-cancer drug nanocarriers, were prepared via zinc phthalocyanine (ZnPc) deposition on TiO 2 . In order to provide the selectivity of prepared hybrid nanostructures towards cancer cells they were modified with folic acid molecules (FA). The efficient attachment of both ZnPc and FA molecules was confirmed with dynamic light scattering (DLS), zeta potential measurements and X-ray photoelectron spectroscopy (XPS). It was presented that ZnPc and FA attachment has a strong effect on fluorescence emission properties of TiO 2 nanostructures, which can be further used for their simultaneous visualization upon cellular uptake. ZnPc@TiO 2 and FA/ZnPc@TiO 2 hybrid nanotubes were then employed as doxorubicin nanocarriers. It was demonstrated that doxorubicin can be easily loaded on these hybrid nanostructures via an electrostatic interaction and then released. In vitro cytotoxicity and photo-cytotoxic activity studies showed that prepared hybrid nanostructures were selectively targeting to cancer cells. Doxorubicin loaded hybrid nanostructures were significantly more cytotoxic than un-loaded ones and their cytotoxic effect was even more severe upon irradiation. The cellular uptake of prepared hybrid nanostructures and their localization in cells was monitored in vitro in 2D cell culture and tumor-like 3D multicellular culture environment with fluorescent confocal microscopy. These hybrid nanostructures preferentially penetrated into human cervical cancer cells (HeLa) than into normal fibroblasts (MSU-1.1) and were mainly localized within the cell cytoplasm. HeLa cells spheroids were also efficiently labelled by prepared hybrid nanostructures. Fluorescent imaging of Hela cells treated with doxorubicin loaded hybrid nanostructures showed that doxorubicin was effectively delivered into cells

Acute treatment with doxorubicin induced neurochemical impairment of the function of dopamine system in rat brain structures.

PubMed

Antkiewicz-Michaluk, Lucyna; Krzemieniecki, Krzysztof; Romanska, Irena; Michaluk, Jerzy; Krygowska-Wajs, Anna

2016-06-01

The clinical studies have shown that chemotherapy may impair cognitive functions especially in the patients treated for breast cancer. It should be mention that only few studies have made use of animals to investigate the effects of chemotherapy on the brain function. Doxorubicin (Adriamycin) is an anthracycline antibiotic commonly used for chemotherapy of breast cancer. This study examined the effect of doxorubicin (1.5 and 3.0mg/kg ip) after acute administration on the levels of dopamine, noradrenaline, serotonin and their metabolites in the rat brain structures connected with cognition and psychiatric disorders. The data indicate that doxorubicin produced a significant and specific for the dopamine system inhibition of its activity in the investigated structures connected with the fall of dopamine concentration (decrease from 25 to 30% in the frontal cortex; from 30 to 60% in the hippocampus and about 20% of the control in the striatum, p<0.05) and its extraneuronal metabolite, 3-MT (from 35% in the frontal cortex to 60% in the hippocampus of the control level, p<0.01). However, doxorubicin did not affect others monoaminergic transmitters in the brain: noradrenaline and serotonin. Summing up, these data indicate that a single injection of doxorubicin produced a clear and significant inhibition of dopamine system activity in all investigated structures with the strongest effect in the hippocampus what may lead to the disturbances of the cognitive functions at the patients treated for cancer. Moreover, such treatment did not significantly affect others monoaminergic transmitters such as noradrenaline and serotonin. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation.

PubMed

VanKlompenberg, Monica K; Leyden, Emily; Arnason, Anne H; Zhang, Jian-Ting; Stefanski, Casey D; Prosperi, Jenifer R

2017-11-28

Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT; Apc Min/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT; Apc Min/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT; Apc Min/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.

CARDIOSELECTIVE AND CUMULATIVE OXIDATION OF MITOCHONDRIAL DNA FOLLOWING SUBCHRONIC DOXORUBICIN ADMINISTRATION

EPA Science Inventory

We recently reported the preferential accumulation of 8-hydroxydeoxyguanosine (80HdG) adducts in cardiac mitrochondrial DNA (mDNA) following acute intoxication of rats with doxorubicin. The concentration of 80HdG adducts decreased to control values within 2 weeks. Since conventio...

FL3, a Synthetic Flavagline and Ligand of Prohibitins, Protects Cardiomyocytes via STAT3 from Doxorubicin Toxicity

PubMed Central

Gasser, Adeline; Basmadjian, Christine; Zhao, Qian; Wilmet, Jean-Philippe; Désaubry, Laurent; Nebigil, Canan G.

2015-01-01

Aims The clinical use of doxorubicin for the treatment of cancer is limited by its cardiotoxicity. Flavaglines are natural products that have both potent anticancer and cardioprotective properties. A synthetic analog of flavaglines, FL3, efficiently protects mice from the cardiotoxicity of doxorubicin. The mechanism underlying this cardioprotective effect has yet to be elucidated. Methods and Results Here, we show that FL3 binds to the scaffold proteins prohibitins (PHBs) and thus promotes their translocation to mitochondria in the H9c2 cardiomyocytes. FL3 induces heterodimerization of PHB1 with STAT3, thereby ensuring cardioprotection from doxorubicin toxicity. This interaction is associated with phosphorylation of STAT3. A JAK2 inhibitor, WP1066, suppresses both the phosphorylation of STAT3 and the protective effect of FL3 in cardiomyocytes. The involvement of PHBs in the FL3-mediated cardioprotection was confirmed by means of small interfering RNAs (siRNAs) targeting PHB1 and PHB2. The siRNA knockdown of PHBs inhibits both phosphorylation of STAT3 and the cardioprotective effect of FL3. Conclusion Activation of mitochondrial STAT3/PHB1 complex by PHB ligands may be a new strategy against doxorubicin-induced cardiotoxicity and possibly other cardiac problems. PMID:26536361

Pegylated liposomal formulation of doxorubicin overcomes drug resistance in a genetically engineered mouse model of breast cancer.

PubMed

Füredi, András; Szebényi, Kornélia; Tóth, Szilárd; Cserepes, Mihály; Hámori, Lilla; Nagy, Veronika; Karai, Edina; Vajdovich, Péter; Imre, Tímea; Szabó, Pál; Szüts, Dávid; Tóvári, József; Szakács, Gergely

2017-09-10

Success of cancer treatment is often hampered by the emergence of multidrug resistance (MDR) mediated by P-glycoprotein (ABCB1/Pgp). Doxorubicin (DOX) is recognized by Pgp and therefore it can induce therapy resistance in breast cancer patients. In this study our aim was to evaluate the susceptibility of the pegylated liposomal formulation of doxorubicin (PLD/Doxil®/Caelyx®) to MDR. We show that cells selected to be resistant to DOX are cross-resistant to PLD and PLD is also ineffective in an allograft model of doxorubicin-resistant mouse B-cell leukemia. In contrast, PLD was far more efficient than DOX as reflected by a significant increase of both relapse-free and overall survival of Brca1 -/- ;p53 -/- mammary tumor bearing mice. Increased survival could be explained by the delayed onset of drug resistance. Consistent with the higher Pgp levels needed to confer resistance, PLD administration was able to overcome doxorubicin insensitivity of the mouse mammary tumors. Our results indicate that the favorable pharmacokinetics achieved with PLD can effectively overcome Pgp-mediated resistance, suggesting that PLD therapy could be a promising strategy for the treatment of therapy-resistant breast cancer patients. Copyright © 2017 Elsevier B.V. All rights reserved.

TLR2 and TLR3 expression as a biomarker for the risk of doxorubicin-induced heart failure.

PubMed

Liang, Shao; Xinyong, Cai; Hongmin, Zhu; Jing, Wang; Lang, Hong; Ping, Zhang

2018-06-27

Doxorubicin (Dox) is limited in its use because of its adverse effect of inducing irreversible heart dysfunction. Innate immune factors, including toll-like receptors (TLRs), play important roles in most cardiac diseases and doxorubicin-induced cardiotoxicity. In this study, subjects were divided into the following groups: healthy controls (n = 62), HF group (n = 60), Dox group (n = 82), and Dox-HF group (n = 32). Expressions of TLR mRNAs in peripheral blood mononuclear cells were detected by RT-PCR. Western blotting was used to quantify protein expressions of Peripheral blood mononuclear cells (PBMCs) TLRs and their downstream signal proteins. The release of inflammatory factors was detected by ELISA. Results indicated that TLR2 was increased and TLR3 was decreased between the control group and Dox group, and between the Dox group and Dox-HF group. Serum inflammatory factors were comparable between the HF group, the Dox group, and the Dox-HF group. This study suggested that TLR2 and TLR3 are up- and down-regulated, respectively, in doxorubicin-treated patients who develop heart dysfunctions. This may suggest a predictive role for TLR2-TLR3 imbalance in doxorubicin-induced heart failure. Copyright © 2018. Published by Elsevier B.V.

Recirculation and reutilization of micellar bile lecithin.

PubMed

Robins, S J

1975-09-01

Bile lecithins, solubilized in micellar bile salt and radiolabeled in the 1-acyl fatty acid, phosphorus, and choline positions, were infused in the small bowel of fasted rats. Absorption of each label was virtually complete after 24 h. However, these lecithins were extensively hydrolyzed in the bowel lumen as well as after absorption, and neither the fatty acid nor phosphorus was significantly retained in the enterohepatic circulation or reutilized for biliary lecithin synthesis. In contrast, while choline was also dissociated from absorbed lecithin, choline was instead retained in the liver, reincorporated into newly synthesized hepatic lecithin, and sercreted in biliary lecithin in 10-fold greater amounts than either the fatty acid or phosphorus. However, the extent of choline incorporation into bile lecithin was limited and was not further increased when free choline was directly injected into the portal vein. The data therefore suggest that although only choline of absorbed lecithin is retained in the enterohepatic circulation and preserved for new biliary lecithin synthesis, exogenous choline utilization is regulated by the size of the available hepatic pool.

In vitro and in vivo characterization of doxorubicin and vincristine coencapsulated within liposomes through use of transition metal ion complexation and pH gradient loading.

PubMed

Abraham, Sheela A; McKenzie, Cheryl; Masin, Dana; Ng, Rebecca; Harasym, Troy O; Mayer, Lawrence D; Bally, Marcel B

2004-01-15

There is an opportunity to augment the therapeutic potential of drug combinations through use of drug delivery technology. This report summarizes data obtained using a novel liposomal formulation with coencapsulated doxorubicin and vincristine. The rationale for selecting these drugs is due in part to the fact that liposomal formulations of doxorubicin and vincristine are being separately evaluated as components of drug combinations. Doxorubicin and vincristine were coencapsulated into liposomes using two distinct methods of drug loading. A manganese-based drug loading procedure, which relies on drug complexation with a transition metal, was used to encapsulate doxorubicin. Subsequently the ionophore A23187 was added to induce formation of a pH gradient, which promoted vincristine encapsulation. Plasma elimination studies in mice indicated that the drug:drug ratio before injection [4:1 doxorubicin:vincristine (wt:wt ratio)] changed to 20:1 at the 24-h time point, indicative of more rapid release of vincristine from the liposomes than doxorubicin. Efficacy studies completed in MDA MB-435/LCC6 tumor-bearing mice suggested that at the maximum tolerated dose, the coencapsulated formulation was therapeutically no better than liposomal vincristine. This result was explained in part by in vitro cytotoxicity studies evaluating doxorubicin and vincristine combinations analyzed using the Chou and Talalay median effect principle. These data clearly indicated that simultaneous addition of vincristine and doxorubicin resulted in pronounced antagonism. These results emphasize that in vitro drug combination screens can be used to predict whether a coformulated drug combination will act in an antagonistic or synergistic manner.

Telomerase Responsive Delivery of Doxorubicin from Mesoporous Silica Nanoparticles in Multiple Malignancies: Therapeutic Efficacies against Experimental Aggressive Murine Lymphoma.

PubMed

Srivastava, Prateek; Hira, Sumit Kumar; Sharma, Amod; Kashif, Mohammad; Srivastava, Prashant; Srivastava, Divesh N Narayan; Singh, Ram Adhar; Manna, Partha Pratim

2018-05-25

Mammalian telomerase maintain the length and integrity of telomeres by adding the telomeric repeats to chromosome end. This work describes the telomerase responsive delivery of doxorubicin against telomerase positive human and murine cancer cells. Wrapping of doxorubicin loaded mesoporous silica nanoparticles with specific oligonucleotide sequence, containing telomeric repeat complementary sequence and a telomerase substrate primer sequence resulted slow and sustained release of doxorubicin, contiguous to the tumor cells. The DNA wrapped nano probe significantly inhibit the proliferation and enhanced the cytotoxicity in telomerase positive human and mouse tumor cells, and its function is impeded following exposure to specific telomerase inhibitor, AZT. Entrapping of doxorubicin by telomerase specific oligo, manifests enhanced apoptosis and significantly higher uptake of the drug in the tumor cells. Treatment of telomerase positive Dalton's lymphoma bearing mice with a novel and newly designed oligo wrapped nano probe, specific for mouse telomerase, significantly enhanced the survival and improved the histopathological parameters. In addition, the treatment also induced significant reduction in the number of tumor foci and restored the normal architecture of the vascularised organs, besides preventing metastasis.

Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells.

PubMed

Rathos, Maggie J; Khanwalkar, Harshal; Joshi, Kavita; Manohar, Sonal M; Joshi, Kalpana S

2013-01-23

In the present study, we show that the combination of doxorubicin with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces extensive apoptosis than either drug alone in H-460 human NSCLC cells. Synergistic effects of P276-00 and doxorubicin on growth inhibition was studied using the Propidium Iodide (PI) assay. The doses showing the best synergistic effect was determined and these doses were used for further mechanistic studies such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of the combination was evaluated using the H-460 xenograft model. The combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced G2/M arrest and induction of apoptosis was observed in the combination treatment. This was associated with induction of tumor suppressor protein p53 and reduction of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced COX-2, a NF-κB target and Cdk-1, a target of P276-00, which was downregulated by P276-00 in the combination. Doxorubicin when combined with P276-00 in a sequence-specific manner significantly inhibited tumor growth, compared with either doxorubicin or P276-00 alone in H-460 xenograft model. These findings suggest that this combination may increase the therapeutic index over doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-κB signaling and inhibition of Cdk-1 which is involved in cell cycle progression.

Potentiation of in vitro and in vivo antitumor efficacy of doxorubicin by cyclin-dependent kinase inhibitor P276-00 in human non-small cell lung cancer cells

PubMed Central

2013-01-01

Background In the present study, we show that the combination of doxorubicin with the cyclin-dependent kinase inhibitor P276-00 was synergistic at suboptimal doses in the non-small cell lung carcinoma (NSCLC) cell lines and induces extensive apoptosis than either drug alone in H-460 human NSCLC cells. Methods Synergistic effects of P276-00 and doxorubicin on growth inhibition was studied using the Propidium Iodide (PI) assay. The doses showing the best synergistic effect was determined and these doses were used for further mechanistic studies such as western blotting, cell cycle analysis and RT-PCR. The in vivo efficacy of the combination was evaluated using the H-460 xenograft model. Results The combination of 100 nM doxorubicin followed by 1200 nM P276-00 showed synergistic effect in the p53-positive and p53-mutated cell lines H-460 and H23 respectively as compared to the p53-null cell line H1299. Abrogation of doxorubicin-induced G2/M arrest and induction of apoptosis was observed in the combination treatment. This was associated with induction of tumor suppressor protein p53 and reduction of anti-apoptotic protein Bcl-2. Furthermore, doxorubicin alone greatly induced COX-2, a NF-κB target and Cdk-1, a target of P276-00, which was downregulated by P276-00 in the combination. Doxorubicin when combined with P276-00 in a sequence-specific manner significantly inhibited tumor growth, compared with either doxorubicin or P276-00 alone in H-460 xenograft model. Conclusion These findings suggest that this combination may increase the therapeutic index over doxorubicin alone and reduce systemic toxicity of doxorubicin most likely via an inhibition of doxorubicin-induced chemoresistance involving NF-κB signaling and inhibition of Cdk-1 which is involved in cell cycle progression. PMID:23343191

Bypassing multidrug resistant ovarian cancer using ultrasound responsive doxorubicin/curcumin co-deliver alginate nanodroplets.

PubMed

Baghbani, Fatemeh; Moztarzadeh, Fathollah

2017-05-01

Ultrasound-responsive perfluorocarbon nanoemulsions are a class of new multifunctional smart nanocarriers which combine diagnostic properties with therapeutic properties and release their drug payload in a controlled manner in response to ultrasound. Therefore, combination therapy using chemotherapeutic and chemosensitizing agents co-entrapped in these nanocarriers seems beneficial for cancer treatment. In the present study, multifunctional smart alginate/perfluorohexane nanodroplets were developed for co-delivery of doxorubicin and curcumin (a strong chemosensitizer). The nanodroplets with the average particle size of 55.1nm were synthesized via nanoemulsion process. The entrapment efficiency of doxorubicin was 92.3%. To improve curcumin entrapment into the alginate shell, Span 60 was added to the formulation as a co-surfactant and finally curcumin entrapment of about 40% was achieved. Ultrasound-mediated drug release kinetic was evaluated at two different frequencies of 28kHz (low frequency) and 1MHz (high frequency). Low frequency ultrasound resulted in higher triggered drug release from nanodroplets. The nanodroplets showed strong ultrasound contrast via droplet to bubble transition as confirmed via B-mode ultrasound imaging. Enhanced cytotoxicity in adriamycin-resistant A2780 ovarian cancer cells was observed for Dox-Cur-NDs compared to Dox-NDs because of the synergistic effects of doxorubicin and curcumin. However, ultrasound irradiation significantly increased the cytotoxicity of Dox-Cur-NDs. Finally, in vivo ovarian cancer treatment using Dox/Cur-NDs combined with ultrasound irradiation resulted in efficient tumor regression. According to the present study, nanotherapy of multidrug resistant human ovarian cancer using ultrasound responsive doxorubicin/curcumin co-loaded alginate-shelled nanodroplets combined with ultrasound irradiation could be a promising modality for the future of cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

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.

Recovery of intrinsic fluorescence from single-point interstitial measurements for quantification of doxorubicin concentration

PubMed Central

Baran, Timothy M.; Foster, Thomas H.

2014-01-01

Background and Objective We developed a method for the recovery of intrinsic fluorescence from single-point measurements in highly scattering and absorbing samples without a priori knowledge of the sample optical properties. The goal of the study was to demonstrate accurate recovery of fluorophore concentration in samples with widely varying background optical properties, while simultaneously recovering the optical properties. Materials and Methods Tissue-simulating phantoms containing doxorubicin, MnTPPS, and Intralipid-20% were created, and fluorescence measurements were performed using a single isotropic probe. The resulting spectra were analyzed using a forward-adjoint fluorescence model in order to recover the fluorophore concentration and background optical properties. Results We demonstrated recovery of doxorubicin concentration with a mean error of 11.8%. The concentration of the background absorber was recovered with an average error of 23.2% and the scattering spectrum was recovered with a mean error of 19.8%. Conclusion This method will allow for the determination of local concentrations of fluorescent drugs, such as doxorubicin, from minimally invasive fluorescence measurements. This is particularly interesting in the context of transarterial chemoembolization (TACE) treatment of liver cancer. PMID:24037853

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.

Measurement of Nitroaromatic Explosives by Micellar Electrokinetic Chromatography in Waters Collected Along a Tropical Estuary

DTIC Science & Technology

2014-02-07

Naval Research Laboratory Washington, DC 20375-5320 NRL/MR/ 6110 --14-9504 Measurement of Nitroaromatic Explosives by Micellar Electrokinetic...Carolina CaMeron lindsay Science & Engineering Apprenticeship Program Office of Naval Research Arlington, Virginia i REPORT DOCUMENTATION PAGE Form...GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 2 . REPORT TYPE1. REPORT DATE (DD-MM-YYYY) 4. TITLE

Synergistic Cytotoxicity Effect by Combination Treatment of Polyketide Derivatives from Annona muricata Linn Leaves and Doxorubicin as Potential Anticancer Material on Raji Cell Line

NASA Astrophysics Data System (ADS)

Artanti, A. N.; Astirin, O. P.; Prayito, A.; Fisma, R.; Prihapsara, F.

2018-03-01

Nasopharynx cancer is one of the most deadly cancer. The main priority of nasopharynx cancer treatment is the use of chemotherapeutic agents, especially doxorubicin. However, doxorubicin might also lead to diverse side effect. An approach recently develop to overcome side effect of doxorubicin is to used of combined chemotherapeutic agent. One of the compounds found effication as an anticancer agent on nasopharynx cancer is acetogenin, a polyketide compound that is abundant in Annona muricata L. leaves. This study has been done to examine polyketide derivatives was isolated from Annona muricata L. which has potency to induce apoptosis by p53 expression on raji cell line. The determination of cytotoxic combination activity from polyketide derivative and doxorubicin was evaluated using MTT assay to obtain the value of CI (combination index). Data analysis showed that combination of polyketide derivative from Annona muricata L. (14,4 µg/ml) and doxorubicin with all of concentration performed synergistic effect on raji cell line with CI value from 0.13 – 0.65.

Probing pH difference between micellar solution and nanoscale water within common black film by fluorescent dye

NASA Astrophysics Data System (ADS)

Fu, Jingni; Zhang, Luning

2018-03-01

The protonation/deprotonation equilibrium of a fluorescent pH probe (carboxy-seminaphthorhodafluor-1, SNARF-1) within the nanoscale water layer confined in common black films (CBFs) has been studied. We find that SNARF-1 molecules feel a more acidic environment in CBFs than when they are in the bulk micellar solution, using the base/acid peak area ratio of the dye to indicate its microenvironment pH. Three surfactants are used to study the dependence of the pH drop versus charge: cationic (cetyltrimethylammonium bromide, CTAB), anionic (sodium dodecylsulphate, SDS) and nonionic (Triton X-100) species. The decrease of CBFs pH versus the pH of the micellar solution is the following: ΔpH ≈ 1.5 for CTAB (pH: 7.0-9.0), ΔpH ≈ 0.8 for SDS, and ΔpH ≈ 0.4 for Triton X-100. With the addition of electrolyte in CBFs, we observe large decrease the amplitude of the pH anomaly, thus suggesting an electrostatic origin of the pH change at nanoscale environment.

Enhancing the Effects of Low Dose Doxorubicin Treatment by the Radiation in T47D and SKBR3 Breast Cancer Cells

PubMed Central

Aghaee, Fahimeh; Baradaran, Behzad; Mesbahi, Asghar; Mohammadzadeh, Mohammad; Jafarabadi, Mohammad Asghari

2013-01-01

Purpose Breast cancer is the most common malignancy of women worldwide. Radiotherapy consists of a vital element in the treatment of breast cancer but relative side effects and different radioactive responses are limiting factors for a successful treatment. Doxorubicin has been used to treat cancers for over 30 years and is considered as the most effective drug in the treatment of breast cancer. There are also many chronic side effects that limit the amount of doxorubicin that can be administered. The combined radio-drug treatment, with low doses, can be an approach for reducing side effects from single modality treatments instead of suitable cure rates. Methods We have studied the effect of 1, 1.5, and 2 Gy doses of 9 MV X-rays along with 1 µM doxorubicin on inducing cell death, apoptosis and also p53 and PTEN gene expression in T47D and SKBR3 breast cancer cells. Results Doxorubicin treatment resulted in upregulation of radiation-induced levels of p53 and downregulation of PTEN at 1 and 1.5 Gy in T47D breast cancer cells, as well as downregulation of p53 mRNA level of expression and upregulation of PTEN mRNA level of expression in SKBR3 breast cancer cell line. In addition, doxorubicin in combination with radiation decreased the viability of breast cancer cell lines in the both cell lines. Conclusion Low doses of doxorubicin, with least cell toxicity, may be an effective treatment for breast cancer when used in conjunction with ionizing radiation. PMID:23843848

Crystallization in Micellar Cores: confinement effects and dynamics

NASA Astrophysics Data System (ADS)

Lund, Reidar; Zinn, Thomas; Willner, Lutz; Department of Chemistry, University of Oslo Team; Forschungszentrum Jülich Collaboration

It is well known that liquids confined to small nanoscopic pores and droplets exhibit thermal behavior very different from bulk samples. Here we demonstrate that n-alkanes forming 2-3 nm small micellar cores are considerably affected by confinement in analogue with hard confined systems. We study micelles form by self-assembly of a series of well-defined n-Alkyl-PEO polymers in aqueous solutions. By using small-angle X-ray scattering (SAXS), densiometry and differential scanning calorimetry (DSC), we show that n-alkane exhibit a first-order phase transition i.e. melting. Correlating the structural and thermodynamic data, we find that a melting depression can be accurately described by the Gibbs-Thomson equation. ∖f1 The effect of core crystallinity on the molecular exchange kinetics is investigated using time-resolved small-angle neutron scattering (TR-SANS). We show that there are considerable entropic and enthalpic contributions from the chain packing that affect the kinetic stability of micelles. ∖pard

Chiral separation of vinpocetine using cyclodextrin-modified micellar electrokinetic chromatography.

PubMed

Wan Ibrahim, Wan Aini; Abd Wahib, Siti Munirah; Hermawan, Dadan; Sanagi, Mohd Marsin; Aboul-Enein, Hassan Y

2012-03-01

A cyclodextrin-modified micellar electrokinetic chromatography (CD-MEKC) technique has been developed for enantioseparation of vinpocetine using an inexpensive 2-hydroxypropyl-β-CD (HP-β-CD) as the chiral selector (CS). The best chiral separation was achieved using 40 mM HP-β-CD as the CS in 50 mM phosphate buffer (pH 7.0) consisting of 40 mM sodium dodecyl sulfate (SDS) at a separation temperature and separation voltage of 25°C and 25 kV, respectively. To the author's best knowledge, this is the first CD-MEKC study able to successfully separate the four stereoisomer of vinpocetine in separation time of 9.5 min and resolution of 1.04-3.87. Copyright © 2012 Wiley Periodicals, Inc.

Amphiphilic Polysaccharide Block Copolymers for pH-Responsive Micellar Nanoparticles.

PubMed

Breitenbach, Benjamin B; Schmid, Ira; Wich, Peter R

2017-09-11

A full polysaccharide amphiphilic block copolymer was prepared from end group-functionalized dextrans using copper-mediated azide-alkyne click chemistry. Sufficient modification of the reducing end in both blocks was achieved by microwave-enhanced reductive amination in a borate-buffer/methanol solvent system. The combination of a hydrophilic dextran block with a hydrophobic acetalated dextran block results in an amphiphilic structure that turns water-soluble upon acid treatment. The material has a low critical micelle concentration and self-assembles in water to spherical micellar nanoparticles. The formed nanoparticles have a narrow size distribution below 70 nm in diameter and disassemble in slightly acidic conditions. The amphiphilic polysaccharide system shows low toxicity and can stabilize the hydrophobic model drug curcumin in aqueous solutions over extended time periods.

Cell penetrating peptides fused to a thermally targeted biopolymer drug carrier improve the delivery and antitumor efficacy of an acid-sensitive doxorubicin derivative.

PubMed

Walker, Leslie; Perkins, Eddie; Kratz, Felix; Raucher, Drazen

2012-10-15

Elastin-like polypeptide (ELP) is a macromolecular carrier with thermally responsive properties that can passively accumulate in solid tumors and additionally aggregate in tumor tissue when exposed to hyperthermia. In this study, ELP was conjugated to the anticancer drug doxorubicin (DOXO) and three different cell penetrating peptides (CPP) in order to inhibit tumor growth in mice compared to free doxorubicin. Fluorescence microscopy studies in MCF-7 breast carcinoma cells demonstrated that the three different CPP-ELP-DOXO conjugates delivered doxorubicin to the cell nucleus. All CPP-ELP-DOXO conjugates showed cytotoxicity with IC(50) values in the range of 12-30 μM at 42 °C, but the ELP carrier with SynB1 as the cell penetrating peptide had the lowest intrinsic cytotoxicity. Therefore, the antitumor efficacy of SynB1-ELP-DOXO was compared to doxorubicin under hyperthermic conditions. C57BL/6 female mice bearing syngeneic E0771 murine breast tumors were treated with either free doxorubicin or the SynB1-ELP-DOXO conjugate with or without focused hyperthermia on the tumor. Under hyperthermic conditions, tumor inhibition with SynB1-ELP-DOXO was 2-fold higher than under therapy with free doxorubicin at the equivalent dose, and is thus a promising lead candidate for optimizing thermally responsive drug polymer conjugates. Copyright © 2012 Elsevier B.V. All rights reserved.

Determination of lysergic acid diethylamide (LSD) in mouse blood by capillary electrophoresis/ fluorescence spectroscopy with sweeping techniques in micellar electrokinetic chromatography.

PubMed

Fang, Ching; Liu, Ju-Tsung; Chou, Shiu-Huey; Lin, Cheng-Huang

2003-03-01

The separation and on-line concentration of lysergic acid diethylamide (LSD) in mouse blood was achieved by means of capillary electrophoresis/fluorescence spectroscopy using sodium dodecyl sulfate (SDS) as the surfactant. Techniques involving on-line sample concentration, including sweeping micellar electrokinetic chromatography (sweeping-MEKC) and cation-selective exhaustive injection-sweep-micellar electrokinetic chromatography (CSEI-sweep-MEKC) were applied; the optimum on-line concentration and separation conditions were determined. In the analysis of an actual sample, LSD was found in a blood sample from a test mouse (0.1 mg LSD fed to a 20 g mouse; approximately 1/10 to the value of LD(50)). As a result, 120 and 30 ng/mL of LSD was detected at 20 and 60 min, respectively, after ingestion of the doses.

Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells

PubMed Central

LI, BO; KIM, DO SUNG; YADAV, RAJ KUMAR; KIM, HYUNG RYONG; CHAE, HAN JUNG

2015-01-01

Sulforaphane, a natural isothiocyanate compound found in cruciferous vegetables, has been shown to exert cardioprotective effects during ischemic heart injury. However, the effects of sulforaphane on cardiotoxicity induced by doxorubicin are unknown. Thus, in the present study, H9c2 rat myoblasts were pre-treated with sulforaphane and its effects on cardiotoxicity were then examined. The results revealed that the pre-treatment of H9c2 rat myoblasts with sulforaphane decreased the apoptotic cell number (as shown by trypan blue exclusion assay) and the expression of pro-apoptotic proteins (Bax, caspase-3 and cytochrome c; as shown by western blot analysis and immunostaining), as well as the doxorubicin-induced increase in mitochondrial membrane potential (measured by JC-1 assay). Furthermore, sulforaphane increased the mRNA and protein expression of heme oxygenase-1 (HO-1, measured by RT-qPCR), which consequently reduced the levels of reactive oxygen species (ROS, measured using MitoSOX Red reagent) in the mitochondria which were induced by doxorubicin. The cardioprotective effects of sulforaphane were found to be mediated by the activation of the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor-2 (Nrf2)/antioxidant-responsive element (ARE) pathway, which in turn mediates the induction of HO-1. Taken together, the findings of this study demonstrate that sulforaphane prevents doxorubicin-induced oxidative stress and cell death in H9c2 cells through the induction of HO-1 expression. PMID:25936432

Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells.

PubMed

Li, Bo; Kim, Do Sung; Yadav, Raj Kumar; Kim, Hyung Ryong; Chae, Han Jung

2015-07-01

Sulforaphane, a natural isothiocyanate compound found in cruciferous vegetables, has been shown to exert cardioprotective effects during ischemic heart injury. However, the effects of sulforaphane on cardiotoxicity induced by doxorubicin are unknown. Thus, in the present study, H9c2 rat myoblasts were pre-treated with sulforaphane and its effects on cardiotoxicity were then examined. The results revealed that the pre-treatment of H9c2 rat myoblasts with sulforaphane decreased the apoptotic cell number (as shown by trypan blue exclusion assay) and the expression of pro-apoptotic proteins (Bax, caspase-3 and cytochrome c; as shown by western blot analysis and immunostaining), as well as the doxorubicin-induced increase in mitochondrial membrane potential (measured by JC-1 assay). Furthermore, sulforaphane increased the mRNA and protein expression of heme oxygenase-1 (HO-1, measured by RT-qPCR), which consequently reduced the levels of reactive oxygen species (ROS, measured using MitoSOX Red reagent) in the mitochondria which were induced by doxorubicin. The cardioprotective effects of sulforaphane were found to be mediated by the activation of the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor-2 (Nrf2)/antioxidant-responsive element (ARE) pathway, which in turn mediates the induction of HO-1. Taken together, the findings of this study demonstrate that sulforaphane prevents doxorubicin-induced oxidative stress and cell death in H9c2 cells through the induction of HO-1 expression.

AMP-activated protein kinase α2 and E2F1 transcription factor mediate doxorubicin-induced cytotoxicity by forming a positive signal loop in mouse embryonic fibroblasts and non-carcinoma cells.

PubMed

Yang, Wookyeom; Park, In-Ja; Yun, Hee; Im, Dong-Uk; Ock, Sangmi; Kim, Jaetaek; Seo, Seon-Mi; Shin, Ha-Yeon; Viollet, Benoit; Kang, Insug; Choe, Wonchae; Kim, Sung-Soo; Ha, Joohun

2014-02-21

Doxorubicin is one of the most widely used anti-cancer drugs, but its clinical application is compromised by severe adverse effects in different organs including cardiotoxicity. In the present study we explored mechanisms of doxorubicin-induced cytotoxicity by revealing a novel role for the AMP-activated protein kinase α2 (AMPKα2) in mouse embryonic fibroblasts (MEFs). Doxorubicin robustly induced the expression of AMPKα2 in MEFs but slightly reduced AMPKα1 expression. Our data support the previous notion that AMPKα1 harbors survival properties under doxorubicin treatment. In contrast, analyses of Ampkα2(-/-) MEFs, gene knockdown of AMPKα2 by shRNA, and inhibition of AMPKα2 activity with an AMPK inhibitor indicated that AMPKα2 functions as a pro-apoptotic molecule under doxorubicin treatment. Doxorubicin induced AMPKα2 at the transcription level via E2F1, a transcription factor that regulates apoptosis in response to DNA damage. E2F1 directly transactivated the Ampkα2 gene promoter. In turn, AMPKα2 significantly contributed to stabilization and activation of E2F1 by doxorubicin, forming a positive signal amplification loop. AMPKα2 directly interacted with and phosphorylated E2F1. This signal loop was also detected in H9c2, C2C12, and ECV (human epithelial cells) cells as well as mouse liver under doxorubicin treatment. Resveratrol, which has been suggested to attenuate doxorubicin-induced cytotoxicity, significantly blocked induction of AMPKα2 and E2F1 by doxorubicin, leading to protection of these cells. This signal loop appears to be non-carcinoma-specific because AMPKα2 was not induced by doxorubicin in five different tested cancer cell lines. These results suggest that AMPKα2 may serve as a novel target for alleviating the cytotoxicity of doxorubicin.

Efficacy of doxorubicin-based chemotherapy for non-resectable canine subcutaneous haemangiosarcoma.

PubMed

Wiley, J L; Rook, K A; Clifford, C A; Gregor, T P; Sorenmo, K U

2010-09-01

Eighteen dogs with measurable subcutaneous haemangiosarcoma (SQHSA) were treated with doxorubicin-based chemotherapy. Response assessment was evaluated and compared using World Health Organization (WHO), Response Evaluation Criteria in Solid Tumours (RECIST) and tumour volume criteria. The overall response rate for all dogs was 38.8% using WHO criteria, 38.8% using RECIST criteria and 44% using tumour volume criteria. One dog had a complete response. The median response duration for all dogs was 53 days (range 13-190 days). Four dogs had complete surgical excision after neoadjuvant chemotherapy. The median progression-free interval for dogs with complete surgical excision after neoadjuvant chemotherapy was significantly longer than those not having surgical excision (207 days versus 83 days, respectively) (P = 0.003). No significant difference in metastasis-free interval or survival time was found between the groups. Doxorubicin-based chemotherapy appears to be effective for non-resectable canine SQHSA, although the response duration is relatively short.

Activity of trypsin-like enzymes and gelatinases in rats with doxorubicin cardiomyopathy.

PubMed

Gordiienko, Iu A; Babets, Ya V; Kulinich, A O; Shevtsova, A I; Ushakova, G O

2014-01-01

Activity of trypsin-like enzymes (ATLE) and gelatinases A and B were studied in the blood plasma and extracts from cardiac muscle, cerebral cortex and cerebellum of rats with cardiomyopathy caused by anthracycline antibiotic doxorubicin against the background of preventive application of corvitin and α-ketoglutarate. ATLE significantly increased in blood plasma and extracts from cerebral cortex but decreased in extracts from cardiac muscle and cerebellum in doxorubicin cardiomyopathy (DCMP). In addition, a significant increase of activity of both gelatinases in plasma and tissue extracts was observed. Preventive administration of corvitin and α-ketoglutarate resulted in differently directed changes of activity of the above mentioned enzymes in heart and brain tissues. Obtained data confirm the hypothesis about activation of proteolysis under the influence of anthracycline antibiotics and testify to selective effect of corvitin and α-ketoglutarate on ATLE and gelatinases.

Treatment of experimental extravasation of amrubicin, liposomal doxorubicin, and mitoxantrone with dexrazoxane.

PubMed

Langer, Seppo W; Thougaard, Annemette V; Sehested, Maxwell; Jensen, Peter Buhl

2012-02-01

Dexrazoxane is an established treatment option in extravasation of the classic anthracyclines such as doxorubicin, epirubicin, and daunorubicin. However, it is not known whether the protection against the devastating tissue injuries extends into extravasation with new types of anthracyclines, the anthracenediones, or the liposomal pegylated anthracycline formulations. We therefore tested the antidotal efficacy of dexrazoxane against extravasation of amrubicin, mitoxantrone, and liposomal pegylated doxorubicin in mice. A total of 80 female B6D2F1 mice were tested in an established mouse extravasation model. The mice had experimental extravasations of amrubicin, mitoxtanrone, and Caelyx and were immediately hereafter treated with systemic dexrazoxane or saline. Systemic treatment with dexrazoxane resulted in significant protection against extravasation injuries from all three drugs. Moreover, the vesicant potential of the three test drugs was weaker than seen in previous experiments with the classic anthracyclines.

Pt/glassy carbon model catalysts prepared from PS-b-P2VP micellar templates.

PubMed

Gu, Yunlong; St-Pierre, Jean; Ploehn, Harry J

2008-11-04

Poly(styrene)-block-poly(2-vinylpyridine) (PS-b-P2VP) diblock copolymer was used as a micellar template to fabricate arrays of Pt nanoparticles on mica and glassy carbon (GC) supports. Polymer micellar deposition yields Pt nanoparticles with tunable particle size and surface number density on both mica and GC. After deposition of precursor-loaded micelles onto GC, oxygen plasma etching removes the polymer shell, followed by thermal treatment with H2 gas to reduce the Pt. Etching conditions were optimized to maximize removal of the polymer while minimizing damage to the GC. Arrays of Pt nanoparticles with controlled size and surface number density can be prepared on mica (for particle size characterization) and GC to make Pt/GC model catalysts. These model catalysts were characterized by tapping mode atomic force microscopy, X-ray photoelectron spectroscopy, and cyclic voltammetry to measure activity for oxidation of carbon monoxide or methanol. Cyclic voltammetry results demonstrate the existence of a correlation between Pt particle size and electrocatalytic properties including onset potential, tolerance of carbonaceous adsorbates, and intrinsic activity (based on active Pt area from CO stripping voltammetry). Results obtained with Pt/GC model catalysts duplicate prior results obtained with Pt/porous carbon catalysts therefore validating the synthesis approach and offering a new, tunable platform to study catalyst structure and other effects such as aging on proton exchange membrane fuel cell (PEMFC) reactions.

Electron spin resonance and electron spin echo modulation of n-doxylstearic acid and N,N,N',N'-tetramethylbenzidine photoionization in sodium versus lithium dodecyl sulfate micellar solutions: effect of 15-crown-5 and 18-crown-6 ether addition

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

Baglioni, P.; Rivara-Minten, E.; Kevan, L.

1988-08-11

Electron spin echo modulation and electron spin resonance spectra of photogenerated N,N,N',N'-tetramethylbenzidine (TMB) cation radical and n-doxylstearic acids (n-DSA) in frozen micellar solutions of sodium and lithium dodecyl sulfate containing 15-crown-5 and 18-crown-6 ethers in D/sub 2/O have been studied as a function of crown ether concentration. Modulation effects due to N-DSA with water deuteriums give direct evidence that both crown ethers are mainly located at the micellar interface and that this causes a decrease of the hydration of the micellar interface. Crown ether complexation constants for sodium and lithium micellar counterions are reported and show that 18-crown-6 > 15-crown-5more » for sodium counterion and 15-crown-5 > 18-crown-6 for lithium counterion. Modulation effects from TMB/sup +/ interaction with water deuteriums indicate that the TMB molecule moves toward the micelle interfacial region when sodium or lithium cations are complexed by crown ethers. The TMB/sup +/ yield upon TMB photoionization increases by about 10% with crown ether addition for SDS and LDS micellar systems, but it is greater if the absolute values for the LDS system are compared to those for the SDS micellar system. This behavior correlates with the strength of TMB/sup +/-water interactions and suggests that the main factor in the photoionization efficiency is the photocation-water interaction.« less

Optical absorption, electron spin resonance, and electron spin echo studies of the photoionization of tetramethylbenzidine in cationic and anionic synthetic vesicles: comparison with analogous micellar systems

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

Li, A.S.W.; Kevan, L.

1983-09-07

The photoionization of N,N,N',N'-tetramethylbenzidine (TMB) in dihexadecylphosphate anionic vesicles and in dioctadecyldimethylammonium chloride cationic vesicles has been studied by optical absorption and electron spin resonance in liquid and frozen solutions. The TMB cation has been observed to be stabilized in both types of vesicles. The photoionization efficiency is about twofold greater in the cationic vesicles compared to the anionic vesicles. Shifts in the optical absorption maximum between micellar and vesicle solutions indicate that TMB is in a less polar environment in the vesicle systems. Electron spin echo modulation spectrometry has been used to detect TMB cation-water interactions that are foundmore » to be weaker than in previously studied micellar solutions. This is consistent with the optical absorption results and with an asymmetric solubilization site for TMB and TMB/sup +/ within the vesicular structure. A new absorption in the photoionized vesicles is assigned to a nonparamagnetic diamine-diimine charge-transfer complex between two TMB cations in the same vesicle. This complex is not formed in micellar systems. 5 figures.« less

Radiation-induced polymerization of glass-forming systems. IV. Effect of the homogeneity of polymerization phase and polymer concentration on temperature dependence of initial polymerization rate

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

Kaetsu, I.; Ito, A.; Hayashi, K.

1973-06-01

The effect of homogeneity of polymerization phase and monomer concentration on the temperature dependence of initial polymerization rate was studied in the radiation-induced radical polymerization of binary systems consisting of glass-forming monomer and solvent. In the polymerization of a completely homogeneous system such as HEMA-propylene glycol, a maximum and a minimum in polymerization rates as a function of temperature, characteristic of the polymerization in glass-forming systems, were observed for all monomer concentrations. However, in the heterogeneous polymerization systems such as HEMA-triacetin and HEMAisoamyl acetate, maximum and minimum rates were observed in monomer-rich compositions but not at low monomer concentrations. Furthermore,more » in the HEMA-dioctyl phthalate polymerization system, which is extremely heterogeneous, no maximum and minimum rates were observed at any monomer concentration. The effect of conversion on the temperature dependence of polymerization rate in homogeneous bulk polymerization of HEMA and GMA was investigated. Maximum and minimum rates were observed clearly in conversions less than 10% in the case of HEMA and less than 50% in the case of GMA, but the maximum and minimum changed to a mere inflection in the curve at higher conversions. A similar effect of polymer concentration on the temperature dependence of polymerization rate in the GMA-poly(methyl methacrylate) system was also observed. It is deduced that the change in temperature dependence of polymerization rate is attributed to the decrease in contribution of mutual termination reaction of growing chain radicals to the polymerization rate. (auth)« less

Dynamics and Regulation of RecA Polymerization and De-Polymerization on Double-Stranded DNA

PubMed Central

Muniyappa, Kalappa; Yan, Jie

2013-01-01

The RecA filament formed on double-stranded (ds) DNA is proposed to be a functional state analogous to that generated during the process of DNA strand exchange. RecA polymerization and de-polymerization on dsDNA is governed by multiple physiological factors. However, a comprehensive understanding of how these factors regulate the processes of polymerization and de-polymerization of RecA filament on dsDNA is still evolving. Here, we investigate the effects of temperature, pH, tensile force, and DNA ends (in particular ssDNA overhang) on the polymerization and de-polymerization dynamics of the E. coli RecA filament at a single-molecule level. Our results identified the optimal conditions that permitted spontaneous RecA nucleation and polymerization, as well as conditions that could maintain the stability of a preformed RecA filament. Further examination at a nano-meter spatial resolution, by stretching short DNA constructs, revealed a striking dynamic RecA polymerization and de-polymerization induced saw-tooth pattern in DNA extension fluctuation. In addition, we show that RecA does not polymerize on S-DNA, a recently identified novel base-paired elongated DNA structure that was previously proposed to be a possible binding substrate for RecA. Overall, our studies have helped to resolve several previous single-molecule studies that reported contradictory and inconsistent results on RecA nucleation, polymerization and stability. Furthermore, our findings also provide insights into the regulatory mechanisms of RecA filament formation and stability in vivo. PMID:23825559

Therapeutic Efficacy of Orally Delivered Doxorubicin Nanoparticles in Rat Tongue Cancer Induced by 4-Nitroquinoline 1-Oxide

PubMed Central

Moradzadeh Khiavi, Monir; Rostami, Ahamd; Hamishekar, Hamed; Mesgari Abassi, Mehran; Aghbali, Amirala; Salehi, Roya; Abdollahi, Bita; Fotoohi, Soheila; Sina, Mahmud

2015-01-01

Purpose: Oral cancer is one of the most significant cancers in the world, and squamous cell carcinoma makes up about 94% of oral malignancies. The aim of the present study was to compare the efficacy of doxorubicin plus methotrexate - loaded nanoparticles on tongue squamous cell carcinoma induced by 4NQO and compare it with the commercial doxorubicin and methotrexate delivered orally on seventy SD male rats. Methods: 70 rats were divided into five groups. During the study, the animals were weighed by a digital scale once a week. Number of mortalities was recorded in the data collection forms. At the end of the treatment, biopsy samples were taken from rat tongues in order to evaluate the severity of dysplasia and the extent of cell proliferation. The results were analyzed using ANOVA, descriptive statistics and chi-square test. Results: No statistically significant difference was found in the mean weight of five groups (p>0.05). No significant relationship was found between groups and mortality rate (P = 0. 39). In addition, there was a significant relationship between groups and the degree of dysplasia (P <0.001). The statistical analysis showed a significant relationship between groups and the rate of cell proliferation (p <0.001). Conclusion: The results of the present study showed that the use of doxorubicin plus methotrexate - loaded nanoparticles orally had more therapeutic effects than commercial doxorubicin plus methotrexate. PMID:26236659

Therapeutic Efficacy of Orally Delivered Doxorubicin Nanoparticles in Rat Tongue Cancer Induced by 4-Nitroquinoline 1-Oxide.

PubMed

Moradzadeh Khiavi, Monir; Rostami, Ahamd; Hamishekar, Hamed; Mesgari Abassi, Mehran; Aghbali, Amirala; Salehi, Roya; Abdollahi, Bita; Fotoohi, Soheila; Sina, Mahmud

2015-06-01

Oral cancer is one of the most significant cancers in the world, and squamous cell carcinoma makes up about 94% of oral malignancies. The aim of the present study was to compare the efficacy of doxorubicin plus methotrexate - loaded nanoparticles on tongue squamous cell carcinoma induced by 4NQO and compare it with the commercial doxorubicin and methotrexate delivered orally on seventy SD male rats. 70 rats were divided into five groups. During the study, the animals were weighed by a digital scale once a week. Number of mortalities was recorded in the data collection forms. At the end of the treatment, biopsy samples were taken from rat tongues in order to evaluate the severity of dysplasia and the extent of cell proliferation. The results were analyzed using ANOVA, descriptive statistics and chi-square test. No statistically significant difference was found in the mean weight of five groups (p>0.05). No significant relationship was found between groups and mortality rate (P = 0. 39). In addition, there was a significant relationship between groups and the degree of dysplasia (P <0.001). The statistical analysis showed a significant relationship between groups and the rate of cell proliferation (p <0.001). The results of the present study showed that the use of doxorubicin plus methotrexate - loaded nanoparticles orally had more therapeutic effects than commercial doxorubicin plus methotrexate.

Comparing Apoptosis and Necrosis Effects of Arctium Lappa Root Extract and Doxorubicin on MCF7 and MDA-MB-231 Cell Lines

PubMed Central

Ghafari, Fereshteh; Rajabi, Mohammad Reza; Mazoochi, Tahereh; Taghizadeh, Mohsen; Nikzad, Hossein; Atlasi, Mohammad Ali; Taherian, Aliakbar

2017-01-01

Objective: Breast cancer is a heterogeneous disease and very common malignancy in women worldwide. The efficacy of chemotherapy as an important part of breast cancer treatment is limited due to its side effects. While pharmaceutical companies are looking for better chemicals, research on traditional medicines that generally have fewer side effects is quite interesting. In this study, apoptosis and necrosis effect of Arctium lappa and doxorubicin was compared in MCF7, and MDA-MB-231 cell lines. Materials and Methods: MCF7 and MDA-MB-231 cells were cultured in RPMI 1640 containing 10% FBS and 100 U/ml penicillin/streptomycin. MTT assay and an annexin V/propidium iodide (AV/PI) kit were used respectively to compare the survival rate and apoptotic effects of different concentrations of doxorubicin and Arctium lappa root extract on MDA-MB-231 and MCF7 cells. Results: Arctium lappa root extract was able to reduce cell viability of the two cell lines in a dose and time dependent manner similar to doxorubicin. Flow cytometry results showed that similar to doxorubicin, Arctium Lappa root extract had a dose and time dependent apoptosis effect on both cell lines. 10µg/mL of Arctium lappa root extract and 5 µM of doxorubicin showed the highest anti-proliferative and apoptosis effect in MCF7 and MDA231 cells. Conclusion: The MCF7 (ER/PR-) and MDA-MB-231 (ER/PR+) cell lines represent two major breast cancer subtypes. The similar anti-proliferative and apoptotic effects of Arctium lappa root extract and doxorubicin (which is a conventional chemotherapy drug) on two different breast cancer cell lines strongly suggests its anticancer effects and further studies. PMID:28441789

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.

Doxorubicin delivery to 3D multicellular spheroids and tumors based on boronic acid-rich chitosan nanoparticles.

PubMed

Wang, Xin; Zhen, Xu; Wang, Jing; Zhang, Jialiang; Wu, Wei; Jiang, Xiqun

2013-06-01

Boronic acid-rich chitosan-poly(N-3-acrylamidophenylboronic acid) nanoparticles (CS-PAPBA NPs) with the tunable size were successfully prepared by polymerizing N-3-acrylamidophenylboronic acid in the presence of chitosan in an aqueous solution. The CS-PAPBA NPs were then functionalized by a tumor-penetrating peptide iRGD and loading doxorubicin (DOX). The interaction between boronic acid groups of hydrophobic PAPBA and the amino groups of hydrophilic chitosan inside the nanoparticles was examined by solid-state NMR measurement. The size and morphology of nanoparticles were characterized by dynamic light scattering and electron microscopy. The cellular uptake, tumor penetration, biodistribution and antitumor activity of the nanoparticles were evaluated by using three-dimensional (3-D) multicellular spheroids (MCs) as the in vitro model and H22 tumor-bearing mice as the in vivo model. It was found that the iRGD-conjugated nanoparticles significantly improved the efficiency of DOX penetration in MCs, compared with free DOX and non-conjugated nanoparticles, resulting in the efficient cell killing in the MCs. In vivo antitumor activity examination indicated that iRGD-conjugated CS-PAPBA nanoparticles promoted the accumulation of nanoparticles in tumor tissue and enhanced their penetration in tumor areas, both of which improved the efficiency of DOX-loaded nanoparticles in restraining tumor growth and prolonging the life time of H22 tumor-bearing mice. Copyright © 2013 Elsevier Ltd. All rights reserved.

Elevation of cAMP Levels Inhibits Doxorubicin-Induced Apoptosis in Pre- B ALL NALM- 6 Cells Through Induction of BAD Phosphorylation and Inhibition of P53 Accumulation.

PubMed

Fatemi, Ahmad; Kazemi, Ahmad; Kashiri, Meysam; Safa, Majid

2015-01-01

Recognition of the molecular mechanisms of cAMP action against DNA damage-induced apoptosis can be useful to improve the efficacy of DNA damaging therapeutic agents. Considering the critical role of bcl-2-associated death promoter (BAD) and p53 proteins in DNA damage -induced apoptosis, the aim of this study was to assess the effect of cAMP-elevating agents on these proteins in doxorubicin-treated pre-B acute lymphoblastic leukemia (pre-B ALL) NALM-6 cells.The pre-B ALL cell line NALM-6 was cultured and treated with doxorubicin in combination with or without cAMP-elevating agents forskolin and 3-isobutyl-1-methylxanthine (IBMX). Cell viability was measured by trypan blue staining and MTT assay. For evaluation of apoptosis, annexin-V staining by flow cytometry and caspase-3 activity assay were used. Protein expression of p53, BAD and phoshorylated BAD was detected by western blotting analysis.cAMP-increasing agents diminished the doxorubicin-mediated cytotoxicity in NALM-6 cells as indicated by the viability assays. Annexin-V apoptosis assay showed that the cAMP-elevating agents decreased doxorubicin-induced apoptosis. Moreover, doxorubicin-induced caspase-3 activity was attenuated in the presence of cAMP-increasing agents. Western blot results revealed the reduced expression of p53 protein in cells treated with combination of cAMP-elevating agents and doxorubicin in contrast to cells treated with doxorubicin alone. Expression of total BAD protein was not affected by doxorubicin and cAMP-elevating agents. However, phosphorylation of BAD protein was induced in the presence of cAMP-elevating agents. Our study suggests that elevated cAMP levels inhibit doxorubicin-induced apoptosis in pre-B ALL cells through induction of BAD phosphorylation and abrogation of p53 accumulation.

Facile preparation of antibacterial chitosan/graphene oxide-Ag bio-nanocomposite hydrogel beads for controlled release of doxorubicin.

PubMed

Rasoulzadehzali, Monireh; Namazi, Hassan

2018-04-27

The present project describes the facile preparation of novel pH-sensitive bio-nanocomposite hydrogel beads based on chitosan (CH) and GO-Ag nanohybrid particles for controlled release of anti-cancer drugs such as doxorubicin (DOX). The loading efficiency of doxorubicin into test beads was measured via UV-vis spectroscopy analysis and was found to be high. The formation of silver nanoparticles on the GO sheets and structural characteristics were evaluated via FT-IR, TEM, XRD, and SEM techniques. In addition, the antibacterial activity, swelling and drug release profiles of prepared nanocomposite beads were evaluated. Also, in vitro drug release test was performed in order to investigate the efficiency of CH/GO-Ag nanocomposite hydrogel beads as a drug carrier for controlled release of anti-cancer drugs such as doxorubicin (DOX). A more sustained and controlled drug release profile was observed for CH/GO-Ag nanocomposite hydrogel beads that enhanced by increasing the GO-Ag nanohybrid particles content. Copyright © 2018 Elsevier B.V. All rights reserved.

Micellar modified spectrophotometric determination of nitrobenzenes based upon reduction with tin(II), diazotisation and coupling with the Bratton-Marshall reagent.

PubMed

Escrig-Tena, I; Alvarez Rodríguez, L; Esteve-Romero, J; García-Alvarez-Coque, M C

1998-09-01

Nitrobenzenes, such as the antibiotic chloramphenicol, the vasodilator nicardipine, and the herbicides dinitramin, dinobuton, fenitrothion, methylparathion, oxyfluorfen, parathion, pendimethalin, quintozene, and trifluralin, were determined by using a spectrophotometric method in the visible region (540 nm). The method was based on the reduction of the nitrobenzenes to arylamines with tin(II) chloride, diazotisation of the arylamines and coupling of the diazonium ions with the Bratton-Marshall reagent. The two latter reactions were performed in a micellar medium of sodium dodecyl sulphate. The linear calibration range was 2x10(-6) to 7x10(-5) M (r>0.999), with limits of detection in the 10(-7) M level, which is 2-6 fold lower with respect to the corresponding spectrophotometric procedure in non-micellar medium. The procedure was applied to the analysis of the compounds in commercial preparations (pharmaceuticals and herbicide formulations) and in water samples, with good recoveries.

Nanoformulations of doxorubicin: how far have we come and where do we go from here?

PubMed

Borišev, Ivana; Mrđanovic, Jasminka; Petrovic, Danijela; Seke, Mariana; Jović, Danica; Srđenović, Branislava; Latinovic, Natasa; Djordjevic, Aleksandar

2018-08-17

Nanotechnology, focused on discovery and development of new pharmaceutical products is known as nanopharmacology, and one research area this branch is engaged in are nanopharmaceuticals. The importance of being nano has been particularly emphasized in scientific areas dealing with nanomedicine and nanopharmaceuticals. Nanopharmaceuticals, their routes of administration, obstacles and solutions concerning their improved application and enhanced efficacy have been briefly yet comprehensively described. Cancer is one of the leading causes of death worldwide and evergrowing number of scientific research on the topic only confirms that the needs have not been completed yet and that there is a wide platform for improvement. This is undoubtedly true for nanoformulations of an anticancer drug doxorubicin, where various nanocarrriers were given an important role to reduce the drug toxicity, while the efficacy of the drug was supposed to be retained or preferably enhanced. Therefore, we present an interdisciplinary comprehensive overview of interdisciplinary nature on nanopharmaceuticals based on doxorubicin and its nanoformulations with valuable information concerning trends, obstacles and prospective of nanopharmaceuticals development, mode of activity of sole drug doxorubicin and its nanoformulations based on different nanocarriers, their brief descriptions of biological activity through assessing in vitro and in vivo behavior.

Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer.

PubMed

Lv, Li; Liu, Chunxia; Chen, Chuxiong; Yu, Xiaoxia; Chen, Guanghui; Shi, Yonghui; Qin, Fengchao; Ou, Jiebin; Qiu, Kaifeng; Li, Guocheng

2016-05-31

The combination of a chemotherapeutic drug with a chemosensitizer has emerged as a promising strategy for cancers showing multidrug resistance (MDR). Herein we describe the simultaneous targeted delivery of two drugs to tumor cells by using biotin-decorated poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles encapsulating the chemotherapeutic drug doxorubicin and the chemosensitizer quercetin (BNDQ). Next, the potential ability of BNDQ to reverse MDR in vitro and in vivo was investigated. Studies demonstrated that BNDQ was more effectively taken up with less efflux by doxorubicin-resistant MCF-7 breast cancer cells (MCF-7/ADR cells) than by the cells treated with the free drugs, single-drug-loaded nanoparticles, or non-biotin-decorated nanoparticles. BNDQ exhibited clear inhibition of both the activity and expression of P-glycoprotein in MCF-7/ADR cells. More importantly, it caused a significant reduction in doxorubicin resistance in MCF-7/ADR breast cancer cells both in vitro and in vivo, among all the groups. Overall, this study suggests that BNDQ has a potential role in the treatment of drug-resistant breast cancer.

Micellar induced regioselectivity in the two-step consecutive reaction of SO3(2-) with Br-(CH2CH2)n-Br (n=2-5).

PubMed

Currie, Fredrik; Jarvoll, Patrik; Holmberg, Krister; Romsted, Laurence S; Gunaseelan, Krishnan

2007-08-15

High field (800 MHz) (1)H NMR was used to monitor the two-step consecutive reaction of excess SO(3)(2-) with symmetrical bifunctional alpha,omega-dibromoalkanes with butane (DBB), hexane (DBH), octane (DBO), and decane (DBD) chains in CTAB micelles at 25 degrees C. The first-order rate constant for the first substitution step for DBB and DBH is about 5 times faster than for the second, but the kinetics for DBO and DBD were not cleanly first-order. After 40 min, the solution contained about 80% of the intermediate bromoalkanesulfonate from DBB and DBH and the remainder is alkanedisulfonate and unreacted starting material. The same reactions were carried out in homogeneous MeOH/D(2)O solutions at 50 degrees C. The rate constants for all four alpha,omega-dibromoalkanes were first-order throughout the time course of the reaction and the same within +/-10%. However, because micellar solutions are organized on the nanoscale and bring together lipophilic and hydrophilic reactants into a small reaction volume at the micellar interface, they speed this substitution reaction considerably compared to reaction in MeOH/D(2)O. The CTAB micelles also induce a significant regioselectivity in product formation by speeding the first step of the consecutive reaction more than the second. The results are consistent with the bromoalkanesulfonate intermediates having a radial orientation within the micelles with the -CH(2)SO(3)(-) group in the interfacial region and the -CH(2)Br group directed into the micellar core such that the concentration of -CH(2)Br groups in the reactive zone, i.e., the micellar interface, is significantly reduced. These results provide the first example of self-assembled surfactant system altering the relative rates of the reaction steps of a consecutive reaction and, in doing so, enhancing monosubstitution of a symmetrically disubstituted species.

Influence of solvent on micellar morphologies of semifluorinated block copolymers.

PubMed

Lee, Min Young; Kim, Sang Jae; Jeong, Yeon Tae; Kim, Joo Hyun; Gal, Yeong-Soon; Lim, Kwon Taek

2009-12-01

The influence of solvents on micellar architectures of block copolymers composed of poly(1H,1H-dihydroperfluorooctyl methacrylate) and poly(ethylene oxide) was investigated. In this study, binary solvents with desired proportions were chosen, which had remarkable influence on the morphology of the resulting micelles. With simple adjusting the composition of the binary solvent of chloroform and trichlorofluoromethane, interesting shapes of micelle-like aggregates, such as core-shell, cylinder, worm-like and inverted micelles were formed with sizes of 15, 70, 30 and 250 nm, respectively. In the case of methanol/water system, core-shell spheres and vesicles were produced by varying the proportion of the contents. The morphologies were also tuned to honeycomb-like and bowl-shaped micelles as well as large planar lamellae with holes in DMF and water binary solvent.

Multiple sessions of liposomal doxorubicin delivery via focused ultrasound mediated blood-brain barrier disruption: a safety study.

PubMed

Aryal, Muna; Vykhodtseva, Natalia; Zhang, Yong-Zhi; McDannold, Nathan

2015-04-28

Transcranial MRI-guided focused ultrasound is a rapidly advancing method for delivering therapeutic and imaging agents to the brain. It has the ability to facilitate the passage of therapeutics from the vasculature to the brain parenchyma, which is normally protected by the blood-brain barrier (BBB). The method's main advantages are that it is both targeted and noninvasive, and that it can be easily repeated. Studies have shown that liposomal doxorubicin (Lipo-DOX), a chemotherapy agent with promise for tumors in the central nervous system, can be delivered into the brain across BBB. However, prior studies have suggested that doxorubicin can be significantly neurotoxic, even at small concentrations. Here, we studied whether multiple sessions of Lipo-DOX administered after FUS-induced BBB disruption (FUS-BBBD) induces severe adverse events in the normal brain tissues. First, we used fluorometry to measure the doxorubicin concentrations in the brain after FUS-BBBD to ensure that a clinically relevant doxorubicin concentration was achieved in the brain. Next, we performed three weekly sessions with FUS-BBBD±Lipo-DOX administration. Five to twelve targets were sonicated each week, following a schedule described previously in a survival study in glioma-bearing rats (Aryal et al., 2013). Five rats received three weekly sessions where i.v. injected Lipo-DOX was combined with FUS-BBBD; an additional four rats received FUS-BBBD only. Animals were euthanized 70days from the first session and brains were examined in histology. We found that clinically-relevant concentrations of doxorubicin (4.8±0.5μg/g) were delivered to the brain with the sonication parameters (0.69MHz; 0.55-0.81MPa; 10ms bursts; 1Hz PRF; 60s duration), microbubble concentration (Definity, 10μl/kg), and the administered Lipo-DOX dose (5.67mg/kg) used. The resulting concentration of Lipo-DOX was reduced by 32% when it was injected 10min after the last sonication compared to cases where the agent was

Dexrazoxane treatment of doxorubicin extravasation injury in four dogs.

PubMed

Venable, Rachel O; Saba, Corey F; Endicott, Melissa M; Northrup, Nicole C

2012-02-01

4 dogs were treated with dexrazoxane for known or suspected doxorubicin extravasation. Records were retrospectively reviewed. Doses and number of doses of dexrazoxane were variable. Dexrazoxane was administered within 2 hours after known extravasation in 3 dogs and 48 hours after suspected extravasation in 1 dog. Additional medical treatments included tissue cooling in all dogs, topically administered dimethyl sulfoxide ointment in 3, and orally administered piroxicam in 1. Mild erythema and edema at the extravasation site developed within 1 to 6 days after extravasation in the 3 dogs that received dexrazoxane within 2 hours after extravasation. Extensive tissue necrosis occurred in the dog treated 48 hours after suspected extravasation. Only the dog with severe tissue necrosis required surgical intervention. Lesions in the other 3 dogs resolved with medical management alone. All dogs survived the event. To date, use of dexrazoxane in the management of doxorubicin extravasation has not been reported in dogs. Treatment was successful in 3 of 4 patients. The most effective dosage and timing of administration are unknown; however, there is evidence to suggest that administration within 6 hours after the event is warranted. Further studies are needed to confirm efficacy and to optimize use of this drug in the prevention and treatment of anthracycline extravasation injury in veterinary patients.

Designing Drug Conjugates Based on Sugar Decorated V-Shape and Star Polymethacrylates: Influence of Composition and Architecture of Polymeric Carrier.

PubMed

Mielańczyk, Anna; Neugebauer, Dorota

2015-12-16

Amphiphilic ethylenediamine (EDA)-functionalized V-shape and star copolymers with centrally placed methyl-α,D-glucopyranoside were designed as nanocarriers. Anticancer doxorubicin (DOX) was conjugated in water via amine groups in copolymers to form ketimine linkers. Variations of arm length and number (40-65 units per arm and 2 vs 3 vs 4 arms), DOX feed amount, and conjugation site content (50-160 units of EDA groups), as responsible for efficiency of drug attachment (10-60 units of conjugated DOX) and its release at various pH (5.0 vs 7.4), were studied to demonstrate potential for drug delivery. Size of conjugate particles (10-195 nm) formed in aqueous solution was strongly dependent on the polymer composition and topology. The broad range of drug amounts (25-95%) were detected by the precipitation method, showing pH sensitivity by some polymeric conjugates with faster DOX release in acidic conditions.

Self-association of analgesics in aqueous solution: micellar properties of dextropropoxyphene hydrochloride and methadone hydrochloride.

PubMed

Attwood, D; Tolley, J A

1980-08-01

The solution properties of several analgesics including dextropropoxyphene hydrochloride, methadone hydrochloride, dextromoramide acid tartrate and dipipanone hydrochloride have been examined using light scattering, conductivity, vapour pressure osmometry and surface tension techniques. A micellar pattern of association was established for dextropropoxyphene hydrochloride and methadone hydrochloride and critical micelle concentrations and aggregation numbers are reported. The hydrophobic contribution to the free energy of micellization of dextropropoxyphene was determined from measurement of the critical micelle concentration in the presence of added electrolyte.

Comparing Apoptosis and Necrosis Effects of Arctium Lappa Root Extract and Doxorubicin on MCF7 and MDA-MB-231 Cell Lines

PubMed

Ghafari, Fereshteh; Rajabi, Mohammad Reza; Mazoochi, Tahereh; Taghizadeh, Mohsen; Nikzad, Hossein; Atlasi, Mohammad Ali; Taherian, Aliakbar

2017-03-01

Objective: Breast cancer is a heterogeneous disease and very common malignancy in women worldwide. The efficacy of chemotherapy as an important part of breast cancer treatment is limited due to its side effects. While pharmaceutical companies are looking for better chemicals, research on traditional medicines that generally have fewer side effects is quite interesting. In this study, apoptosis and necrosis effect of Arctium lappa and doxorubicin was compared in MCF7, and MDA-MB-231 cell lines. Materials and Methods: MCF7 and MDA-MB-231 cells were cultured in RPMI 1640 containing 10% FBS and 100 U/ml penicillin/streptomycin. MTT assay and an annexin V/propidium iodide (AV/PI) kit were used respectively to compare the survival rate and apoptotic effects of different concentrations of doxorubicin and Arctium lappa root extract on MDA-MB-231 and MCF7 cells. Results: Arctium lappa root extract was able to reduce cell viability of the two cell lines in a dose and time dependent manner similar to doxorubicin. Flow cytometry results showed that similar to doxorubicin, Arctium Lappa root extract had a dose and time dependent apoptosis effect on both cell lines. 10μg/mL of Arctium lappa root extract and 5 μM of doxorubicin showed the highest anti-proliferative and apoptosis effect in MCF7 and MDA231 cells. Conclusion: The MCF7 (ER/PR-) and MDA-MB-231 (ER/PR+) cell lines represent two major breast cancer subtypes. The similar anti-proliferative and apoptotic effects of Arctium lappa root extract and doxorubicin (which is a conventional chemotherapy drug) on two different breast cancer cell lines strongly suggests its anticancer effects and further studies. Creative Commons Attribution License

Determination of adulteration of malachite green in green pea and some prepared foodstuffs by micellar liquid chromatography.

PubMed

Ashok, Vipin; Agrawal, Nitasha; Durgbanshi, Abhilasha; Esteve-Romero, Josep; Bose, Devasish

2014-01-01

A simple, fast, and robust micellar LC method was developed for the separation and identification of the nonpermitted color malachite green in green pea and some ready-to-eat foodstuffs. Malachite green (4-[(4-dimethylaminophenyl) phenyl-methyl]-N,N-dimethylaniline) is a hazardous dye that is used to treat fungal and protozoan infections in fish and is a common adulterant (coloring agent) in green pea and other green vegetables because of its green color. In the present work, malachite green was determined in various foodstuffs using a direct injection technique on an RP C18 column with isocratic elution. The optimum mobile phase consisted of 0.15 M sodium dodecyl sulfate (SDS), 6% pentanol buffered at pH 5. Detection was carried out at 620 nm. Malachite green was eluted in 9.2 min without any interference caused by endogenous compounds. Linearities (r > 0.9999), intraday and interday precision (RSD less than 1.00%) in micellar media, and robustness were studied for method validation. LOD and LOQ were 0.10 and 0.25 ppm, respectively. The simplicity of the developed method makes it useful for routine analysis in the area of food QC.

Polymerization of perfluorobutadiene

NASA Technical Reports Server (NTRS)

Newman, J.; Toy, M. S.

1970-01-01

Diisopropyl peroxydicarbonate dissolved in liquid perfluorobutadiene is conducted in a sealed vessel at the autogenous pressure of polymerization. Reaction temperature, ratio of catalyst to monomer, and amount of agitation determine degree of polymerization and product yield.

SOX2OT variant 7 contributes to the synergistic interaction between EGCG and Doxorubicin to kill osteosarcoma via autophagy and stemness inhibition.

PubMed

Wang, Wanchun; Chen, Ding; Zhu, Kewei

2018-02-23

Doxorubicin is the preferred chemotherapeuticdrug for osteosarcoma treatment of which clinical efficacy is limited because of its chemo-resistance and cardiac toxicity. It is necessary to develop the combination regimen with complementary molecular mechanisms to reduce the side effects and enhance sensitivity of Doxorubicin. EGCG is a polyphenol in green tea with antitumor bioactivity,which has been found that its combination with certain chemotherapeutic drugs could improve the antitumor efficiency. In this study, MTT assay was used to detect the cell growth inhibition The CD133+/CD44+ cells were isolated from U2OS and SaoS2 cell lines using magnetic-activated cell sorting and identified by flow cytometry analysis. qRT-PCR was used for determining the relative mRNA levels of key genes. Immunofluorescence was performed to evaluate the autophagy flux alterations. Self-renewal ability was accessed by sphere-forming assay. Tumorigenicity in nude mice was preformed to evaluate tumorigenicity in vivo. We found that EGCG targeting LncRNA SOX2OT variant 7 produced synergistic effects with Doxorubicin on osteosarcoma cell growth inhibition. On the one hand, EGCG could reduce the Doxorubicin-induced pro-survival autophagy through decreasing SOX2OT variant 7 to improve the growth inhibition of Doxorubicin. On the other hand, EGCG could partially inactivate Notch3/DLL3 signaling cascade targeting SOX2OT variant 7 to reduce the stemness then abated drug-resistance of osteosarcoma cells. This study will help to reveal the molecular mechanisms of synergistic effects of EGCG and Doxorubicin on OS chemotherapy and improve the clinical efficacy of chemotherapy as well as provide a basis for developing antitumor drugs targeting osteosarcoma stem cells.

Effect of Irradiation on Tissue Penetration Depth of Doxorubicin after Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a Novel Ex-Vivo Model.

PubMed

Khosrawipour, Veria; Giger-Pabst, Urs; Khosrawipour, Tanja; Pour, Yousef Hedayat; Diaz-Carballo, David; Förster, Eckart; Böse-Ribeiro, Hugo; Adamietz, Irenäus Anton; Zieren, Jürgen; Fakhrian, Khashayar

2016-01-01

This study was performed to assess the impact of irradiation on the tissue penetration depth of doxorubicin delivered during Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC). Fresh post mortem swine peritoneum was cut into 10 proportional sections. Except for 2 control samples, all received irradiation with 1, 2, 7 and 14 Gy, respectively. Four samples received PIPAC 15 minutes after irradiation and 4 other after 24 hours. Doxorubicin was aerosolized in an ex-vivo PIPAC model at 12 mmHg/36°C. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. Doxorubicin penetration after PIPAC (15 minutes after irradiation) was 476 ± 74 µm for the control sample, 450 ± 45µm after 1 Gy (p > 0.05), 438 ± 29 µm after 2 Gy (p > 0.05), 396 ± 32 µm after 7 Gy (p = 0.005) and 284 ± 57 after 14 Gy irradiation (p < 0.001). The doxorubicin penetration after PIPAC (24 hours after irradiation) was 428 ± 77 µm for the control sample, 393 ± 41 µm after 1 Gy (p > 0.05), 379 ± 56 µm after 2 Gy (p > 0.05), 352 ± 53 µm after 7 Gy (p = 0.008) and 345 ± 53 after 14 Gy irradiation (p = 0.001). Higher (fractional) radiation dose might reduce the tissue penetration depth of doxorubicin in our ex-vivo model. However, irradiation with lower (fractional) radiation dose does not affect the tissue penetration negatively. Further studies are warranted to investigate if irradiation can be used safely as chemopotenting agent for patients with peritoneal metastases treated with PIPAC.

Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats.

PubMed

Kitamura, Yoshihisa; Kanemoto, Erika; Sugimoto, Misaki; Machida, Ayumi; Nakamura, Yuka; Naito, Nanami; Kanzaki, Hirotaka; Miyazaki, Ikuko; Asanuma, Masato; Sendo, Toshiaki

2017-04-01

In the present study, we examined the effects of nicotine on cognitive impairment, anxiety-like behavior, and hippocampal cell proliferation in rats treated with a combination of doxorubicin and cyclophosphamide. Combined treatment with doxorubicin and cyclophosphamide produced cognitive impairment and anxiety-like behavior in rats. Nicotine treatment reversed the inhibition of novel location recognition induced by the combination treatment. This effect of nicotine was blocked by methyllycaconitine, a selective α7 nicotinic acetylcholine receptor (nAChR) antagonist, and dihydro-β-erythroidine, a selective α4β2 nAChR antagonist. In addition, nicotine normalized the amount of spontaneous alternation seen during the Y-maze task, which had been reduced by the combination treatment. This effect of nicotine was inhibited by dihydro-β-erythroidine. In comparison, nicotine did not affect the anxiety-like behavior induced by the combination treatment. Furthermore, the combination treatment reduced the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus, and this was also prevented by nicotine. Finally, the combination of doxorubicin and cyclophosphamide significantly reduced hippocampal α7 nAChR mRNA expression. These results suggest that nicotine inhibits doxorubicin and cyclophosphamide-induced cognitive impairment via α7 nAChR and α4β2 nAChR, and also enhances hippocampal neurogenesis.

Thio-amide functionalized polymers via polymerization or post-polymerization modification

NASA Astrophysics Data System (ADS)

Ozcam, Ali; Henke, Adam; Stibingerova, Iva; Srogl, Jiri; Genzer, Jan

2011-03-01

Decreasing supplies of fresh water and increasing population necessitates development of advanced water cleaning technologies, which would facilitate the removal of water pollutants. Amongst the worst of such contaminants are heavy metals and cyanides, infamous for their high toxicity. To assist the water purification processes, we aim to synthesize functionalized macromolecules that would contribute in the decontamination processes by scavenging detrimental chemicals. Epitomizing this role thio-amide unit features remarkable chemical flexibility that facilitates reversible catch-release of the ions, where the behavior controlled by subtle red-ox changes in the environment. Chemical tunability of the thio-amide moiety enables synthesis of thio-amide based monomers and post-polymerization modification agents. Two distinct synthetic pathways, polymerization and post-polymerization modification, have been exploited, leading to functional thioamide-based macromolecules: thioamide-monomers were copolymerized with N-isopropylacrylamide and post-polymerization modifications of poly(dimethylaminoethyl methacrylate) and poly(propargyl methacrylate) were accomplished via quarternization and ``click'' reactions, respectively.

Structural transformations in diluted micellar and lamellar systems

NASA Astrophysics Data System (ADS)

Zelaya-Rincon, Blanca