Liquid crystalline systems for transdermal delivery of celecoxib: in vitro drug release and skin permeation studies.

PubMed

Estracanholli, Eder André; Praça, Fabíola Silva Garcia; Cintra, Ana Beatriz; Pierre, Maria Bernadete Riemma; Lara, Marilisa Guimarães

2014-12-01

Liquid crystalline systems of monoolein/water could be a promising approach for the delivery of celecoxib (CXB) to the skin because these systems can sustain drug release, improve drug penetration into the skin layers and minimize side effects. This study evaluated the potential of these systems for the delivery of CXB into the skin based on in vitro drug release and skin permeation studies. The amount of CXB that permeated into and/or was retained in the skin was assayed using an HPLC method. Polarizing light microscopy studies showed that liquid crystalline systems of monoolein/water were formed in the presence of CXB, without any changes in the mesophases. The liquid crystalline systems decreased drug release when compared to control solution. Drug release was independent of the initial water content of the systems and CXB was released from cubic phase systems, irrespective of the initial water content. The systems released the CXB following zero-order release kinetics. In vitro drug permeation studies showed that cubic phase systems allowed drug permeation and retention in the skin layers. Cubic phase systems of monoolein/water may be promising vehicles for the delivery of CXB in/through the skin because it improved CXB skin permeation compared with the control solution.

Osmotically driven drug delivery through remote-controlled magnetic nanocomposite membranes.

PubMed

Zaher, A; Li, S; Wolf, K T; Pirmoradi, F N; Yassine, O; Lin, L; Khashab, N M; Kosel, J

2015-09-01

Implantable drug delivery systems can provide long-term reliability, controllability, and biocompatibility, and have been used in many applications, including cancer pain and non-malignant pain treatment. However, many of the available systems are limited to zero-order, inconsistent, or single burst event drug release. To address these limitations, we demonstrate prototypes of a remotely operated drug delivery device that offers controllability of drug release profiles, using osmotic pumping as a pressure source and magnetically triggered membranes as switchable on-demand valves. The membranes are made of either ethyl cellulose, or the proposed stronger cellulose acetate polymer, mixed with thermosensitive poly(N-isopropylacrylamide) hydrogel and superparamagnetic iron oxide particles. The prototype devices' drug diffusion rates are on the order of 0.5-2 μg/h for higher release rate designs, and 12-40 ng/h for lower release rates, with maximum release ratios of 4.2 and 3.2, respectively. The devices exhibit increased drug delivery rates with higher osmotic pumping rates or with magnetically increased membrane porosity. Furthermore, by vapor deposition of a cyanoacrylate layer, a drastic reduction of the drug delivery rate from micrograms down to tens of nanograms per hour is achieved. By utilizing magnetic membranes as the valve-control mechanism, triggered remotely by means of induction heating, the demonstrated drug delivery devices benefit from having the power source external to the system, eliminating the need for a battery. These designs multiply the potential approaches towards increasing the on-demand controllability and customizability of drug delivery profiles in the expanding field of implantable drug delivery systems, with the future possibility of remotely controlling the pressure source.

Osmotically driven drug delivery through remote-controlled magnetic nanocomposite membranes

PubMed Central

Zaher, A.; Li, S.; Wolf, K. T.; Pirmoradi, F. N.; Yassine, O.; Lin, L.; Khashab, N. M.; Kosel, J.

2015-01-01

Implantable drug delivery systems can provide long-term reliability, controllability, and biocompatibility, and have been used in many applications, including cancer pain and non-malignant pain treatment. However, many of the available systems are limited to zero-order, inconsistent, or single burst event drug release. To address these limitations, we demonstrate prototypes of a remotely operated drug delivery device that offers controllability of drug release profiles, using osmotic pumping as a pressure source and magnetically triggered membranes as switchable on-demand valves. The membranes are made of either ethyl cellulose, or the proposed stronger cellulose acetate polymer, mixed with thermosensitive poly(N-isopropylacrylamide) hydrogel and superparamagnetic iron oxide particles. The prototype devices' drug diffusion rates are on the order of 0.5–2 μg/h for higher release rate designs, and 12–40 ng/h for lower release rates, with maximum release ratios of 4.2 and 3.2, respectively. The devices exhibit increased drug delivery rates with higher osmotic pumping rates or with magnetically increased membrane porosity. Furthermore, by vapor deposition of a cyanoacrylate layer, a drastic reduction of the drug delivery rate from micrograms down to tens of nanograms per hour is achieved. By utilizing magnetic membranes as the valve-control mechanism, triggered remotely by means of induction heating, the demonstrated drug delivery devices benefit from having the power source external to the system, eliminating the need for a battery. These designs multiply the potential approaches towards increasing the on-demand controllability and customizability of drug delivery profiles in the expanding field of implantable drug delivery systems, with the future possibility of remotely controlling the pressure source. PMID:26487899

Gelatin device for the delivery of growth factors involved in endochondral ossification.

PubMed

Ahrens, Lucas A J; Vonwil, Daniel; Christensen, Jon; Shastri, V Prasad

2017-01-01

Controlled release drug delivery systems are well established as oral and implantable dosage forms. However, the controlled release paradigm can also be used to present complex soluble signals responsible for cellular organization during development. Endochondral ossification (EO), the developmental process of bone formation from a cartilage matrix is controlled by several soluble signals with distinct functions that vary in structure, molecular weight and stability. This makes delivering them from a single vehicle rather challenging. Herein, a gelatin-based delivery system suitable for the delivery of small molecules as well as recombinant human (rh) proteins (rhWNT3A, rhFGF2, rhVEGF, rhBMP4) is reported. The release behavior and biological activity of the released molecules was validated using analytical and biological assays, including cell reporter systems. The simplicity of fabrication of the gelatin device should foster its adaptation by the diverse scientific community interested in interrogating developmental processes, in vivo.

Gelatin device for the delivery of growth factors involved in endochondral ossification

PubMed Central

Ahrens, Lucas A. J.; Vonwil, Daniel; Christensen, Jon

2017-01-01

Controlled release drug delivery systems are well established as oral and implantable dosage forms. However, the controlled release paradigm can also be used to present complex soluble signals responsible for cellular organization during development. Endochondral ossification (EO), the developmental process of bone formation from a cartilage matrix is controlled by several soluble signals with distinct functions that vary in structure, molecular weight and stability. This makes delivering them from a single vehicle rather challenging. Herein, a gelatin-based delivery system suitable for the delivery of small molecules as well as recombinant human (rh) proteins (rhWNT3A, rhFGF2, rhVEGF, rhBMP4) is reported. The release behavior and biological activity of the released molecules was validated using analytical and biological assays, including cell reporter systems. The simplicity of fabrication of the gelatin device should foster its adaptation by the diverse scientific community interested in interrogating developmental processes, in vivo. PMID:28380024

Construction of a controlled-release delivery system for pesticides using biodegradable PLA-based microcapsules.

PubMed

Liu, Baoxia; Wang, Yan; Yang, Fei; Wang, Xing; Shen, Hong; Cui, Haixin; Wu, Decheng

2016-08-01

Conventional pesticides usually need to be used in more than recommended dosages due to their loss and degradation, which results in a large waste of resources and serious environmental pollution. Encapsulation of pesticides in biodegradable carriers is a feasible approach to develop environment-friendly and efficient controlled-release delivery system. In this work, we fabricated three kinds of polylactic acid (PLA) carriers including microspheres, microcapsules, and porous microcapsules for controlled delivery of Lambda-Cyhalothrin (LC) via premix membrane emulsification (PME). The microcapsule delivery system had better water dispersion than the other two systems. Various microcapsules with a high LC contents as much as 40% and tunable sizes from 0.68 to 4.6μm were constructed by manipulating the process parameters. Compared with LC technical and commercial microcapsule formulation, the microcapsule systems showed a significantly sustained release of LC for a longer period. The LC release triggered by LC diffusion and matrix degradation could be optimally regulated by tuning LC contents and particle sizes of the microcapsules. This multi-regulated release capability is of great significance to achieve the precisely controlled release of pesticides. A preliminary bioassay against plutella xylostella revealed that 0.68μm LC-loaded microcapsules with good UV and thermal stability exhibited an activity similar to a commercial microcapsule formulation. These results demonstrated such an aqueous microcapsule delivery system had a great potential to be further explored for developing an effective and environmentally friendly pesticide-release formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Recent advances on smart TiO2 nanotube platforms for sustainable drug delivery applications.

PubMed

Wang, Qun; Huang, Jian-Ying; Li, Hua-Qiong; Zhao, Allan Zi-Jian; Wang, Yi; Zhang, Ke-Qin; Sun, Hong-Tao; Lai, Yue-Kun

To address the limitations of traditional drug delivery, TiO 2 nanotubes (TNTs) are recognized as a promising material for localized drug delivery systems. With regard to the excellent biocompatibility and physicochemical properties, TNTs prepared by a facile electrochemical anodizing process have been used to fabricate new drug-releasing implants for localized drug delivery. This review discusses the development of TNTs applied in localized drug delivery systems, focusing on several approaches to control drug release, including the regulation of the dimensions of TNTs, modification of internal chemical characteristics, adjusting pore openings by biopolymer coatings, and employing polymeric micelles as drug nanocarriers. Furthermore, rational strategies on external conditions-triggered stimuli-responsive drug release for localized drug delivery systems are highlighted. Finally, the review concludes with the recent advances on TNTs for controlled drug delivery and corresponding prospects in the future.

Recent advances on smart TiO2 nanotube platforms for sustainable drug delivery applications

PubMed Central

Wang, Qun; Huang, Jian-Ying; Li, Hua-Qiong; Zhao, Allan Zi-Jian; Wang, Yi; Zhang, Ke-Qin; Sun, Hong-Tao; Lai, Yue-Kun

2017-01-01

To address the limitations of traditional drug delivery, TiO2 nanotubes (TNTs) are recognized as a promising material for localized drug delivery systems. With regard to the excellent biocompatibility and physicochemical properties, TNTs prepared by a facile electrochemical anodizing process have been used to fabricate new drug-releasing implants for localized drug delivery. This review discusses the development of TNTs applied in localized drug delivery systems, focusing on several approaches to control drug release, including the regulation of the dimensions of TNTs, modification of internal chemical characteristics, adjusting pore openings by biopolymer coatings, and employing polymeric micelles as drug nanocarriers. Furthermore, rational strategies on external conditions-triggered stimuli-responsive drug release for localized drug delivery systems are highlighted. Finally, the review concludes with the recent advances on TNTs for controlled drug delivery and corresponding prospects in the future. PMID:28053530

Self-Assembled Smart Nanocarriers for Targeted Drug Delivery.

PubMed

Cui, Wei; Li, Junbai; Decher, Gero

2016-02-10

Nanostructured drug-carrier systems promise numerous benefits for drug delivery. They can be engineered to precisely control drug-release rates or to target specific sites within the body with a specific amount of therapeutic agent. However, to achieve the best therapeutic effects, the systems should be designed for carrying the optimum amount of a drug to the desired target where it should be released at the optimum rate for a specified time. Despite numerous attempts, fulfilling all of these requirements in a synergistic way remains a huge challenge. The trend in drug delivery is consequently directed toward integrated multifunctional carrier systems, providing selective recognition in combination with sustained or triggered release. Capsules as vesicular systems enable drugs to be confined for controlled release. Furthermore, carriers modified with recognition groups can enhance the capability of encapsulated drug efficacy. Here, recent advances are reviewed regarding designing and preparing assembled capsules with targeting ligands or size controllable for selective recognition in drug delivery. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fabrication of Plasmonic Nanorod-Embedded Dipeptide Microspheres via the Freeze-Quenching Method for Near-Infrared Laser-Triggered Drug-Delivery Applications.

PubMed

Erdogan, Hakan; Yilmaz, Mehmet; Babur, Esra; Duman, Memed; Aydin, Halil M; Demirel, Gokhan

2016-05-09

Control of drug release by an external stimulus may provide remote controllability, low toxicity, and reduced side effects. In this context, varying physical external stimuli, including magnetic and electric fields, ultrasound, light, and pharmacological stimuli, have been employed to control the release rate of drug molecules in a diseased region. However, the design and development of alternative on-demand drug-delivery systems that permit control of the dosage of drug released via an external stimulus are still required. Here, we developed near-infrared laser-activatable microspheres based on Fmoc-diphenylalanine (Phe-Phe) dipeptides and plasmonic gold nanorods (AuNRs) via a simple freeze-quenching approach. These plasmonic nanoparticle-embedded microspheres were then employed as a smart drug-delivery platform for native, continuous, and pulsatile doxorubicin (DOX) release. Remarkable sustained, burst, and on-demand DOX release from the fabricated microspheres were achieved by manipulating the laser exposure time. Our results demonstrate that AuNR-embedded dipeptide microspheres have great potential for controlled drug-delivery systems.

Glucose-Responsive Supramolecular Vesicles Based on Water-Soluble Pillar[5]arene and Pyridylboronic Acid Derivatives for Controlled Insulin Delivery.

PubMed

Gao, Lei; Wang, Tingting; Jia, Keke; Wu, Xuan; Yao, Chenhao; Shao, Wei; Zhang, Dongmei; Hu, Xiao-Yu; Wang, Leyong

2017-05-11

The stimuli-responsive behavior of supramolecular nanocarriers is crucial for their potential applications as smart drug delivery systems. We hereby constructed a glucose-responsive supramolecular drug delivery system based on the host-guest interaction between a water-soluble pillar[5]arene (WP5) and a pyridylboronic acid derivative (G) for insulin delivery and controlled release under physiological conditions. The approach represents the ideal treatment of diabetes mellitus. The drug loading and in vitro drug release experiments demonstrated that large molecular weight insulin could be encapsulated into the vesicles with high loading efficiency, which, to our knowledge, is the first example of small-size supramolecular vesicles with excellent encapsulation capacity of a large protein molecule. Moreover, FITC-labeled insulin was used to evaluate the release behavior of insulin, and it was demonstrated that high glucose concentration could facilitate the quick release of insulin, suggesting a smart drug delivery system for potential application in controlled insulin release only under hyperglycemic conditions. Finally, we demonstrated that these supramolecular nanocarriers have good cytocompatibility, which is essential for their further biomedical applications. The present study provides a novel strategy for the construction of glucose-responsive smart supramolecular drug delivery systems, which has potential applications for the treatment of diabetes mellitus. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Controlled drug release by polymer dissolution. II: Enzyme-mediated delivery device.

PubMed

Heller, J; Trescony, P V

1979-07-01

A novel, closed-loop drug delivery system was developed where the presence or absence of an external compound controls drug delivery from a bioerodible polymer. In the described delivery system, hydrocortisone was incorporated into a n-hexyl half-ester of a methyl vinyl ehter-maleic anhydride copolymer, and the polymer-drug mixture was fabricated into disks. These disks were then coated with a hydrogel containing immobilized urease. In a medium of constant pH and in the absence of external urea, the hydrocortisone release was that normally expected for that polymer at the given pH. With external urea, ammonium bicarbonate and ammonium hydroxide were generated within the hydrogel, which accelerated polymer erosion and drug release. The drug delivery rate increase was proportional to the amount of external urea and was reversible; that is, when external urea was removed, the drug release rate gradually returned to its original value.

Evaluation of superabsorbent linseed-polysaccharides as a novel stimuli-responsive oral sustained release drug delivery system.

PubMed

Haseeb, Muhammad Tahir; Hussain, Muhammad Ajaz; Bashir, Sajid; Ashraf, Muhammad Umer; Ahmad, Naveed

2017-03-01

Advancement in technology has transformed the conventional dosage forms to intelligent drug delivery systems. Such systems are helpful for targeted and efficient drug delivery with minimum side effects. Drug release from these systems is governed and controlled by external stimuli (pH, enzymes, ions, glucose, etc.). Polymeric biomaterial having stimuli-responsive properties has opened a new area in drug delivery approach. Potential of a polysaccharide (rhamnogalacturonan)-based hydrogel from Linseeds (Linum usitatissimum L.) was investigated as an intelligent drug delivery material. Different concentrations of Linseed hydrogel (LSH) were used to prepare caffeine and diacerein tablets and further investigated for pH and salt solution-responsive swelling, pH-dependent drug release, and release kinetics. Morphology of tablets was observed using SEM. LSH tablets exhibited dynamic swelling-deswelling behavior with tendency to swell at pH 7.4 and in deionized water while deswell at pH 1.2, in normal saline and ethanol. Consequently, pH controlled release of the drugs was observed from tablets with lower release (<10%) at pH 1.2 and higher release at pH 6.8 and 7.4. SEM showed elongated channels in swollen then freeze-dried tablets. The drug release was greatly influenced by the amount of LSH in the tablets. Drug release from LSH tablets was governed by the non-Fickian diffusion. These finding indicates that LSH holds potential to be developed as sustained release material for tablet.

Design Project on Controlled-Release Drug Delivery Devices: Implementation, Management, and Learning Experiences

ERIC Educational Resources Information Center

Xu, Qingxing; Liang, Youyun; Tong, Yen Wah; Wang, Chi-Hwa

2010-01-01

A design project that focuses on the subject of controlled-release drug delivery devices is presented for use in an undergraduate course on mass transfer. The purpose of the project is to introduce students to the various technologies used in the fabrication of drug delivery systems and provide a practical design exercise for understanding the…

The Research Progress of Targeted Drug Delivery Systems

NASA Astrophysics Data System (ADS)

Zhan, Jiayin; Ting, Xizi Liang; Zhu, Junjie

2017-06-01

Targeted drug delivery system (DDS) means to selectively transport drugs to targeted tissues, organs, and cells through a variety of drugs carrier. It is usually designed to improve the pharmacological and therapeutic properties of conventional drugs and to overcome problems such as limited solubility, drug aggregation, poor bio distribution and lack of selectivity, controlling drug release carrier and to reduce normal tissue damage. With the characteristics of nontoxic and biodegradable, it can increase the retention of drug in lesion site and the permeability, improve the concentration of the drug in lesion site. at present, there are some kinds of DDS using at test phase, such as slow controlled release drug delivery system, targeted drug delivery systems, transdermal drug delivery system, adhesion dosing system and so on. This paper makes a review for DDS.

Elastin-Like Recombinamers As Smart Drug Delivery Systems.

PubMed

Arias, F Javier; Santos, Mercedes; Ibanez-Fonseca, Arturo; Pina, Maria Jesus; Serrano, Sofía

2018-02-19

Drug delivery systems that are able to control the release of bioactive molecules and designed to carry drugs to target sites are of particular interest for tissue therapy. Moreover, systems comprising materials that can respond to environmental stimuli and promote self-assembly and higher order supramolecular organization are especially useful in the biomedical field. Objetive: This review focuses on biomaterials suitable for this purpose and that include elastin-like recombinamers (ELRs), a class of proteinaceous polymers bioinspired by natural elastin, designed using recombinant technologies. The self-assembly and thermoresponsive behaviour of these systems, along with their biodegradability, biocompatibility and well-defined composition as a result of their tailormade design, make them particularly attractive for controlled drug delivery. ELR-based delivery systems that allow targeted delivery are reviewed, especially ELR-drug recombinant fusion constructs, ELR-drug systems chemically bioconjugated in their monomeric and soluble forms, and drug encapsulation by nanoparticle-forming ELRs. Subsequently, the review focuses on those drug carriers in which smart release is triggered by pH or temperature with a particular focus on cancer treatments. Systems for controlled drug release based on depots and hydrogels that act as both a support and reservoir in which drugs can be stored will be described, and their applications in drug delivery discussed. Finally, smart drug-delivery systems not based on ELRs, including those comprising proteins, synthetic polymers and non-polymeric systems, will also be briefly discussed. Several different constructions based on ELRs are potential candidates for controlled drug delivery to be applied in advanced biomedical treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Programmable release of multiple protein drugs from aptamer-functionalized hydrogels via nucleic acid hybridization.

PubMed

Battig, Mark R; Soontornworajit, Boonchoy; Wang, Yong

2012-08-01

Polymeric delivery systems have been extensively studied to achieve localized and controlled release of protein drugs. However, it is still challenging to control the release of multiple protein drugs in distinct stages according to the progress of disease or treatment. This study successfully demonstrates that multiple protein drugs can be released from aptamer-functionalized hydrogels with adjustable release rates at predetermined time points using complementary sequences (CSs) as biomolecular triggers. Because both aptamer-protein interactions and aptamer-CS hybridization are sequence-specific, aptamer-functionalized hydrogels constitute a promising polymeric delivery system for the programmable release of multiple protein drugs to treat complex human diseases.

Classification of stimuli-responsive polymers as anticancer drug delivery systems.

PubMed

Taghizadeh, Bita; Taranejoo, Shahrouz; Monemian, Seyed Ali; Salehi Moghaddam, Zoha; Daliri, Karim; Derakhshankhah, Hossein; Derakhshani, Zaynab

2015-02-01

Although several anticancer drugs have been introduced as chemotherapeutic agents, the effective treatment of cancer remains a challenge. Major limitations in the application of anticancer drugs include their nonspecificity, wide biodistribution, short half-life, low concentration in tumor tissue and systemic toxicity. Drug delivery to the tumor site has become feasible in recent years, and recent advances in the development of new drug delivery systems for controlled drug release in tumor tissues with reduced side effects show great promise. In this field, the use of biodegradable polymers as drug carriers has attracted the most attention. However, drug release is still difficult to control even when a polymeric drug carrier is used. The design of pharmaceutical polymers that respond to external stimuli (known as stimuli-responsive polymers) such as temperature, pH, electric or magnetic field, enzymes, ultrasound waves, etc. appears to be a successful approach. In these systems, drug release is triggered by different stimuli. The purpose of this review is to summarize different types of polymeric drug carriers and stimuli, in addition to the combination use of stimuli in order to achieve a better controlled drug release, and it discusses their potential strengths and applications. A survey of the recent literature on various stimuli-responsive drug delivery systems is also provided and perspectives on possible future developments in controlled drug release at tumor site have been discussed.

Ibuprofen-loaded poly(lactic-co-glycolic acid) films for controlled drug release.

PubMed

Pang, Jianmei; Luan, Yuxia; Li, Feifei; Cai, Xiaoqing; Du, Jimin; Li, Zhonghao

2011-01-01

Ibuprofen- (IBU) loaded biocompatible poly(lactic-co-glycolic acid) (PLGA) films were prepared by spreading polymer/ibuprofen solution on the nonsolvent surface. By controlling the weight ratio of drug and polymer, different drug loading polymer films can be obtained. The synthesized ibuprofen-loaded PLGA films were characterized with scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry. The drug release behavior of the as-prepared IBU-loaded PLGA films was studied to reveal their potential application in drug delivery systems. The results show the feasibility of the as-obtained films for controlling drug release. Furthermore, the drug release rate of the film could be controlled by the drug loading content and the release medium. The development of a biodegradable ibuprofen system, based on films, should be of great interest in drug delivery systems.

Ocular delivery of macromolecules

PubMed Central

Kim, Yoo-Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.

2014-01-01

Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromolecular drugs are typically given by physician-administered invasive delivery methods, because non--invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug delivery and improved drug targeting within the eye to increase efficacy and reduce side effects. This review discusses the barriers to drug delivery via various ophthalmic routes of administration in the context of macromolecule delivery and discusses efforts to develop controlled-release systems for delivery of biopharmaceuticals to the eye. The growing number of macromolecular therapies in the eye needs improved drug delivery methods that increase drug efficacy, safety and patient compliance. PMID:24998941

Chitosan nanoparticle based delivery systems for sustainable agriculture.

PubMed

Kashyap, Prem Lal; Xiang, Xu; Heiden, Patricia

2015-01-01

Development of technologies that improve food productivity without any adverse impact on the ecosystem is the need of hour. In this context, development of controlled delivery systems for slow and sustained release of agrochemicals or genetic materials is crucial. Chitosan has emerged as a valuable carrier for controlled delivery of agrochemicals and genetic materials because of its proven biocompatibility, biodegradability, non-toxicity, and adsorption abilities. The major advantages of encapsulating agrochemicals and genetic material in a chitosan matrix include its ability to function as a protective reservoir for the active ingredients, protecting the ingredients from the surrounding environment while they are in the chitosan domain, and then controlling their release, allowing them to serve as efficient gene delivery systems for plant transformation or controlled release of pesticides. Despite the great progress in the use of chitosan in the area of medical and pharmaceutical sciences, there is still a wide knowledge gap regarding the potential application of chitosan for encapsulation of active ingredients in agriculture. Hence, the present article describes the current status of chitosan nanoparticle-based delivery systems in agriculture, and to highlight challenges that need to be overcome. Copyright © 2015 Elsevier B.V. All rights reserved.

Advances in bioresponsive closed-loop drug delivery systems.

PubMed

Yu, Jicheng; Zhang, Yuqi; Yan, Junjie; Kahkoska, Anna R; Gu, Zhen

2017-11-27

Controlled drug delivery systems are able to improve efficacy and safety of therapeutics by optimizing the duration and kinetics of release. Among them, closed-loop delivery strategies, also known as self-regulated administration, have proven to be a practical tool for homeostatic regulation, by tuning drug release as a function of biosignals relevant to physiological and pathological processes. A typical example is glucose-responsive insulin delivery system, which can mimic the pancreatic beta cells to release insulin with a proper dose at a proper time point by responding to plasma glucose levels. Similar self-regulated systems are also important in the treatment of other diseases including thrombosis and bacterial infection. In this review, we survey the recent advances in bioresponsive closed-loop drug delivery systems, including glucose-responsive, enzyme-activated, and other biosignal-mediated delivery systems. We also discuss the future opportunities and challenges in this field. Copyright © 2017 Elsevier B.V. All rights reserved.

Smart linkers in polymer-drug conjugates for tumor-targeted delivery.

PubMed

Chang, Minglu; Zhang, Fang; Wei, Ting; Zuo, Tiantian; Guan, Yuanyuan; Lin, Guimei; Shao, Wei

2016-01-01

To achieve effective chemotherapy, many types of drug delivery systems have been developed for the specific environments in tumor tissues. Polymer-drug conjugates are increasingly used in tumor therapy due to several significant advantages over traditional delivery systems. In the fabrication of polymer-drug conjugates, a smart linker is an important component that joins two fragments or molecules together and can be cleared by a specific stimulus, which results in targeted drug delivery and controlled release. By regulating the conjugation between the drug and the nanocarriers, stimulus-sensitive systems based on smart linkers can offer high payloads, certified stability, controlled release and targeted delivery. In this review, we summarize the current state of smart linkers (e.g. disulfide, hydrazone, peptide, azo) used recently in various polymer-drug conjugate-based delivery systems with a primary focus on their sophisticated design principles and drug delivery mechanisms as well as in vivo processes.

Laser based synthesis of nanofunctionalized particulates for pulmonary based controlled drug delivery applications

NASA Astrophysics Data System (ADS)

Singh, R. K.; Kim, W.-S.; Ollinger, M.; Craciun, V.; Coowantwong, I.; Hochhaus, G.; Koshizaki, N.

2002-09-01

There is an urgent need to develop controlled drug release systems for the delivery of drugs via the pulmonary route. A key issue in pulmonary dry delivery systems is to reduce the amount of biodegradable polymers that are added to control the drug release. We have synthesized nanofunctionalized drug particles using the pulsed laser deposition on particles (PLDP) (e.g. budesonide) in an effort to control the architecture and thickness of a nanoscale polymer coating on the drug particles. In vitro studies indicated that the dry half-life release for budesonide can be enhanced from 1.2 to over 60 min by a nanoscale coating on the drug particle. Extensive studies have been conducted to characterize the bonding and composition of the polymer film deposited on drug particles.

Silk-elastin-like protein biomaterials for the controlled delivery of therapeutics.

PubMed

Huang, Wenwen; Rollett, Alexandra; Kaplan, David L

2015-05-01

Genetically engineered biomaterials are useful for controlled delivery owing to their rational design, tunable structure-function, biocompatibility, degradability and target specificity. Silk-elastin-like proteins (SELPs), a family of genetically engineered recombinant protein polymers, possess these properties. Additionally, given the benefits of combining semi-crystalline silk-blocks and elastomeric elastin-blocks, SELPs possess multi-stimuli-responsive properties and tunability, thereby becoming promising candidates for targeted cancer therapeutics delivery and controlled gene release. An overview of SELP biomaterials for drug delivery and gene release is provided. Biosynthetic strategies used for SELP production, fundamental physicochemical properties and self-assembly mechanisms are discussed. The review focuses on sequence-structure-function relationships, stimuli-responsive features and current and potential drug delivery applications. The tunable material properties allow SELPs to be pursued as promising biomaterials for nanocarriers and injectable drug release systems. Current applications of SELPs have focused on thermally-triggered biomaterial formats for the delivery of therapeutics, based on local hyperthermia in tumors or infections. Other prominent controlled release applications of SELPs as injectable hydrogels for gene release have also been pursued. Further biomedical applications that utilize other stimuli to trigger the reversible material responses of SELPs for targeted delivery, including pH, ionic strength, redox, enzymatic stimuli and electric field, are in progress. Exploiting these additional stimuli-responsive features will provide a broader range of functional biomaterials for controlled therapeutics release and tissue regeneration.

Responsive copolymer–graphene oxide hybrid microspheres with enhanced drug release properties

DOE PAGES

Dong, Fuping; Firkowska-Boden, Izabela; Arras, Matthias M. L.; ...

2017-01-13

Here, the ability to integrate both high encapsulation efficiency and controlled release in a drug delivery system (DDS) is a highly sought solution to cure major diseases. However, creation of such a system is challenging. This study was aimed at constructing a new delivery system based on thermoresponsive poly(N-isopropylacrylamide-co-styrene) (PNIPAAm-co-PS) hollow microspheres prepared via two-step precipitation polymerization. To control the diffusion-driven drug release, the PNIPAAm-co-PS spheres were electrostatically coated with graphene oxide (GO) nanosheets. As a result of the coating the permeability of such copolymer-GO hybrid microspheres was reduced to the extent that suppressed the initial burst release and enabledmore » sustained drug release in in vitro testing. The hybrid microspheres showed improved drug encapsulation by 46.4% which was attributed to the diffusion barrier properties and -conjugated structure of GO. The system presented here is promising to advance, e.g., the anticancer drug delivery technologies by enabling sustained drug release and thus minimizing local and systemic side effects.« less

Responsive copolymer–graphene oxide hybrid microspheres with enhanced drug release properties

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

Dong, Fuping; Firkowska-Boden, Izabela; Arras, Matthias M. L.

Here, the ability to integrate both high encapsulation efficiency and controlled release in a drug delivery system (DDS) is a highly sought solution to cure major diseases. However, creation of such a system is challenging. This study was aimed at constructing a new delivery system based on thermoresponsive poly(N-isopropylacrylamide-co-styrene) (PNIPAAm-co-PS) hollow microspheres prepared via two-step precipitation polymerization. To control the diffusion-driven drug release, the PNIPAAm-co-PS spheres were electrostatically coated with graphene oxide (GO) nanosheets. As a result of the coating the permeability of such copolymer-GO hybrid microspheres was reduced to the extent that suppressed the initial burst release and enabledmore » sustained drug release in in vitro testing. The hybrid microspheres showed improved drug encapsulation by 46.4% which was attributed to the diffusion barrier properties and -conjugated structure of GO. The system presented here is promising to advance, e.g., the anticancer drug delivery technologies by enabling sustained drug release and thus minimizing local and systemic side effects.« less

Sustained, Controlled and Stimuli-Responsive Drug Release Systems Based on Nanoporous Anodic Alumina with Layer-by-Layer Polyelectrolyte

NASA Astrophysics Data System (ADS)

Porta-i-Batalla, Maria; Eckstein, Chris; Xifré-Pérez, Elisabet; Formentín, Pilar; Ferré-Borrull, J.; Marsal, Lluis F.

2016-08-01

Controlled drug delivery systems are an encouraging solution to some drug disadvantages such as reduced solubility, deprived biodistribution, tissue damage, fast breakdown of the drug, cytotoxicity, or side effects. Self-ordered nanoporous anodic alumina is an auspicious material for drug delivery due to its biocompatibility, stability, and controllable pore geometry. Its use in drug delivery applications has been explored in several fields, including therapeutic devices for bone and dental tissue engineering, coronary stent implants, and carriers for transplanted cells. In this work, we have created and analyzed a stimuli-responsive drug delivery system based on layer-by-layer pH-responsive polyelectrolyte and nanoporous anodic alumina. The results demonstrate that it is possible to control the drug release using a polyelectrolyte multilayer coating that will act as a gate.

Building a polysaccharide hydrogel capsule delivery system for control release of ibuprofen.

PubMed

Chen, Zhi; Wang, Ting; Yan, Qing

2018-02-01

Development of a delivery system which can effectively carry hydrophobic drugs and have pH response is becoming necessary. Here we demonstrate that through preparation of β-cyclodextrin polymer (β-CDP), a hydrophobic drug molecule of ibuprofen (IBU) was incorporated into our prepared β-CDP inner cavities, aiming to improve the poor water solubility of IBU. A core-shell capsule structure has been designed for achieving the drug pH targeted and sustained release. This delivery system was built with polysaccharide polymer of Sodium alginate (SA), sodium carboxymethylcellulose (CMC) and hydroxyethyl cellulose (HEC) by physical cross-linking. The drug pH-response control release is this hydrogel system's chief merit, which has potential value for synthesizing enteric capsule. Besides, due to our simple preparing strategy, optimal conditions can be readily determined and the synthesis process can be accurately controlled, leading to consistent and reproducible hydrogel capsules. In addition, phase-solubility method was used to investigate the solubilization effect of IBU by β-CDP. SEM was used to prove the forming of core and shell structure. FT-IR and 1 H-NMR were also used to perform structural characteristics. By the technique of UV determination, the pH targeted and sustained release study were also performed. The results have proved that our prepared polysaccharide hydrogel capsule delivery system has potential applications as oral drugs delivery in the field of biomedical materials.

[Smart drug delivery systems based on nanoscale ZnO].

PubMed

Huang, Xiao; Chen, Chun; Yi, Caixia; Zheng, Xi

2018-04-01

In view of the excellent biocompatibility as well as the low cost, nanoscale ZnO shows great potential for drug delivery application. Moreover, The charming character enable nanoscale ZnO some excellent features (e.g. dissolution in acid, ultrasonic permeability, microwave absorbing, hydrophobic/hydrophilic transition). All of that make nanoscale ZnO reasonable choices for smart drug delivery. In the recent decade, more and more studies have focused on controlling the drug release behavior via smart drug delivery systems based on nanoscale ZnO responsive to some certain stimuli. Herein, we review the recent exciting progress on the pH-responsive, ultrasound-responsive, microwave-responsive and UV-responsive nanoscale ZnO-based drug delivery systems. A brief introduction of the drug controlled release behavior and its effect of the drug delivery systems is presented. The biocompatibility of nanoscale ZnO is also discussed. Moreover, its development prospect is looked forward.

A concise review on smart polymers for controlled drug release.

PubMed

Aghabegi Moghanjoughi, Arezou; Khoshnevis, Dorna; Zarrabi, Ali

2016-06-01

Design and synthesis of efficient drug delivery systems are of critical importance in health care management. Innovations in materials chemistry especially in polymer field allows introduction of advanced drug delivery systems since polymers could provide controlled release of drugs in predetermined doses over long periods, cyclic and tunable dosages. To this end, researchers have taken advantages of smart polymers since they can undergo large reversible, chemical, or physical fluctuations as responses to small changes in environmental conditions, for instance, in pH, temperature, light, and phase transition. The present review aims to highlight various kinds of smart polymers, which are used in controlled drug delivery systems as well as mechanisms of action and their applications.

Nanocomposite thin films for triggerable drug delivery.

PubMed

Vannozzi, Lorenzo; Iacovacci, Veronica; Menciassi, Arianna; Ricotti, Leonardo

2018-05-01

Traditional drug release systems normally rely on a passive delivery of therapeutic compounds, which can be partially programmed, prior to injection or implantation, through variations in the material composition. With this strategy, the drug release kinetics cannot be remotely modified and thus adapted to changing therapeutic needs. To overcome this issue, drug delivery systems able to respond to external stimuli are highly desirable, as they allow a high level of temporal and spatial control over drug release kinetics, in an operator-dependent fashion. Areas covered: On-demand drug delivery systems actually represent a frontier in this field and are attracting an increasing interest at both research and industrial level. Stimuli-responsive thin films, enabled by nanofillers, hold a tremendous potential in the field of triggerable drug delivery systems. The inclusion of responsive elements in homogeneous or heterogeneous thin film-shaped polymeric matrices strengthens and/or adds intriguing properties to conventional (bare) materials in film shape. Expert opinion: This Expert Opinion review aims to discuss the approaches currently pursued to achieve an effective on-demand drug delivery, through nanocomposite thin films. Different triggering mechanisms allowing a fine control on drug delivery are described, together with current challenges and possible future applications in therapy and surgery.

Calcium phosphate ceramics in drug delivery

NASA Astrophysics Data System (ADS)

Bose, Susmita; Tarafder, Solaiman; Edgington, Joe; Bandyopadhyay, Amit

2011-04-01

Calcium phosphate (CaP) particulates, cements and scaffolds have attracted significant interest as drug delivery vehicles. CaP systems, including both hydroxyapaptite and tricalcium phosphates, possess variable stoichiometry, functionality and dissolution properties which make them suitable for cellular delivery. Their chemical similarity to bone and thus biocompatibility, as well as variable surface charge density contribute to their controlled release properties. Among specific research areas, nanoparticle size, morphology, surface area due to porosity, and chemistry controlled release kinetics are the most active. This article discusses CaP systems in their particulate, cements, and scaffold forms for drug, protein, and growth factor delivery toward orthopedic and dental applications.

An overview of in vitro dissolution/release methods for novel mucosal drug delivery systems.

PubMed

Jug, Mario; Hafner, Anita; Lovrić, Jasmina; Kregar, Maja Lusina; Pepić, Ivan; Vanić, Željka; Cetina-Čižmek, Biserka; Filipović-Grčić, Jelena

2018-01-05

In vitro dissolution/release tests are an important tool in the drug product development phase as well as in its quality control and the regulatory approval process. Mucosal drug delivery systems are aimed to provide both local and systemic drug action via mucosal surfaces of the body and exhibit significant differences in formulation design, as well as in their physicochemical and release characteristics. Therefore it is not possible to devise a single test system which would be suitable for release testing of such complex dosage forms. This article is aimed to provide a comprehensive review of both compendial and noncompendial methods used for in vitro dissolution/release testing of novel mucosal drug delivery systems aimed for ocular, nasal, oromucosal, vaginal and rectal administration. Copyright © 2017 Elsevier B.V. All rights reserved.

Light-stimulated cargo release from a core–shell structured nanocomposite for site-specific delivery

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

Cai, Yun; Ling, Li; Li, Xiaofang

This paper reported a core–shell structured site-specific delivery system with a light switch triggered by low energy light (λ=510 nm). Its core was composed of supermagnetic Fe{sub 3}O{sub 4} nanoparticles for magnetic guiding and targeting. Its outer shell consisted of mesoporous silica molecular sieve MCM-41 which offered highly ordered hexagonal tunnels for cargo capacity. A light switch N1-(4aH-cyclopenta[1,2-b:5,4-b′]dipyridin-5(5aH)-ylidene)benzene-1, 4-diamine (CBD) was covalently grafted into these hexagonal tunnels, serving as light stimuli acceptor with loading content of 1.1 μM/g. This composite was fully characterized and confirmed by SEM, TEM, XRD patterns, N{sub 2} adsorption/desorption, thermogravimetric analysis, IR, UV–vis absorption and emissionmore » spectra. Experimental data suggested that this composite had a core as wide as 150 nm and could be magnetically guided to specific sites. Its hexagonal tunnels were as long as 180 nm. Upon light stimuli of “on” and “off” states, controllable release was observed with short release time of ~900 s (90% capacity). - Graphical abstract: A core–shell structured site-specific delivery system with a light switch triggered by yellow light was constructed. Controllable release was observed with short release time of ~900 s (90% capacity). - Highlights: • A core–shell structured site-specific delivery system was constructed. • It consisted of Fe{sub 3}O{sub 4} core and MCM-41 shell grafted with light switch. • This delivery system was triggered by low energy light. • Controllable release was observed with short release time of ~900 s.« less

Enhancement of Antiviral Agents Through the Use of Controlled-Release Technology.

DTIC Science & Technology

DL-lactide-co-glycolide) to be used as the polymeric excipients in the microencapsulation work. In addition, we have actively pursued development and testing of poly(I.C) and Je vaccine microcapsule formulations....of this research program are a) To develop a programmed-release delivery system ( microcapsule system) designed to enhance the immunogenic potential of...release microcapsule delivery systems that will enhance the effects of the following immune modulators and antiviral agents: muramyl tripeptide (MTP

Cross-linked β-cyclodextrin and carboxymethyl cellulose hydrogels for controlled drug delivery of acyclovir

PubMed Central

Malik, Nadia Shamshad; Ahmad, Mahmood; Minhas, Muhammad Usman

2017-01-01

To explore the potential role of polymers in the development of drug-delivery systems, this study investigated the use of β-cyclodextrin (β-CD), carboxymethyl cellulose (CMC), acrylic acid (AA) and N’ N’-methylenebis-acrylamide (MBA) in the synthesis of hydrogels for controlled drug delivery of acyclovir (ACV). Different proportions of β-CD, CMC, AA and MBA were blended with each other to fabricate hydrogels via free radical polymerization technique. Fourier transform infrared spectroscopy (FTIR) revealed successful grafting of components into the polymeric network. Thermal and morphological characterization confirmed the formation of thermodynamically stable hydrogels having porous structure. The pH-responsive behaviour of hydrogels has been documented by swelling dynamics and drug release behaviour in simulated gastrointestinal fluids. Drug release kinetics revealed controlled release behaviour of the antiviral drug acyclovir in developed polymeric network. Cross-linked β-cyclodextrin and carboxymethyl cellulose hydrogels can be used as promising candidates for the design and development of controlled drug-delivery systems. PMID:28245257

Chitosan cross-linked with poly(ethylene glycol)dialdehyde via reductive amination as effective controlled release carriers for oral protein drug delivery.

PubMed

Jing, Zi-Wei; Ma, Zhi-Wei; Li, Chen; Jia, Yi-Yang; Luo, Min; Ma, Xi-Xi; Zhou, Si-Yuan; Zhang, Bang-Le

2017-02-15

The covalently cross-linked chitosan-poly(ethylene glycol) 1540 derivatives have been developed as a controlled release system with potential for the delivery of protein drug. The swelling characteristics of the hydrogels based on these derivatives as the function of different PEG content and the release profiles of a model protein (bovine serum albumin, BSA) from the hydrogels were evaluated in simulated gastric fluid with or without enzyme in order to simulate the gastrointestinal tract conditions. The derivatives cross-linked with difunctional PEG 1540 -dialdehyde via reductive amination can swell in alkaline pH and remain insoluble in acidic medium. The cumulative release amount of BSA was relatively low in the initial 2h and increased significantly at pH 7.4 with intestinal lysozyme for additional 12h. The results proved that the release-and-hold behavior of the cross-linked CS-PEG 1540 H-CS hydrogel provided a swell and intestinal enzyme controlled release carrier system, which is suitable for oral protein drug delivery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Conductive polymer nanotube patch for fast and controlled in vivo transdermal drug delivery

NASA Astrophysics Data System (ADS)

Nguyen, Thao M.

Transdermal drug delivery has created new applications for existing therapies and offered an alternative to the traditional oral route where drugs can prematurely metabolize in the liver causing adverse side effects. Opening the transdermal delivery route to large hydrophilic drugs is one of the greatest challenges due to the hydrophobicity of the skin. However, the ability to deliver hydrophilic drugs using a transdermal patch would provide a solution to problems of other delivery methods for hydrophilic drugs. The switching of conductive polymers (CP) between redox states cause simultaneous changes in the polymer charge, conductivity, and volume—properties that can all be exploited in the biomedical field of controlled drug delivery. Using the template synthesis method, poly(3,4-ethylenedioxythiophene (PEDOT) nanotubes were synthesized electrochemically and a transdermal drug delivery patch was successfully designed and developed. In vitro and in vivo uptake and release of hydrophilic drugs were investigated. The relationship between the strength of the applied potential and rate of drug release were also investigated. Results revealed that the strength of the applied potential is proportional to the rate of drug release; therefore one can control the rate of drug release by controlling the applied potential. The in vitro studies focused on the kinetics of the drug delivery system. It was determined that the drug released mainly followed zero-order kinetics. In addition, it was determined that applying a releasing potential to the transdermal drug delivery system lead to a higher release rate constant (up to 7 times greater) over an extended period of time (˜24h). In addition, over 24 hours, an average of 80% more model drug molecules were released with an applied potential than without. The in vivo study showed that the drug delivery system was capable of delivering model hydrophilic drugs molecules through the dermis layer of the skin within 30 minutes, while the control showed no visible drugs at the same depth. Most importantly, it was determined that the delivery of drugs into the blood stream was stable within 20 minutes. The functionalization of CP was also studied in order to enhance the properties and drug loading capabilities of the polymers. The co-polymerization of poly(3,4-(2-methylene)propylenedioxythiophene) (PMProDot) with polystyrene (PS) and polyvinylcarbazole (PVK) through the highly reactive methylene group was achieved. The modified PMProDot nanotubes demonstrated response times that were two times faster than without modification. The modification of PEDOT nanotubes with polydopamine, a biocompatible polymer, was also investigated and achieved. In depth characterization of functionalized CP demonstrate the ability to fine tune the properties of the polymer in order to achieve the required therapeutic drug release profile.

AND logic-like pH- and light-dual controlled drug delivery by surface modified mesoporous silica nanoparticles.

PubMed

Zhao, Junwei; He, Zhaoshuai; Li, Biao; Cheng, Tanyu; Liu, Guohua

2017-04-01

Recently, the controlled drug delivery system has become a potential platform for biomedical application. Herein, we developed a pH and light-dual controlled cargo release system exhibiting AND logic based on MCM-41 mesoporous silica nanoparticles, which was surface modified using β-cyclodextrin (β-CD) with imine bond and azobenzene derivative. The complex of β-CD and azobenzene derivative effectively blocked the cargo delivery in pH=7.0 phosphate buffered saline (PBS) solution without 365nm UV light irradiation. The cargo was fully released when both factors of acidic environment (pH=5.0 PBS) and 365nm UV light irradiation were satisfied, meanwhile only very little cargo was delivered if one factor was satisfied. The result also demonstrates that the opening/closing of the gate and the release of the cargo in small portions can be controlled. Copyright © 2016 Elsevier B.V. All rights reserved.

Reversible formation of aminals: a new strategy to control the release of bioactive volatiles from dynamic mixtures.

PubMed

Godin, Guillaume; Levrand, Barbara; Trachsel, Alain; Lehn, Jean-Marie; Herrmann, Andreas

2010-05-14

Dynamic mixtures generated by reversible aminal formation of fragrance aldehydes with N,N-dibenzyl alkyldiamines in aqueous systems were found to be suitable delivery systems for the controlled release of bioactive volatiles.

Smart Micro/Nano-robotic Systems for Gene Delivery.

PubMed

Pedram, Alireza; Pishkenari, Hossein Nejat

2017-01-01

Small scale robotics have attracted growing attention for the prospect of targeting and accessing cell-sized sites, necessary for high precision biomedical applications and drug/gene delivery. The loss of controlled gene therapy, inducing systemic side effects and reduced therapeutic efficiency, can be settled utilizing these intelligent carriers. Newly proposed solutions for the main challenges of control, power supplying, gene release and final carrier extraction/degradation have shifted these smart miniature robots to the point of being employed for practical applications of transferring oligonucleotides (pDNA, siRNA, mRNA, etc.) in near future. In this paper, different scenarios and their endeavors to address the vital working demands and steps, in particular, carrier attachment and release, cell internalization, manipulation concerns as well as actuation systems are discussed.This review highlights some promising experimental results showing controlled gene release of robotic systems in comparison with current non-specific gene delivery methods. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Free-standing few-layered graphene oxide films: selective, steady and lasting permeation of organic molecules with adjustable speeds

NASA Astrophysics Data System (ADS)

Huang, Tao; An, Qi; Luan, Xinglong; Zhang, Qian; Zhang, Yihe

2016-01-01

A variety of small molecules with diameters around 1 nm possess a range of functions, such as antibiotic, antimicrobic, anticoagulant, pesticidal and chemotherapy effects, making these molecules especially useful in various applications ranging from medical treatment to environmental microbiological control. However, the long-term steady delivery (release or permeation) of these small molecules with adjustable and controllable speeds has remained an especially challenging task. In this study, we prepared covalently cross-linked free-standing few-layered GO films using a layer-by-layer technique in combination with photochemical cross-linkages, and achieved a controlled release of positively charged, negatively charged, and zwitterionic small molecules with adjustable and controllable speeds. The steady delivery of the small molecule lasted up to 9 days. Other functionalities, such as graphene-enhanced Raman spectra and electrochemical properties that could also be integrated or employed in delivery systems, were also studied for our films. We expect the special molecular delivery properties of our films to lead to new possibilities in drug/fertilizer delivery and environmental microbiological control applications.A variety of small molecules with diameters around 1 nm possess a range of functions, such as antibiotic, antimicrobic, anticoagulant, pesticidal and chemotherapy effects, making these molecules especially useful in various applications ranging from medical treatment to environmental microbiological control. However, the long-term steady delivery (release or permeation) of these small molecules with adjustable and controllable speeds has remained an especially challenging task. In this study, we prepared covalently cross-linked free-standing few-layered GO films using a layer-by-layer technique in combination with photochemical cross-linkages, and achieved a controlled release of positively charged, negatively charged, and zwitterionic small molecules with adjustable and controllable speeds. The steady delivery of the small molecule lasted up to 9 days. Other functionalities, such as graphene-enhanced Raman spectra and electrochemical properties that could also be integrated or employed in delivery systems, were also studied for our films. We expect the special molecular delivery properties of our films to lead to new possibilities in drug/fertilizer delivery and environmental microbiological control applications. Electronic supplementary information (ESI) available: AFM images of GO and GO films, UV-vis spectra of delayed release, and permeation fidelities. See DOI: 10.1039/c5nr08129g

Therapeutic applications of hydrogels in oral drug delivery

PubMed Central

Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D; Peppas, Nicholas A

2015-01-01

Introduction Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. Areas covered This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Expert opinion Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest. PMID:24848309

Zn(2+)-Triggered Drug Release from Biocompatible Zirconium MOFs Equipped with Supramolecular Gates.

PubMed

Tan, Li-Li; Li, Haiwei; Zhou, Yue; Zhang, Yuanyuan; Feng, Xiao; Wang, Bo; Yang, Ying-Wei

2015-08-01

A new theranostic nanoplatform, comprising of monodisperse zirconium metal-organic frameworks (MOFs) as drug carriers and carboxylatopillar[5]arene-based supramolecular switches as gating entities, is constructed, and controlled drug release triggered by bio-friendly Zn(2+) ions (abundant in synaptic vesicles) and auxiliary thermal stimulus is realized. This on-command drug delivery system exhibits large pore sizes for drug encapsulation, excellent biodegradability and biocompatibility, extremely low cytotoxicity and premature drug release, and superior dual-stimuli responsiveness, opening a new avenue in targeted drug delivery and controlled release of therapeutic agents, especially in the treatment of central nervous system diseases. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Membrane-targeting liquid crystal nanoparticles (LCNPs) for drug delivery

NASA Astrophysics Data System (ADS)

Nag, Okhil K.; Naciri, Jawad; Spillmann, Christopher M.; Delehanty, James B.

2016-03-01

In addition to maintaining the structural integrity of the cell, the plasma membrane regulates multiple important cellular processes, such as endocytosis and trafficking, apoptotic pathways and drug transport. The modulation or tracking of such cellular processes by means of controlled delivery of drugs or imaging agents via nanoscale delivery systems is very attractive. Nanoparticle-mediated delivery systems that mediate long-term residence (e.g., days) and controlled release of the cargoes in the plasma membrane while simultaneously not interfering with regular cellular physiology would be ideal for this purpose. Our laboratory has developed a plasma membrane-targeted liquid crystal nanoparticle (LCNP) formulation that can be loaded with dyes or drugs which can be slowly released from the particle over time. Here we highlight the utility of these nanopreparations for membrane delivery and imaging.

Control of drug release through the in situ assembly of stimuli-responsive ordered mesoporous silica with magnetic particles.

PubMed

Zhu, Shenmin; Zhou, Zhengyang; Zhang, Di

2007-12-03

A site-selective controlled delivery system for controlled drug release is fabricated through the in situ assembly of stimuli-responsive ordered SBA-15 and magnetic particles. This approach is based on the formation of ordered mesoporous silica with magnetic particles formed from Fe(CO)5 via the surfactant-template sol-gel method and control of transport through polymerization of N-isopropyl acrylamide inside the pores. Hydrophobic Fe(CO)5 acts as a swelling agent as well as being the source of the magnetic particles. The obtained system demonstrates a high pore diameter (7.1 nm) and pore volume (0.41 cm(3) g(-1)), which improves drug storage for relatively large molecules. Controlled drug release through the porous network is demonstrated by measuring the uptake and release of ibuprofen (IBU). The delivery system displays a high IBU storage capacity of 71.5 wt %, which is almost twice as large as the highest value based on SBA-15 ever reported. In vitro testing of IBU loading and release exhibits a pronounced transition at around 32 degrees C, indicating a typical thermosensitive controlled release.

Growth factor delivery: How surface interactions modulate release in vitro and in vivo

PubMed Central

King, William J.; Krebsbach, Paul H.

2013-01-01

Biomaterial scaffolds have been extensively used to deliver growth factors to induce new bone formation. The pharmacokinetics of growth factor delivery has been a critical regulator of their clinical success. This review will focus on the surface interactions that control the non-covalent incorporation of growth factors into scaffolds and the mechanisms that control growth factor release from clinically relevant biomaterials. We will focus on the delivery of recombinant human bone morphogenetic protein-2 from materials currently used in the clinical practice, but also suggest how general mechanisms that control growth factor incorporation and release delineated with this growth factor could extend to other systems. A better understanding of the changing mechanisms that control growth factor release during the different stages of preclinical development could instruct the development of future scaffolds for currently untreatable injuries and diseases. PMID:22433783

Characterization of hybrid microparticles/Montmorillonite composite with raspberry-like morphology for Atorvastatin controlled release.

PubMed

García-Guzmán, Perla; Medina-Torres, Luis; Calderas, Fausto; Bernad-Bernad, María Josefa; Gracia-Mora, Jesús; Mena, Baltasar; Manero, Octavio

2018-07-01

In this work, we prepared a novel composite based on hybrid gelatin carriers and montmorillonite clay (MMT) to analyze its viability as controlled drug delivery system. The objective of this research involves the characterization of composites formed by structured lipid-gelatin micro-particles (MP) and MMT clay. This analysis included the evaluation of the composite according to its rheological properties, morphology (SEM), particle size, XRD, FT-IR, and in vitro drug release. The effect of pH in the properties of the composite is evaluated. A novel raspberry-like or armor MP/MMT clay composite is reported, in which the pH has an important effect on the final structure of the composite for ad-hoc drug delivery systems. For pH values below the isoelectric point, we obtained defined morphologies with entrapment efficiencies up to 67%. The pH level controls the MP/MMT composite release mechanism, restringing drug release in the stomach-like environment. Intended for oral administration, these results evidence that the MP/MMT composite represents an attractive alternative for intestinal-colonic controlled drug delivery systems. Copyright © 2018 Elsevier B.V. All rights reserved.

Controlled Drug Delivery Using Microdevices

PubMed Central

Sanjay, Sharma T.; Dou, Maowei; Fu, Guanglei; Xu, Feng; Li, XiuJun

2016-01-01

Therapeutic drugs administered systematically are evenly distributed to the whole body through blood circulation and have to cross many biological barriers before reaching the pathological site. Conventional drug delivery may make drugs inactive or reduce their potency as they may be hydrolyzed or degraded enzymatically and are rapidly excreted through the urinary system resulting in suboptimal concentration of drugs at the desired site. Controlled drug delivery aims to localize the pharmacological activity of the drug to the desired site at desired release rates. The advances made by micro/nanofluidic technologies have provided new opportunities for better-controlled drug delivery. Various components of a drug delivery system can be integrated within a single tiny micro/nanofluidic chip. This article reviews recent advances of controlled drug delivery made by microfluidic/nanofluidic technologies. We first discuss microreservoir-based drug delivery systems. Then we highlight different kinds of microneedles used for controlled drug delivery, followed with a brief discussion about the current limitations and the future prospects of controlled drug delivery systems. PMID:26813304

Controlled Drug Delivery Using Microdevices.

PubMed

Sanjay, Sharma T; Dou, Maowei; Fu, Guanglei; Xu, Feng; Li, XiuJun

Therapeutic drugs administered systematically are evenly distributed to the whole body through blood circulation and have to cross many biological barriers before reaching the pathological site. Conventional drug delivery may make drugs inactive or reduce their potency as they may be hydrolyzed or degraded enzymatically and are rapidly excreted through the urinary system resulting in suboptimal concentration of drugs at the desired site. Controlled drug delivery aims to localize the pharmacological activity of the drug to the desired site at desired release rates. The advances made by micro/nanofluidic technologies have provided new opportunities for better-controlled drug delivery. Various components of a drug delivery system can be integrated within a single tiny micro/nanofluidic chip. This article reviews recent advances of controlled drug delivery made by microfluidic/nanofluidic technologies. We first discuss microreservoir-based drug delivery systems. Then we highlight different kinds of microneedles used for controlled drug delivery, followed with a brief discussion about the current limitations and the future prospects of controlled drug delivery systems.

Injectable nanocomposite cryogels for versatile protein drug delivery.

PubMed

Koshy, Sandeep T; Zhang, David K Y; Grolman, Joshua M; Stafford, Alexander G; Mooney, David J

2018-01-01

Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems. Here we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein's activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Controlled release of GAG-binding enhanced transduction (GET) peptides for sustained and highly efficient intracellular delivery.

PubMed

Abu-Awwad, Hosam Al-Deen M; Thiagarajan, Lalitha; Dixon, James E

2017-07-15

Controlled release systems for therapeutic molecules are vital to allow the sustained local delivery of their activities which direct cell behaviour and enable novel regenerative strategies. Direct programming of cells using exogenously delivered transcription factors can by-pass growth factor signalling but there is still a requirement to deliver such activity spatio-temporally. We previously developed a technology termed GAG-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding domains which promote cell targeting, and cell penetrating peptides (CPPs) which allow cell entry. Herein we demonstrate that GET system can be used in controlled release systems to mediate sustained intracellular transduction over one week. We assessed the stability and activity of GET peptides in poly(dl-lactic acid-co-glycolic acid) (PLGA) microparticles (MPs) prepared using a S/O/W double emulsion method. Efficient encapsulation (∼65%) and tailored protein release profiles could be achieved, however intracellular transduction was significantly inhibited post-release. To retain GET peptide activity we optimized a strategy of co-encapsulation of l-Histidine, which may form a complex with the PLGA degradation products under acidic conditions. Simulations of the polymer microclimate showed that hydrolytic acidic PLGA degradation products directly inhibited GET peptide transduction activity, and use of l-Histidine significantly enhanced released protein delivery. The ability to control the intracellular transduction of functional proteins into cells will facilitate new localized delivery methods and allow approaches to direct cellular behaviour for many regenerative medicine applications. The goal for regenerative medicine is to restore functional biological tissue by controlling and augmenting cellular behaviour. Either Transcription (TFs) or growth factors (GFs) can be presented to cells in spatio-temporal gradients for programming cell fate and gene expression. Here, we have created a sustained and controlled release system for GET (Glycosaminoglycan-enhanced transducing)-tagged proteins using S/O/W PLGA microparticle fabrication. We demonstrated that PLGA and its acidic degradants inhibit GET-mediated transduction, which can be overcome by using pH-activated l-Histidine. l-Histidine inhibits the electrostatic interaction of GET/PLGA and allows enhanced intracellular transduction. GET could provide a powerful tool to program cell behaviour either in gradients or with sustained delivery. We believe that our controlled release systems will allow application of GET for tissue regeneration directly by TF cellular programming. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery.

PubMed

Zhao, Chun-Xia

2013-11-01

Considerable effort has been directed towards developing novel drug delivery systems. Microfluidics, capable of generating monodisperse single and multiple emulsion droplets, executing precise control and operations on these droplets, is a powerful tool for fabricating complex systems (microparticles, microcapsules, microgels) with uniform size, narrow size distribution and desired properties, which have great potential in drug delivery applications. This review presents an overview of the state-of-the-art multiphase flow microfluidics for the production of single emulsions or multiple emulsions for drug delivery. The review starts with a brief introduction of the approaches for making single and multiple emulsions, followed by presentation of some potential drug delivery systems (microparticles, microcapsules and microgels) fabricated in microfluidic devices using single or multiple emulsions as templates. The design principles, manufacturing processes and properties of these drug delivery systems are also discussed and compared. Furthermore, drug encapsulation and drug release (including passive and active controlled release) are provided and compared highlighting some key findings and insights. Finally, site-targeting delivery using multiphase flow microfluidics is also briefly introduced. Copyright © 2013 Elsevier B.V. All rights reserved.

Evaluation of an injectable polymeric delivery system for controlled and localized release of biological factors to promote therapeutic angiogenesis

NASA Astrophysics Data System (ADS)

Rocker, Adam John

Cardiovascular disease remains as the leading cause of death worldwide and is frequently associated with partial or full occlusion of coronary arteries. Currently, angioplasty and bypass surgery are the standard approaches for treating patients with these ischemic heart conditions. However, a large number of patients cannot undergo these procedures. Therapeutic angiogenesis provides a minimally invasive tool for treating cardiovascular diseases by inducing new blood vessel growth from the existing vasculature. Angiogenic growth factors can be delivered locally through gene, cell, and protein therapy. Natural and synthetic polymer growth factor delivery systems are under extensive investigation due their widespread applications and promising therapeutic potential. Although biocompatible, natural polymers often suffer from batch-to-batch variability which can cause unpredictable growth factor release rates. Synthetic polymers offer advantages for growth factor delivery as they can be easily modified to control release kinetics. During the angiogenesis process, vascular endothelial growth factor (VEGF) is necessary to initiate neovessel formation while platelet-derived growth factor (PDGF) is needed later to help stabilize and mature new vessels. In the setting of myocardial infarction, additional anti-inflammatory cytokines like IL-10 are needed to help optimize cardiac repair and limit the damaging effects of inflammation following infarction. To meet these angiogenic and anti-inflammatory needs, an injectable polymer delivery system created from a sulfonated reverse thermal gel encapsulating micelle nanoparticles was designed and evaluated. The sulfonate groups on the thermal gel electrostatically bind to VEGF which controls its release rate, while the micelles are loaded with PDGF and are slowly released as the gel degrades. IL-10 was loaded into the system as well and diffused from the gel over time. An in vitro release study was performed which demonstrated the sequential release capabilities of the polymer system. The ability of the polymer system to induce new blood vessel formation was analyzed in vivo using a subcutaneous injection mouse model. Histological assessment was used to quantify blood vessel formation and an inflammatory response which showed that the polymer delivery system demonstrated a significant increase in functional and mature vessel formation while significantly reducing inflammation.

Magnetic hyperthermia controlled drug release in the GI tract: solving the problem of detection.

PubMed

Bear, Joseph C; Patrick, P Stephen; Casson, Alfred; Southern, Paul; Lin, Fang-Yu; Powell, Michael J; Pankhurst, Quentin A; Kalber, Tammy; Lythgoe, Mark; Parkin, Ivan P; Mayes, Andrew G

2016-09-27

Drug delivery to the gastrointestinal (GI) tract is highly challenging due to the harsh environments any drug- delivery vehicle must experience before it releases it's drug payload. Effective targeted drug delivery systems often rely on external stimuli to effect release, therefore knowing the exact location of the capsule and when to apply an external stimulus is paramount. We present a drug delivery system for the GI tract based on coating standard gelatin drug capsules with a model eicosane- superparamagnetic iron oxide nanoparticle composite coating, which is activated using magnetic hyperthermia as an on-demand release mechanism to heat and melt the coating. We also show that the capsules can be readily detected via rapid X-ray computed tomography (CT) and magnetic resonance imaging (MRI), vital for progressing such a system towards clinical applications. This also offers the opportunity to image the dispersion of the drug payload post release. These imaging techniques also influenced capsule content and design and the delivered dosage form. The ability to easily change design demonstrates the versatility of this system, a vital advantage for modern, patient-specific medicine.

Controlled release of cyclosporine A self-nanoemulsifying systems from osmotic pump tablets: near zero-order release and pharmacokinetics in dogs.

PubMed

Zhang, Xi; Yi, Yueneng; Qi, Jianping; Lu, Yi; Tian, Zhiqiang; Xie, Yunchang; Yuan, Hailong; Wu, Wei

2013-08-16

It is very important to enhance the absorption simultaneously while designing controlled release delivery systems for poorly water-soluble and poorly permeable drugs (BCS IV). In this study, controlled release of cyclosporine (CyA) was achieved by the osmotic release strategy taking advantage of the absorption-enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDSs). The liquid SNEDDS consisting of Labrafil M 1944CS, Transcutol P and Cremophor EL was absorbed by the osmotic tablet core excipients (sucrose, lactose monohydrate, polyethylene oxide, and partly pregelatinized starch) and then transformed into osmotic tablets. Near zero-order release could be achieved for CyA-loaded nanoemulsions reconstituted from the SNEDDS. In general, the influencing factor study indicated that the release rate increased with increase of inner osmotic pressure, ratio of osmotic agent to suspending agent, content of pore-forming agent, and size of release orifice, whereas the thickness of the membrane impeded the release of CyA nanoemulsion. Pharmacokinetic study showed steady blood CyA profiles with prolonged Tmax and MRT, and significantly reduced Cmax for self-nanoemulsifying osmotic pump tablet (SNEOPT) in comparison with highly fluctuating profiles of the core tablet and Sandimmune Neoral(®). However, similar oral bioavailability was observed for either controlled release or non-controlled release formulations. It was concluded that simultaneous controlling on CyA release and absorption-enhancing had been achieved by a combination of osmotic tablet and SNEDDS. Copyright © 2013 Elsevier B.V. All rights reserved.

Controllable delivery of hydrophilic and hydrophobic drugs from electrospun poly(lactic-co-glycolic acid)/mesoporous silica nanoparticles composite mats.

PubMed

Song, Botao; Wu, Chengtie; Chang, Jiang

2012-11-01

Co-delivery of several drugs has been regarded as an alternative strategy for achieving enhanced therapeutic effect. In this study, a co-delivery system based on the electrospun poly(lactic-co-glycolic acid) (PLGA)/mesoporous silica nanoparticles (MSNs) composite mat was designed for the co-encapsulation and prolonged release of one hydrophilic and one hydrophobic drug simultaneously. MSNs were chosen to load the hydrophobic model drug fluorescein (FLU) and hydrophilic model drug rhodamine B (RHB), respectively (named as RHB-loaded MSNs and FLU-loaded MSNs). Two kinds of drug-loaded MSNs were incorporated into the polymer matrix to form a fibrous structure by blending electrospinning. The effect of the weight ratios for the two kinds of drug-loaded MSNs and the initial PLGA concentrations on the drug release kinetics were systematically investigated. The results showed that both model drugs RHB and FLU maintained sustained delivery with controllable release kinetics during the releasing period, and the release kinetics was closely dependent on the loading ratios of two drug-loaded MSNs and the initial PLGA concentrations in the composite mats. The results suggest that the co-drug delivery system may be used for wound dressing that requires the combined therapy of several kinds of drugs. Copyright © 2012 Wiley Periodicals, Inc.

Polypyrrole Film as a Drug Delivery System for the Controlled Release of Risperidone

NASA Astrophysics Data System (ADS)

Svirskis, Darren; Travas-Sejdic, Jadranka; Rodgers, Anthony; Garg, Sanjay

2009-07-01

Conducting polymers are finding applications in medicine including drug delivery systems, biosensors and templates for the regeneration of nervous pathways. We aim to develop a novel system where the drug release rate can be controlled by electrical stimulation. Polypyrrole (PPY) is being used as a drug delivery system due to its inherent electrical conductivity, ease of preparation and apparent biocompatibility. Risperidone is an atypical antipsychotic drug used in the treatment of psychosis and related disorders, including schizophrenia. PPY was synthesised using p-toluene sulfonic acid as a primary dopant, in the presence of risperidone. A validated high performance liquid chromatography (HPLC) analytical method was used to quantify risperidone release. It has been demonstrated that the release rate of risperidone can be altered through the application, or absence, of electrical stimulation. Technology such as this would find use in drug-delivering implants where the dose could be adjusted through application of external stimulus, optimising benefit to side effect ratio, while simultaneously ensuring patient adherence (which is a particular challenge in mental health conditions).

Sequential delivery of TAT-HSP27 and VEGF using microsphere/hydrogel hybrid systems for therapeutic angiogenesis.

PubMed

Shin, Seung-Hwa; Lee, Jangwook; Lim, Kwang Suk; Rhim, Taiyoun; Lee, Sang Kyung; Kim, Yong-Hee; Lee, Kuen Yong

2013-02-28

Ischemic disease is associated with high mortality and morbidity rates, and therapeutic angiogenesis via systemic or local delivery of protein drugs is one potential approach to treat the disease. In this study, we hypothesized that combined delivery of TAT-HSP27 (HSP27 fused with transcriptional activator) and VEGF could enhance the therapeutic efficacy in an ischemic mouse model, and that sequential release could be critical in therapeutic angiogenesis. Alginate hydrogels containing TAT-HSP27 as an anti-apoptotic agent were prepared, and porous PLGA microspheres loaded with VEGF as an angiogenic agent were incorporated into the hydrogels to prepare microsphere/hydrogel hybrid delivery systems. Sequential in vitro release of TAT-HSP27 and VEGF was achieved by the hybrid systems. TAT-HSP27 was depleted from alginate gels in 7 days, while VEGF was continually released for 28 days. The release rate of VEGF was attenuated by varying the porous structures of PLGA microspheres. Sequential delivery of TAT-HSP27 and VEGF was critical to protect against muscle degeneration and fibrosis, as well as to promote new blood vessel formation in the ischemic site of a mouse model. This approach to controlling the sequential release behaviors of multiple drugs could be useful in the design of novel drug delivery systems for therapeutic angiogenesis. Copyright © 2012 Elsevier B.V. All rights reserved.

Coordination responsive tellurium-containing multilayer film for controlled delivery.

PubMed

Cao, Wei; Wang, Lu; Xu, Huaping

2015-03-28

A coordination-responsive tellurium containing film was fabricated for controlled release. The coordination chemistry between telluride molecules and cisplatin was utilized for the loading of cisplatin, while competitive ligands were used for triggered release. This work could enrich the coordination responsive system and further tune the release kinetics of cisplatin.

Recent Advancement and Technological Aspects of Pulsatile Drug Delivery System - A Laconic Review.

PubMed

Pandit, Vinay; Kumar, Ajay; Ashawat, Mahendra S; Verma, Chander P; Kumar, Pravin

2017-01-01

Pulsatile drug delivery system (PDDS) shows potential significance in the field of drug delivery to release the maximum amount of drug at a definite site and at specific time. PDDS are mainly time controlled delivery devices having a definite pause period for drug release, which is not affected by acidity, alkalinity, motility and enzymes present in the gastrointestinal tract. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. The review article, discuss the general concepts, marketed formulations and patents or any other recent advancement in pulsatile release technology. It also highlights on diseases requiring therapy by pulsatile release, various researches on herbal pulsatile formulations and quality control aspects of PDDS. Pulsatile medication possess the potential to deliver the drugs in the therapy of diseases where drug dose is essential during sleep, drugs having greater first pass metabolism and absorption at precise location in digestive tract. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Ion-exchange and iontophoresis-controlled delivery of apomorphine.

PubMed

Malinovskaja, Kristina; Laaksonen, Timo; Kontturi, Kyösti; Hirvonen, Jouni

2013-04-01

The objective of this study was to test a drug delivery system that combines iontophoresis and cation-exchange fibers as drug matrices for the controlled transdermal delivery of antiparkinsonian drug apomorphine. Positively charged apomorphine was bound to the ion-exchange groups of the cation-exchange fibers until it was released by mobile counter-ions in the external solution. The release of the drug was controlled by modifying either the fiber type or the ionic composition of the external solution. Due to high affinity of apomorphine toward the ion-exchanger, a clear reduction in the in vitro transdermal fluxes from the fibers was observed compared to the respective fluxes from apomorphine solutions. Changes in the ionic composition of the donor formulations affected both the release and iontophoretic flux of the drug. Upon the application of higher co-ion concentrations or co-ions of higher valence in the donor formulation, the release from the fibers was enhanced, but the iontophoretic steady-state flux was decreased. Overall, the present study has demonstrated a promising approach using ion-exchange fibers for controlling the release and iontophoretic transdermal delivery of apomorphine. Copyright © 2012 Elsevier B.V. All rights reserved.

Evaluation of intratympanic formulations for inner ear delivery: methodology and sustained release formulation testing

PubMed Central

Liu, Hongzhuo; Feng, Liang; Tolia, Gaurav; Liddell, Mark R.; Hao, Jinsong; Li, S. Kevin

2013-01-01

A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid)–poly(ethylene glycol)–poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions. PMID:23631539

Formulation and evaluation of an in situ gel forming system for controlled delivery of triptorelin acetate.

PubMed

Abashzadeh, Sh; Dinarvand, R; Sharifzadeh, M; Hassanzadeh, G; Amini, M; Atyabi, F

2011-11-20

The novel physical hydrogels composed of chitosan or its water soluble derivatives such as carboxymethyl chitosan (CMCh) and sodium carboxymethyl chitosan (NaCMCh) and opened ring polyvinyl pyrrolidone (OP-PVP) were used as a controlled delivery system for triptorelin acetate, a luteinizing-releasing hormone agonist. The in situ gel forming system designed according to physical interactions such as chains entanglements and hydrophilic attractions especially h-bonds of chitosan and/or NaCMCh and OR-PVP. In order to increase in situ gel forming rate the chitosan microspheres prepared through spray drying technique. The chitosan or NaCMCh/OR-PVP blends prepared at different ratios (0.05, 0.10, 0.12, 0.16, 0.20 and 0.24) and suspended in sesame oil as non-aqueous vehicle at different solid content (10-30%). The suitable ratio of polymers with faster in situ gel forming rate was selected for in vivo studies. The gel formation and drug release from the system was evaluated both in vitro and in vivo. In vitro and in vivo results were compared with Diphereline SR 3.75mg, a commercially available controlled delivery system of triptorelin. In vitro release studies showed a sustained release profile for about 192h with first order kinetics. In vivo studies on male rats by determination of serum testosterone were confirmed the acceptable performance of in situ gel forming system compared with Diphereline SR in decreasing the serum testosterone level for 35days, demonstrating the potential of the novel in situ gel forming system for controlled delivery of peptides. Copyright © 2011 Elsevier B.V. All rights reserved.

Assembled modules technology for site-specific prolonged delivery of norfloxacin.

PubMed

Oliveira, Paulo Renato; Bernardi, Larissa Sakis; Strusi, Orazio Luca; Mercuri, Salvatore; Segatto Silva, Marcos A; Colombo, Paolo; Sonvico, Fabio

2011-02-28

The aim of this research was to design and study norfloxacin (NFX) release in floating conditions from compressed hydrophilic matrices of hydroxypropylmethylcellulose (HPMC) or poly(ethylene oxide) (PEO). Module assembling technology for drug delivery system manufacturing was used. Two differently cylindrical base curved matrix/modules, identified as female and male, were assembled in void configuration by friction interlocking their concave bases obtaining a floating release system. Drug release and floatation behavior of this assembly was investigated. Due to the higher surface area exposed to the release medium, faster release was observed for individual modules compared to their assembled configuration, independently on the polymer used and concentration. The release curves analyzed using the Korsmeyer exponential equation and Peppas & Sahlin binomial equation showed that the drug release was controlled both by drug diffusion and polymer relaxation or erosion mechanisms. However, convective transport was predominant with PEO and at low content of polymers. NFX release from PEO polymeric matrix was more erosion dependent than HPMC. The assembled systems were able to float in vitro for up to 240min, indicating that this drug delivery system of norfloxacin could provide gastro-retentive site-specific release for increasing norfloxacin bioavailability. Copyright © 2010. Published by Elsevier B.V.

Photo-Modulated Therapeutic Protein Release from a Hydrogel Depot Using Visible Light.

PubMed

Basuki, Johan S; Qie, Fengxiang; Mulet, Xavier; Suryadinata, Randy; Vashi, Aditya V; Peng, Yong Y; Li, Lingli; Hao, Xiaojuan; Tan, Tianwei; Hughes, Timothy C

2017-01-19

The use of biomacromolecular therapeutics has revolutionized disease treatment, but frequent injections are required owing to their short half-life in vivo. Thus there is a need for a drug delivery system that acts as a reservoir and releases the drug remotely "on demand". Here we demonstrate a simple light-triggered local drug delivery system through photo-thermal interactions of polymer-coated gold nanoparticles (AuNPs) inside an agarose hydrogel as therapeutic depot. Localized temperature increase induced by the visible light exposure caused reversible softening of the hydrogel matrix to release the pre-loaded therapeutics. The release profile can be adjusted by AuNPs and agarose concentrations, light intensity and exposure time. Importantly, the biological activity of the released bevacizumab was highly retained. In this study we demonstrate the potential application of this facile AuNPs/hydrogel system for ocular therapeutics delivery through its versatility to release multiple biologics, compatibility to ocular cells and spatiotemporal control using visible light. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Preparation of Porous γ-Fe2O3@mWO3 Multifunctional Nanoparticles for Drug Loading and Controlled Release.

PubMed

Peng, Hongxia; Huang, Qin; Wu, Tengyan; Wen, Jin; He, Hengping

2018-02-14

The use of chemotherapy drug is hindered by relatively low selectivity toward cancer cells and severe side effects from uptake by noncancerous cells and tissue. Thus, targeted drug delivery systems are preferred to increase the efficiency of drug delivery to specific tissues as well as to decrease its side effects. The aims of this paper are develop microwave-triggered controlled-release drug delivery systems using porous γ-Fe2O3@mWO3 multifunctional core-shell nanoparticles. We also studied its magnetic- microwave to heat responsive properties and large specific surface area. We chose ibuprofen (IBU) as a model drug to evaluate the loading and release function of the γ- Fe2O3@mWO3 nanoparticles. We used a direct precipitation method and thermal decomposition of CTAB template method to synthesize core-shell structured γ-Fe2O3@mWO3 nanoparticles. The specific surface areas were calculated by the Brunauer-Emmett-Teller (BET) method. The load drug and controlled release of the γ-Fe2O3@mWO3 triggered by microwave was determined with ultraviolet-visible spectroscopic analysis. The γ-Fe2O3@mWO3 nanoparticles possesses high surface area of 100.09 m2/g, provides large accessible pore diameter of 6.0 nm for adsorption of drug molecules, high magnetization saturation value of 43.6 emu/g for drug targeting under foreign magnetic fields, quickly convert electromagnetic energy into thermal energy for controlled release by microwave-triggered which was caused by mWO3 shell. The IBU release of over 78% under microwave discontinuous irradiation out classes the 0.15% within 20s only stirring release. This multifunctional material shows good performance for targeting delivery and mWO3 microwave controlled release of anticancer drugs based on all the properties they possess. The porous shell and the introduction of absorbing material not only increased the drug loading efficiency of the nanoparticles but also realized the microwave-stimulated anticancer drug controlled release. The nanoparticles would be very promising for microwave-induced controlled drug release, targeted drug delivery and hyperthermia therapy using microwave. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

System-based approach for an advanced drug delivery platform

NASA Astrophysics Data System (ADS)

Kulinsky, Lawrence; Xu, Han; Tsai, Han-Kuan A.; Madou, Marc

2006-03-01

Present study is looking at the problem of integrating drug delivery microcapsule, a bio-sensor, and a control mechanism into a biomedical drug delivery system. A wide range of medical practices from cancer therapy to gastroenterological treatments can benefit from such novel bio-system. Drug release in our drug delivery system is achieved by electrochemically actuating an array of polymeric valves on a set of drug reservoirs. The valves are bi-layer structures, made in the shape of a flap hinged on one side to a valve seat, and consisting of thin films of evaporated gold and electrochemically deposited polypyrrole (PPy). These thin PPy(DBS) bi-layer flaps cover access holes of underlying chambers micromachined in a silicon substrate. Chromium and polyimide layers are applied to implement "differential adhesion" to obtain a voltage induced deflection of the bilayer away from the drug reservoir. The Cr is an adhesion-promoting layer, which is used to strongly bind the gold layer down to the substrate, whereas the gold adheres weakly to polyimide. Drug actives (dry or wet) were pre-stored in the chambers and their release is achieved upon the application of a small bias (~ 1V). Negative voltage causes cation adsorption and volume change in PPy film. This translates into the bending of the PPy/Au bi-layer actuator and release of the drug from reservoirs. This design of the drug delivery module is miniaturized to the dimensions of 200μm valve diameter. Galvanostatic and potentiostatic PPy deposition methods were compared, and potentiostatic deposition method yields film of more uniform thickness. PPy deposition experiments with various pyrrole and NaDBS concentrations were also performed. Glucose biosensor based on glucose oxidase (GOx) embedded in the PPy matrix during elechtrochemical deposition was manufactured and successfully tested. Multiple-drug pulsatile release and continuous linear release patterns can be implemented by controlling the operation of an array of valves. Varying amounts of drugs, together with more complex controlling strategies would allow creation of more complex drug delivery patterns.

Development of a sustained fluoride delivery system.

PubMed

Baturina, Olga; Tufekci, Eser; Guney-Altay, Ozge; Khan, Shadeed M; Wnek, Gary E; Lindauer, Steven J

2010-11-01

To develop a novel delivery system by which fluoride incorporated into elastomeric rings, such as those used to ligate orthodontic wires, will be released in a controlled and constant manner. Polyethylene co-vinyl acetate (PEVA) was used as the model elastomer. Samples (N = 3) were prepared by incorporating 0.02 to 0.4 g of sodium fluoride (NaF) into previously prepared PEVA solution. Another group of samples prepared in the same manner were additionally dip-coated in PEVA to create an overcoat. Fluoride release studies were conducted in vitro using an ion selective electrode over a period of 45 days. The amount of fluoride released was compared to the optimal therapeutic dose of 0.7 microg F(-)/ring/d. Only coated samples with the highest fluoride content (group D, 0.4 g of NaF) were able to release fluoride at therapeutic levels. When fluoride release from coated and uncoated samples with the same amount of NaF were compared, it was shown that the dip-coating technique resulted in a fluoride release in a controlled manner while eliminating the initial burst effect. This novel fluoride delivery matrix provided fluoride release at a therapeutically effective rate and profile.

Multi-pulse drug delivery from a resorbable polymeric microchip device

NASA Astrophysics Data System (ADS)

Grayson, Amy C. Richards; Choi, Insung S.; Tyler, Betty M.; Wang, Paul P.; Brem, Henry; Cima, Michael J.; Langer, Robert

2003-11-01

Controlled-release drug delivery systems have many applications, including treatments for hormone deficiencies and chronic pain. A biodegradable device that could provide multi-dose drug delivery would be advantageous for long-term treatment of conditions requiring pulsatile drug release. In this work, biodegradable polymeric microchips were fabricated that released four pulses of radiolabelled dextran, human growth hormone or heparin in vitro. Heparin that was released over 142 days retained on average 96 +/- 12% of its bioactivity. The microchips were 1.2 cm in diameter, 480-560 μm thick and had 36 reservoirs that could each be filled with a different chemical. The devices were fabricated from poly(L-lactic acid) and had poly(D,L-lactic-co-glycolic acid) membranes of different molecular masses covering the reservoirs. A drug delivery system can be designed with the potential to release pulses of different drugs at intervals after implantation in a patient by using different molecular masses or materials for the membrane.

Natural material-decorated mesoporous silica nanoparticle container for multifunctional membrane-controlled targeted drug delivery

PubMed Central

Hu, Yan; Ke, Lei; Chen, Hao; Zhuo, Ma; Yang, Xinzhou; Zhao, Dan; Zeng, Suying; Xiao, Xincai

2017-01-01

To avoid the side effects caused by nonspecific targeting, premature release, weak selectivity, and poor therapeutic efficacy of current nanoparticle-based systems used for drug delivery, we fabricated natural material-decorated nanoparticles as a multifunctional, membrane-controlled targeted drug delivery system. The nanocomposite material coated with a membrane was biocompatible and integrated both specific tumor targeting and responsiveness to stimulation, which improved transmission efficacy and controlled drug release. Mesoporous silica nanoparticles (MSNs), which are known for their biocompatibility and high drug-loading capacity, were selected as a model drug container and carrier. The membrane was established by the polyelectrolyte composite method from chitosan (CS) which was sensitive to the acidic tumor microenvironment, folic acid-modified CS which recognizes the folate receptor expressed on the tumor cell surface, and a CD44 receptor-targeted polysaccharide hyaluronic acid. We characterized the structure of the nanocomposite as well as the drug release behavior under the control of the pH-sensitive membrane switch and evaluated the antitumor efficacy of the system in vitro. Our results provide a basis for the design and fabrication of novel membrane-controlled nanoparticles with improved tumor-targeting therapy. PMID:29200852

A nano-delivery system for bioactive ingredients using supercritical carbon dioxide and its release behaviors.

PubMed

Situ, Wenbei; Song, Xianliang; Luo, Shucan; Liang, Yan

2017-08-01

For the purpose of ensuring the bioavailability of bioactive ingredients, a nano-delivery system with low toxicity was developed using supercritical carbon dioxide (SC-CO 2 ). Compared to thin-film hydration (TFH), obtaining nano-scale liposomes is easier using SC-CO 2 . The characteristic of these liposomes was also demonstrated by the analysis of particle size and morphology. An in vitro release study showed that liposomes produced using SC-CO 2 were resistant to low pH in simulated gastric conditions. In a simulated intestinal environment, enteric solubility of these liposomes was enhanced, which are important properties for controlled releasing bioactive ingredient. Furthermore, SC-CO 2 -produced liposomes had a higher storage stability than those produced using TFH. Analysis of the organic solvent residue in the liposomes by gas chromatography-mass spectrometry (GC-MS) indicated that SC-CO 2 -produced liposomes had lower toxicity than those produced by TFH. A chemical free nano-delivery system using SC-CO 2 has been revealed for storage and controlled release of bioactive ingredients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Polymers for Drug Delivery Systems

PubMed Central

Liechty, William B.; Kryscio, David R.; Slaughter, Brandon V.; Peppas, Nicholas A.

2012-01-01

Polymers have played an integral role in the advancement of drug delivery technology by providing controlled release of therapeutic agents in constant doses over long periods, cyclic dosage, and tunable release of both hydrophilic and hydrophobic drugs. From early beginnings using off-the-shelf materials, the field has grown tremendously, driven in part by the innovations of chemical engineers. Modern advances in drug delivery are now predicated upon the rational design of polymers tailored for specific cargo and engineered to exert distinct biological functions. In this review, we highlight the fundamental drug delivery systems and their mathematical foundations and discuss the physiological barriers to drug delivery. We review the origins and applications of stimuli-responsive polymer systems and polymer therapeutics such as polymer-protein and polymer-drug conjugates. The latest developments in polymers capable of molecular recognition or directing intracellular delivery are surveyed to illustrate areas of research advancing the frontiers of drug delivery. PMID:22432577

Mesoporous inorganic nanoscale particles for drug adsorption and controlled release.

PubMed

Cavallaro, Giuseppe; Lazzara, Giuseppe; Fakhrullin, Rawil

2018-03-01

The review provides an overview of the mesoporous inorganic particles employed as drug delivery systems for controlled and sustained release of drugs. We have classified promising nanomaterials for drug delivery on the basis of their natural or synthetic origin. Nanoclays are available in different morphologies (nanotubes, nanoplates and nanofibers) and they are typically available at low cost from natural resources. The surface chemistry of nanoclays is versatile for targeted modifications to control loading and release properties. Synthetic nanomaterials (imogolite, laponite and mesoporous silica) present the advantages of well-established purity and availability with size features that are finely controlled. Both nanoclays and inorganic synthetic nanoparticles can be functionalized forming organic/inorganic architectures with stimuli-responsive features.

pH-sensitive nano-systems for drug delivery in cancer therapy.

PubMed

Liu, Juan; Huang, Yuran; Kumar, Anil; Tan, Aaron; Jin, Shubin; Mozhi, Anbu; Liang, Xing-Jie

2014-01-01

Nanotechnology has been widely used in the development of new strategies for drug delivery and cancer therapy. Compared to traditional drug delivery systems, nano-based drug delivery system have greater potential in a variety of areas, such as multiple targeting functionalization, in vivo imaging, combined drug delivery, extended circulation time, and systemic control release. Nano-systems incorporating stimulus-responsive materials have remarkable properties which allow them to bypass biological barriers and achieve targeted intracellular drug delivery. As a result of the active metabolism of tumor cells, the tumor microenvironment (TME) is highly acidic compared to normal tissues. pH-Sensitive nano-systems have now been developed in which drug release is specifically triggered by the acidic tumor environment. Studies have demonstrated that novel pH-sensitive drug delivery systems are capable of improving the efficiency of cancer treatment. A number of these have been translated from bench to clinical application and have been approved by the Food and Drug Administration (FDA) for treatment of various cancerous diseases. Herein, this review mainly focuses on pH-sensitive nano-systems, including advances in drug delivery, mechanisms of drug release, and possible improvements in drug absorption, with the emphasis on recent research in this field. With deeper understanding of the difference between normal and tumor tissues, it might be possible to design ever more promising pH-responsive nano-systems for drug delivery and cancer therapy in the near future. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Disease-responsive drug delivery: the next generation of smart delivery devices.

PubMed

Wanakule, Prinda; Roy, Krishnendu

2012-01-01

With the advent of highly potent and cytotoxic drugs, it is increasingly critical that they be targeted and released only in cells of diseased tissues, while sparing physiologically normal neighbors. Simple ligand-based targeting of drug carriers, although promising, cannot always provide the required specificity to achieve this since often normal cells also express significant levels of the targeted receptors. Therefore, stimuli-responsive delivery systems are being explored to allow drug release from nano- and microcarriers and implantable devices, primarily in the presence of physiological or disease-specific pathophysiological signals. Designing smart biomaterials that respond to temperature or pH changes, protein and ligand binding, disease-specific degradation, e.g. enzymatic cleavage, has become an integral part of this approach. These strategies are used in combination with nano- and microparticle systems to improve delivery efficiency through several routes of administration, and with injectable or implantable systems for long term controlled release. This review focuses on recent developments in stimuli-responsive systems, their physicochemical properties, release profiles, efficacy, safety and biocompatibility, as well as future perspectives.

Controlled Release Strategies for Bone, Cartilage, and Osteochondral Engineering—Part I: Recapitulation of Native Tissue Healing and Variables for the Design of Delivery Systems

PubMed Central

Santo, Vítor E.; Mano, João F.; Reis, Rui L.

2013-01-01

The potential of growth factors to stimulate tissue healing through the enhancement of cell proliferation, migration, and differentiation is undeniable. However, critical parameters on the design of adequate carriers, such as uncontrolled spatiotemporal presence of bioactive factors, inadequate release profiles, and supraphysiological dosages of growth factors, have impaired the translation of these systems onto clinical practice. This review describes the healing cascades for bone, cartilage, and osteochondral interface, highlighting the role of specific growth factors for triggering the reactions leading to tissue regeneration. Critical criteria on the design of carriers for controlled release of bioactive factors are also reported, focusing on the need to provide a spatiotemporal control over the delivery and presentation of these molecules. PMID:23268651

Controlled drug delivery through a novel PEG hydrogel encapsulated silica aerogel system.

PubMed

Giray, Seda; Bal, Tuğba; Kartal, Ayse M; Kızılel, Seda; Erkey, Can

2012-05-01

A novel composite material consisting of a silica aerogel core coated by a poly(ethylene) glycol (PEG) hydrogel was developed. The potential of this novel composite as a drug delivery system was tested with ketoprofen as a model drug due to its solubility in supercritical carbon dioxide. The results indicated that both drug loading capacity and drug release profiles could be tuned by changing hydrophobicity of aerogels, and that drug loading capacity increased with decreased hydrophobicity, while slower release rates were achieved with increased hydrophobicity. Furthermore, higher concentration of PEG diacrylate in the prepolymer solution of the hydrogel coating delayed the release of the drug which can be attributed to the lower permeability at higher PEG diacrylate concentrations. The novel composite developed in this study can be easily implemented to achieve the controlled delivery of various drugs and/or proteins for specific applications. Copyright © 2012 Wiley Periodicals, Inc.

Materials to clinical devices: technologies for remotely triggered drug delivery.

PubMed

Timko, Brian P; Kohane, Daniel S

2012-11-01

Technologies in which a remote trigger is used to release drug from an implanted or injected device could enable on-demand release profiles that enhance therapeutic effectiveness or reduce systemic toxicity. A number of new materials have been developed that exhibit sensitivity to light, ultrasound, or electrical or magnetic fields. Delivery systems that incorporate these materials might be triggered externally by the patient, parent or physician to provide flexible control of dose magnitude and timing. To review injectable or implantable systems that are candidates for translation to the clinic, or ones that have already undergone clinical trials. Also considered are applicability in pediatrics and prospects for the future of drug delivery systems. We performed literature searches of the PubMed and Science Citation Index databases for articles in English that reported triggerable drug delivery devices, and for articles reporting related materials and concepts. Approaches to remotely-triggered systems that have clinical potential were identified. Ideally, these systems have been engineered to exhibit controlled on-state release kinetics, low baseline leak rates, and reproducible dosing across multiple cycles. Advances in remotely-triggered drug delivery have been brought about by the convergence of numerous scientific and engineering disciplines, and this convergence is likely to play an important part in the current trend to develop systems that provide more than one therapeutic modality. Preclinical systems must be carefully assessed for biocompatibility, and engineered to ensure pharmacokinetics within the therapeutic window. Future drug delivery systems may incorporate additional modalities, such as closed-loop sensing or onboard power generation, enabling more sophisticated drug delivery regimens. Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.

Temporally controlled release of multiple growth factors from a self-assembling peptide hydrogel

NASA Astrophysics Data System (ADS)

Bruggeman, Kiara F.; Rodriguez, Alexandra L.; Parish, Clare L.; Williams, Richard J.; Nisbet, David R.

2016-09-01

Protein growth factors have demonstrated great potential for tissue repair, but their inherent instability and large size prevents meaningful presentation to biologically protected nervous tissue. Here, we create a nanofibrous network from a self-assembling peptide (SAP) hydrogel to carry and stabilize the growth factors. We significantly reduced growth factor degradation to increase their lifespan by over 40 times. To control the temporal release profile we covalently attached polysaccharide chitosan molecules to the growth factor to increase its interactions with the hydrogel nanofibers and achieved a 4 h delay, demonstrating the potential of this method to provide temporally controlled growth factor delivery. We also describe release rate based analysis to examine the growth factor delivery in more detail than standard cumulative release profiles allow and show that the chitosan attachment method provided a more consistent release profile with a 60% reduction in fluctuations. To prove the potential of this system as a complex growth factor delivery platform we demonstrate for the first time temporally distinct release of multiple growth factors from a single tissue specific SAP hydrogel: a significant goal in regenerative medicine.

Mucosal delivery of liposome-chitosan nanoparticle complexes.

PubMed

Carvalho, Edison L S; Grenha, Ana; Remuñán-López, Carmen; Alonso, Maria José; Seijo, Begoña

2009-01-01

Designing adequate drug carriers has long been a major challenge for those working in drug delivery. Since drug delivery strategies have evolved for mucosal delivery as the outstanding alternative to parenteral administration, many new drug delivery systems have been developed which evidence promising properties to address specific issues. Colloidal carriers, such as nanoparticles and liposomes, have been referred to as the most valuable approaches, but still have some limitations that can become more inconvenient as a function of the specific characteristics of administration routes. To overcome these limitations, we developed a new drug delivery system that results from the combination of chitosan nanoparticles and liposomes, in an approach of combining their advantages, while avoiding their individual limitations. These lipid/chitosan nanoparticle complexes are, thus, expected to protect the encapsulated drug from harsh environmental conditions, while concomitantly providing its controlled release. To prepare these assemblies, two different strategies have been applied: one focusing on the simple hydration of a previously formed dry lipid film with a suspension of chitosan nanoparticles, and the other relying on the lyophilization of both basic structures (nanoparticles and liposomes) with a subsequent step of hydration with water. The developed systems are able to provide a controlled release of the encapsulated model peptide, insulin, evidencing release profiles that are dependent on their lipid composition. Moreover, satisfactory in vivo results have been obtained, confirming the potential of these newly developed drug delivery systems as drug carriers through distinct mucosal routes.

Novel vaginal drug delivery system: deformable propylene glycol liposomes-in-hydrogel.

PubMed

Vanić, Željka; Hurler, Julia; Ferderber, Kristina; Golja Gašparović, Petra; Škalko-Basnet, Nataša; Filipović-Grčić, Jelena

2014-03-01

Deformable propylene glycol-containing liposomes (DPGLs) incorporating metronidazole or clotrimazole were prepared and evaluated as an efficient drug delivery system to improve the treatment of vaginal microbial infections. The liposome formulations were optimized based on sufficient trapping efficiencies for both drugs and membrane elasticity as a prerequisite for successful permeability and therapy. An appropriate viscosity for vaginal administration was achieved by incorporating the liposomes into Carbopol hydrogel. DPGLs were able to penetrate through the hydrogel network more rapidly than conventional liposomes. In vitro studies of drug release from the liposomal hydrogel under conditions simulating human treatment confirmed sustained and diffusion-based drug release. Characterization of the rheological and textural properties of the DPGL-containing liposomal hydrogels demonstrated that the incorporation of DPGLs alone had no significant influence on mechanical properties of hydrogels compared to controls. These results support the great potential of DPGL-in-hydrogel as an efficient delivery system for the controlled and sustained release of antimicrobial drugs in the vagina.

In vitro controlled release of clove essential oil in self-assembly of amphiphilic polyethylene glycol-block-polycaprolactone.

PubMed

Thonggoom, O; Punrattanasin, N; Srisawang, N; Promawan, N; Thonggoom, R

2016-05-01

In this study, a micellar delivery system with an amphiphilic diblock copolymer of poly (ethylene glycol) and poly (ɛ-caprolactone) was synthesised and used to incorporate hydrophobic clove essential oil (CEO). To determine an optimal delivery system, the effects of the copolymer's hydrophobic block length and the CEO-loading content on the encapsulation of CEO were investigated. Percentages of entrapment efficiency (%EE), CEO loading (%CEO), and in vitro release profiles were determined. The size, size distribution, zeta potential, and morphology of the obtained micelles were determined by DLS, FE-SEM, and TEM. The %EE, %CEO, and in vitro release profiles of CEO incorporated in micelles were analysed by HPLC. The study revealed a sustained release profile of CEO from CEO-loaded micelles. The results indicate the successful formulation of CEO-loaded PEG-b-PCL micelle nanoparticles. It is suggested that this micelle system has considerably potential applications in the sustained release of CEO in intravascular drug delivery.

An update on applications of nanostructured drug delivery systems in cancer therapy: a review.

PubMed

Aberoumandi, Seyed Mohsen; Mohammadhosseini, Majid; Abasi, Elham; Saghati, Sepideh; Nikzamir, Nasrin; Akbarzadeh, Abolfazl; Panahi, Yunes; Davaran, Soodabeh

2017-09-01

Cancer is a main public health problem that is known as a malignant tumor and out-of-control cell growth, with the potential to assault or spread to other parts of the body. Recently, remarkable efforts have been devoted to develop nanotechnology to improve the delivery of anticancer drug to tumor tissue as minimizing its distribution and toxicity in healthy tissue. Nanotechnology has been extensively used in the advance of new strategies for drug delivery and cancer therapy. Compared to customary drug delivery systems, nano-based drug delivery method has greater potential in different areas, like multiple targeting functionalization, in vivo imaging, extended circulation time, systemic control release, and combined drug delivery. Nanofibers are used for different medical applications such as drug delivery systems.

Modeling the modified drug release from curved shape drug delivery systems - Dome Matrix®.

PubMed

Caccavo, D; Barba, A A; d'Amore, M; De Piano, R; Lamberti, G; Rossi, A; Colombo, P

2017-12-01

The controlled drug release from hydrogel-based drug delivery systems is a topic of large interest for research in pharmacology. The mathematical modeling of the behavior of these systems is a tool of emerging relevance, since the simulations can be of use in the design of novel systems, in particular for complex shaped tablets. In this work a model, previously developed, was applied to complex-shaped oral drug delivery systems based on hydrogels (Dome Matrix®). Furthermore, the model was successfully adopted in the description of drug release from partially accessible Dome Matrix® systems (systems with some surfaces coated). In these simulations, the erosion rate was used asa fitting parameter, and its dependence upon the surface area/volume ratio and upon the local fluid dynamics was discussed. The model parameters were determined by comparison with the drug release profile from a cylindrical tablet, then the model was successfully used for the prediction of the drug release from a Dome Matrix® system, for simple module configuration and for module assembled (void and piled) configurations. It was also demonstrated that, given the same initial S/V ratio, the drug release is independent upon the shape of the tablets but it is only influenced by the S/V evolution. The model reveals itself able to describe the observed phenomena, and thus it can be of use for the design of oral drug delivery systems, even if complex shaped. Copyright © 2017 Elsevier B.V. All rights reserved.

Chitosan-functionalised single-walled carbon nanotube-mediated drug delivery of SNX-2112 in cancer cells.

PubMed

Zheng, Lixia; Wu, Shao; Tan, Li; Tan, Huo; Yu, Baodan

2016-09-01

Delivery of amphiphobic drugs (insoluble in both water and oil) has been a great challenge in drug delivery. SNX-2112, a novel inhibitor of Hsp90, is a promising drug candidate for treating various types of cancers; however, the insolubility greatly limits its clinical application. This study aimed to build a new type of drug delivery system using single-walled carbon nanotubes (SWNTs) for controllable release of SNX-2112; chitosan (CHI) was non-covalently added to SWNTs to improve their biocompatibility. SWNTs-CHI demonstrated high drug-loading capability; the release of SNX-2112 was pH triggered and time related. The intracellular reactive oxygen species of SWNTs-CHI increased, compared with that of SWNTs, leading to higher mitogen-activated protein kinase and cell apoptosis. The results of western-blotting, lactate dehydrogenase (LDH) release assay, and cell viability assay analyses indicated that apoptosis-related proteins were abundantly expressed in K562 cells and that the drug delivery system significantly inhibited K562 cells. Thus, SWNT-CHI/SNX-2112 shows great potential as a drug delivery system for cancer therapy. © The Author(s) 2016.

Controlled, sustained release of proteins via an injectable, mineral-coated microsphere delivery vehicle

NASA Astrophysics Data System (ADS)

Franklin-Ford, Travelle

Hydroxyapatite interfaces have demonstrated strong protein binding and protein selection from a passing solution and can serve as a biocompatible carrier for controlled protein delivery. Hydroxyapatite is a major component of long bones and tooth enamel and is the most stable of all calcium phosphate isoforms in aqueous solutions at physiologic pH, providing a sensitive chromatographic mechanism for separating proteins. Here we describe an approach to create a synthetic hydroxyapatite coating through a biomimetic, heterogeneous nucleation from a modified simulated body fluid--supersaturated with calcium and phosphate ions on the surface of injectable polymer microspheres. We are able to bind and release bioactive growth factors into a variety of in vitro and in vivo conditions, demonstrating the functionality and advantage of the biomaterial. Creating a hydroxyapatite layer on the Poly(D,L-lactide-co-glycolide) (PLG) microsphere surface, avails the microsphere interior for another application that will not compete with protein binding and release. Encapsulating an imaging agent within the aqueous phase of the emulsion provides a visual reference for the injectable therapy upon microsphere fabrication. Another advantage of this system is that the mineral coating and subsequent protein binding is not compromised by the encapsulated imaging agent. This dual function delivery vehicle is not only advantageous for spatial tracking therapeutic applications, but also determining the longevity of the delivery vehicle once injected. In the broader sense, providing a mechanism to image and track our temporally controlled, sustained delivery system gives more evidence to support the effects of released protein on in vivo responses (bioactivity) and locate microspheres within different biological systems.

Antibiotic-loaded plaster of Paris implants coated with poly lactide-co-glycolide as a controlled release delivery system for the treatment of bone infections.

PubMed

Benoit, M A; Mousset, B; Delloye, C; Bouillet, R; Gillard, J

1997-01-01

Plaster of Paris implants containing vancomycin (60 mg/g of carrier) were prepared in order to be used as local delivery system for the treatment of bone infections. The regulation of the release rate was performed by coating the carrier with a polylactide-co-glycolide polymer composed by 10% (w/w) polyglycolic acid and 90% (w/w) racemic poly (D,L-lactic acid). The release of the antibiotic from the biodegradable matrix was evaluated in vitro. From this investigation, it is clear that the drug elution depends on the coating depth. After a burst effect occurring on the first day of the experiment, therapeutic concentrations were measured during one week when uncoated implants were used. The coating allowed decrease of the burst effect and extended efficient release to more than five weeks when the implants were embedded with six layers (162 microns) of PLA45GA10. This delivery system was implanted into the femoral condyle of rabbits. It was shown that the in vivo release was also closely regulated by the coating depth. In all bone tissues (bone marrow and cortical bone) surrounding the pellets, the drug concentration exceeded the Minimum Inhibitory Concentration for the common causative organisms of bone infections (Staphylococcus aureus) for at least four weeks without inducing serum toxic levels. Due to its cheapness, facility of use and sterilization, biocompatibility and biodegradability, plaster of Paris coated with PLA45GA10 polymer giving a controlled release of vancomycin appears to be a promising sustained release delivery system of antibiotics for the treatment of bone and joint infections.

Nanomedicines based drug delivery systems for anti-cancer targeting and treatment.

PubMed

Jain, Vikas; Jain, Shikha; Mahajan, S C

2015-01-01

Cancer is defined as an uncontrolled growth of abnormal cells. Current treatment strategies for cancer include combination of radiation, chemotherapy and surgery. The long-term use of conventional drug delivery systems for cancer chemotherapy leads to fatal damage of normal proliferate cells and this is particularly used for the management of solid tumors, where utmost tumor cells are not invaded quickly. A targeted drug delivery system (TDDS) is a system, which releases the drug at a preselected biosite in a controlled manner. Nanotechnology based delivery systems are making a significant impact on cancer treatment and the polymers play key role in the development of nanopraticlulate carriers for cancer therapy. Some important technological advantages of nanotherapeutic drug delivery systems (NDDS) include prolonged half-life, improved bio-distribution, increased circulation time of the drug, controlled and sustained release of the drug, versatility of route of administration, increased intercellular concentration of drug and many more. This review covers the current research on polymer based anticancer agents, the rationale for development of these polymer therapeutical systems and discusses the benefits and challenges of cancer nanomedicines including polymer-drug conjugates, micelles, dendrimers, immunoconjugates, liposomes, nanoparticles.

An NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles for tumor targeted drug delivery in vitro and in vivo

NASA Astrophysics Data System (ADS)

Gayam, Srivardhan Reddy; Venkatesan, Parthiban; Sung, Yi-Ming; Sung, Shuo-Yuan; Hu, Shang-Hsiu; Hsu, Hsin-Yun; Wu, Shu-Pao

2016-06-01

The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this smart biocompatible carrier system showed obvious uptake and consequent release of the drug in tumor cells, could selectively induce the tumor cell death and enhance the capability of inhibition of tumor growth in vivo. The controlled drug delivery system demonstrated its use as a potential theranostic material.The synthesis and characterization of an NAD(P)H:quinone oxidoreductase 1 (NQO1) enzyme responsive nanocarrier based on mesoporous silica nanoparticles (MSNPs) for on-command delivery applications has been described in this paper. Gatekeeping of MSNPs is achieved by the integration of mechanically interlocked rotaxane nanovalves on the surface of MSNPs. The rotaxane nanovalve system is composed of a linear stalk anchoring on the surface of MSNPs, an α-cyclodextrin ring that encircles it and locks the payload ``cargo'' molecules in the mesopores, and a benzoquinone stopper incorporated at the end of the stalk. The gate opening and controlled release of the cargo are triggered by cleavage of the benzoquinone stopper using an endogenous NQO1 enzyme. In addition to having efficient drug loading and controlled release mechanisms, this smart biocompatible carrier system showed obvious uptake and consequent release of the drug in tumor cells, could selectively induce the tumor cell death and enhance the capability of inhibition of tumor growth in vivo. The controlled drug delivery system demonstrated its use as a potential theranostic material. Electronic supplementary information (ESI) available: Synthesis and characterization of the functional molecules and MSNPs is available in the ESI. See DOI: 10.1039/c6nr03525f

Chitosan nanoparticles/cellulose nanocrystals nanocomposites as a carrier system for the controlled release of repaglinide.

PubMed

Abo-Elseoud, Wafaa S; Hassan, Mohammad L; Sabaa, Magdy W; Basha, Mona; Hassan, Enas A; Fadel, Shaimaa M

2018-05-01

The aim of the present work was to study the use of cellulose nanocrystals (CNC) and chitosan nanoparticles (CHNP) for developing controlled-release drug delivery system of the anti-hyperglycemic drug Repaglinide (RPG). CNC was isolated from palm fruit stalks by sulfuric acid hydrolysis; the dimensions of the isolated nanocrystals were 86-237 nm in length and 5-7 nm in width. Simple and economic method was used for the fabrication of controlled release drug delivery system from CNC and CHNP loaded with RPG drug via ionic gelation of chitosan in the presence of CNC and RPG. The prepared systems showed high drug encapsulation efficiency of about ~98%. Chemical modification of CNC by oxidation to introduce carboxylic groups on their surface (OXCNC) was also carried out for further controlling of RPG release. Particles size analysis showed that the average size of CHNP was about 197 nm while CHNP/CNC/RPG or CHNP/OXCNC/RPG nanoparticles showed average size of 215-310 nm. Compatibility studies by Fourier transform infrared (FTIR) spectroscopy showed no chemical reaction between RPG and the system's components used. By studying the drug release kinetic, all the prepared RPG formulations followed Higuchi model, indicating that the drug released by diffusion through the nanoparticles polymeric matrix. Copyright © 2018 Elsevier B.V. All rights reserved.

Floating tablets for controlled release of ofloxacin via compression coating of hydroxypropyl cellulose combined with effervescent agent.

PubMed

Qi, Xiaole; Chen, Haiyan; Rui, Yao; Yang, Fengjiao; Ma, Ning; Wu, Zhenghong

2015-07-15

To prolong the residence time of dosage forms within gastrointestinal trace until all drug released at desired rate was one of the real challenges for oral controlled-release drug delivery system. Herein, we developed a fine floating tablet via compression coating of hydrophilic polymer (hydroxypropyl cellulose) combined with effervescent agent (sodium bicarbonate) to achieve simultaneous control of release rate and location of ofloxacin. Sodium alginate was also added in the coating layer to regulate the drug release rate. The effects of the weight ratio of drug and the viscosity of HPC on the release profile were investigated. The optimized formulations were found to immediately float within 30s and remain lastingly buoyant over a period of 12 h in simulated gastric fluid (SGF, pH 1.2) without pepsin, indicating a satisfactory floating and zero-order drug release profile. In addition, the oral bioavailability experiment in New Zealand rabbits showed that, the relative bioavailability of the ofloxacin after administrated of floating tablets was 172.19%, compared to marketed common release tablets TaiLiBiTuo(®). These results demonstrated that those controlled-released floating tables would be a promising gastro-retentive delivery system for drugs acting in stomach. Copyright © 2015 Elsevier B.V. All rights reserved.

A review of integrating electroactive polymers as responsive systems for specialized drug delivery applications.

PubMed

Pillay, Viness; Tsai, Tong-Sheng; Choonara, Yahya E; du Toit, Lisa C; Kumar, Pradeep; Modi, Girish; Naidoo, Dinesh; Tomar, Lomas K; Tyagi, Charu; Ndesendo, Valence M K

2014-06-01

Electroactive polymers (EAPs) are promising candidate materials for the design of drug delivery technologies, especially in conditions where an "on-off" drug release mechanism is required. To achieve this, EAPs such as polyaniline, polypyrrole, polythiophene, ethylene vinyl acetate, and polyethylene may be blended into responsive hydrogels in conjunction with the desired drug to obtain a patient-controlled drug release system. The "on-off" drug release mechanism can be achieved through the environmental-responsive nature of the interpenetrating hydrogel-EAP complex via (i) charged ions initiated diffusion of drug molecules; (ii) conformational changes that occur during redox switching of EAPs; or (iii) electroerosion. These release mechanisms are not exhaustive and new release mechanisms are still under investigation. Therefore, this review seeks to provide a concise incursion and critical overview of EAPs and responsive hydrogels as a strategy for advanced drug delivery, for example, controlled release of neurotransmitters, sulfosalicyclic acid from cross-linked hydrogel, and vaccine delivery. The review further discusses techniques such as linear sweep voltammetry, cyclic voltammetry, impedance spectroscopy, and chronoamperometry for the determination of the redox capability of EAPs. The future implications of the hydrogel-EAP composites include, but not limited to, application toward biosensors, DNA hybridizations, microsurgical tools, and miniature bioreactors and may be utilized to their full potential in the form of injectable devices as nanorobots or nanobiosensors. Copyright © 2013 Wiley Periodicals, Inc.

Clinical translation of controlled protein delivery systems for tissue engineering.

PubMed

Spiller, Kara L; Vunjak-Novakovic, Gordana

2015-04-01

Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed.

Clinical translation of controlled protein delivery systems for tissue engineering

PubMed Central

Spiller, Kara L.; Vunjak-Novakovic, Gordana

2013-01-01

Strategies that utilize controlled release of drugs and proteins for tissue engineering have enormous potential to regenerate damaged organs and tissues. The multiple advantages of controlled release strategies merit overcoming the significant challenges to translation, including high costs and long, difficult regulatory pathways. This review highlights the potential of controlled release of proteins for tissue engineering and regenerative medicine. We specifically discuss treatment modalities that have reached preclinical and clinical trials, with emphasis on controlled release systems for bone tissue engineering, the most advanced application with several products already in clinic. Possible strategies to address translational and regulatory concerns are also discussed. PMID:25787736

Novel Approaches in Formulation and Drug Delivery using Contact Lenses

PubMed Central

Singh, Kishan; Nair, Anroop B; Kumar, Ashok; Kumria, Rachna

2011-01-01

The success of ocular delivery relies on the potential to enhance the drug bioavailability by controlled and extended release of drug on the eye surface. Several new approaches have been attempted to augment the competence and diminish the intrinsic side effects of existing ocular drug delivery systems. In this contest, progress has been made to develop drug-eluting contact lens using different techniques, which have the potential to control and sustain the delivery of drug. Further, the availability of novel polymers have facilitated and promoted the utility of contact lenses in ocular drug delivery. Several research groups have already explored the feasibility and potential of contact lens using conventional drugs for the treatment of periocular and intraocular diseases. Contact lenses formulated using modern technology exhibits high loading, controlled drug release, apposite thickness, water content, superior mechanical and optical properties as compared to commercial lenses. In general, this review discus various factors and approaches designed and explored for the successful delivery of ophthalmic drugs using contact lenses as drug delivery device PMID:24826007

Hindered disulfide bonds to regulate release rate of model drug from mesoporous silica.

PubMed

Nadrah, Peter; Maver, Uroš; Jemec, Anita; Tišler, Tatjana; Bele, Marjan; Dražić, Goran; Benčina, Mojca; Pintar, Albin; Planinšek, Odon; Gaberšček, Miran

2013-05-01

With the advancement of drug delivery systems based on mesoporous silica nanoparticles (MSNs), a simple and efficient method regulating the drug release kinetics is needed. We developed redox-responsive release systems with three levels of hindrance around the disulfide bond. A model drug (rhodamine B dye) was loaded into MSNs' mesoporous voids. The pore opening was capped with β-cyclodextrin in order to prevent leakage of drug. Indeed, in absence of a reducing agent the systems exhibited little leakage, while the addition of dithiothreitol cleaved the disulfide bonds and enabled the release of cargo. The release rate and the amount of released dye were tuned by the level of hindrance around disulfide bonds, with the increased hindrance causing a decrease in the release rate as well as in the amount of released drug. Thus, we demonstrated the ability of the present mesoporous systems to intrinsically control the release rate and the amount of the released cargo by only minor structural variations. Furthermore, an in vivo experiment on zebrafish confirmed that the present model delivery system is nonteratogenic.

Tellurium-containing polymer micelles: competitive-ligand-regulated coordination responsive systems.

PubMed

Cao, Wei; Gu, Yuwei; Meineck, Myriam; Li, Tianyu; Xu, Huaping

2014-04-02

Nanomaterials capable of achieving tunable cargo release kinetics are of significance in a fundamental sense and various biological or medical applications. We report a competitive coordination system based on a novel tellurium-containing polymer and its ligand-regulated release manners. Tellurium was introduced to water-soluble polymers for the first time as drug delivery vehicles. The coordination chemistry between platinum and tellurium was designed to enable the load of platinum-based drugs. Through the competitive coordination of biomolecules, the drugs could be released in a controlled manner. Furthermore, the release kinetics could be modulated by the competitive ligands involved due to their different coordination ability. This tellurium-containing polymer may enrich the family of delivery systems and provide a new platform for future biomedical nanotechnologies.

Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells.

PubMed

Maran, Avudaiappan; Dadsetan, Mahrokh; Buenz, Colleen M; Shogren, Kristen L; Lu, Lichun; Yaszemski, Michael J

2013-09-01

Osteosarcoma is a bone tumor that affects children and young adults. 2-Methoxyestradiol (2-ME), a naturally occurring estrogen metabolite, kills osteosarcoma cells, but does not affect normal osteoblasts. In order to effectively target osteosarcoma and improve the therapeutic index of the drug 2-ME, we have encapsulated 2-ME in a composite of oligo-(polyethylene glycol) fumarate (OPF) hydrogel and poly (lactic-co-glycolic acid) (PLGA) microspheres and investigated the effect of polymer composition on 2-ME release kinetics and osteosarcoma cell survival. The in vitro study shows that 2-ME can be released in a controlled manner over 21-days. The initial burst releases observed on day 1 were 50% and 32% for OPF and OPF/PLGA composites, respectively. The extended release kinetics show that 100% of the encapsulated 2-ME is released by day 12 from OPF, whereas the OPF/PLGA composites showed a release of 85% on day 21. 2-ME released from the polymers was biologically active and blocked osteosarcoma cell proliferation in vitro. Also, comparison of 2-ME delivery in osteosarcoma cells in culture, shows that direct treatment has no effect after 3 days, whereas polymer-mediated delivery produces anti-tumor effects that could be sustained for 21 days. These findings show that the OPF and PLGA polymeric system may prove to be useful in controlled and sustained delivery of 2-ME and could be further explored in the treatment of osteosarcoma. Copyright © 2012 Wiley Periodicals, Inc.

Development of ocular drug delivery systems using molecularly imprinted soft contact lenses.

PubMed

Tashakori-Sabzevar, Faezeh; Mohajeri, Seyed Ahmad

2015-05-01

Recently, significant advances have been made in order to optimize drug delivery to ocular tissues. The main problems in ocular drug delivery are poor bioavailability and uncontrollable drug delivery of conventional ophthalmic preparations (e.g. eye drops). Hydrogels have been investigated since 1965 as new ocular drug delivery systems. Increase of hydrogel loading capacity, optimization of drug residence time on the ocular surface and biocompatibility with the eye tissue has been the main focus of previous studies. Molecular imprinting technology provided the opportunity to fulfill the above-mentioned objectives. Molecularly imprinted soft contact lenses (SCLs) have high potentials as novel drug delivery systems for the treatment of eye disorders. This technique is used for the preparation of polymers with specific binding sites for a template molecule. Previous studies indicated that molecular imprinting technology could be successfully applied for the preparation of SCLs as ocular drug delivery systems. Previous research, particularly in vivo studies, demonstrated that molecular imprinting is a versatile and effective method in optimizing the drug release behavior and enhancing the loading capacity of SCLs as new ocular drug delivery systems. This review highlights various potentials of molecularly imprinted contact lenses in enhancing the drug-loading capacity and controlling the drug release, compared to other ocular drug delivery systems. We have also studied the effects of contributing factors such as the type of comonomer, template/functional monomer molar ratio, crosslinker concentration in drug-loading capacity, and the release properties of molecularly imprinted hydrogels.

A minocycline-releasing PMMA system as a space maintainer for staged bone reconstructions-in vitro antibacterial, cytocompatibility and anti-inflammatory characterization.

PubMed

Silva, Tiago; Grenho, Liliana; Barros, Joana; Silva, José Carlos; Pinto, Rosana V; Matos, Ana; Colaço, Bruno; Fernandes, Maria Helena; Bettencourt, Ana; Gomes, Pedro S

2017-06-06

In the present work, we study the development and biological characterization of a polymethyl methacrylate (PMMA)-based minocycline delivery system, to be used as a space maintainer within craniofacial staged regenerative interventions. The developed delivery systems were characterized regarding solid state characteristics and assayed in vitro for antibacterial and anti-inflammatory activity, and cytocompatibility with human bone cells. A drug release profile allowed for an initial burst release and a more sustained and controlled release over time, with minimum inhibitory concentrations for the assayed and relevant pathogenic bacteria (i.e., Staphylococcus aureus, slime-producer Staphylococcus epidermidis and Escherichia coli) being easily attained in the early time points, and sustained up to 72 h. Furthermore, an improved osteoblastic cell response-with enhancement of cell adhesion and cell proliferation-and increased anti-inflammatory activity were verified in developed systems, compared to a control (non minocycline-loaded PMMA cement). The obtained results converge to support the possible efficacy of the developed PMMA-based minocycline delivery systems for the clinical management of complex craniofacial trauma. Here, biomaterials with space maintenance properties are necessary for the management of staged reconstructive approaches, thus minimizing the risk of peri-operative infections and enhancing the local tissue healing and early stages of regeneration.

Mucoadhesive microparticulates based on polysaccharide for target dual drug delivery of 5-aminosalicylic acid and curcumin to inflamed colon.

PubMed

Duan, Haogang; Lü, Shaoyu; Gao, Chunmei; Bai, Xiao; Qin, Hongyan; Wei, Yuhui; Wu, Xin'an; Liu, Mingzhu

2016-09-01

In this work, thiolated chitosan/alginate composite microparticulates (CMPs) coated by Eudragit S-100 were developed for colon-specific delivery of 5-aminosalicylic acid (5-ASA) and curcumin (CUR), and the use of it as a multi drug delivery system for the treatment of colitis. The physicochemical properties of the CMPs were evaluated. In vitro release was performed in gradually pH-changing medium simulating the conditions of different parts of GIT, and the results showed that the Eudragit S-100 coating has a pH-sensitive release property, which can avoid drug being released at a pH lower than 7. An everted sac method was used to evaluate the mucoadhesion of CMPs. Ex vivo mucoadhesive tests showed CMPs have excellent mucosa adhesion for the colonic mucosa of rats. In vivo treatment effect of enteric microparticulates systems was evaluated in colitis rats. The results showed superior therapeutic efficiency of this drug delivery system for the colitis rats induced by TNBS. Therefore, the enteric microparticulates systems combined the properties of pH dependent delivery, mucoadhesive, and control release, and could be an available tool for the treatment of human inflammatory bowel disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Nanocarriers in ocular drug delivery: an update review.

PubMed

Wadhwa, Sheetu; Paliwal, Rishi; Paliwal, Shivani Rai; Vyas, S P

2009-01-01

Controlled drug delivery to eye is one of the most challenging fields of pharmaceutical research. Low drug-contact time and poor ocular bioavailability due to drainage of solution, tear turnover and its dilution or lacrimation are the problems associated with conventional systems. In addition, anatomical barriers and physiological conditions of eye are also important parameters which control designing of drug delivery systems. Nanosized carriers like micro/nano-suspensions, liposome, niosome, dendrimer, nanoparticles, ocular inserts, implants, hydrogels and prodrug approaches have been developed for this purpose. These novel systems offer manifold advantages over conventional systems as they increase the efficiency of drug delivery by improving the release profile and also reduce drug toxicity. Conventional delivery systems get diluted with tear, washed away through the lacrimal gland and usually require administering at regular time intervals whereas nanocarriers release drug at constant rate for a prolonged period of time and thus enhance its absorption and site specific delivery. This review presents an overview of the various aspects of the ocular drug delivery, with special emphasis on nanocarrier based strategies, including structure of eye, its barriers, delivery routes and the challenges/limitations associated with development of novel nanocarriers. The recent progresses in therapy of ocular disease like gene therapy have also been included so that future options should also be considered from the delivery point of view. Recent progress in the delivery of proteins and peptides via ocular route has also been incorporated for reader benefit.

Lysine-based polycation:heparin coacervate for controlled protein delivery.

PubMed

Johnson, Noah Ray; Ambe, Trisha; Wang, Yadong

2014-01-01

Polycations have good potential as carriers of proteins and genetic material. However, poor control over the release rate and safety issues currently limit their use as delivery vehicles. Here we introduce a new lysine-based polycation, poly(ethylene lysinylaspartate diglyceride) (PELD), which exhibits high cytocompatibility. PELD self-assembles with the biological polyanion heparin into a coacervate that incorporates proteins with high loading efficiency. Coacervates of varying surface charge were obtained by simple alteration of the PELD:heparin ratio and resulted in diverse release profiles of the model protein bovine serum albumin. Therefore, coacervate charge represents a direct means of control over release rate and duration. The PELD coacervate also rapidly adsorbed onto a porous polymeric scaffold, demonstrating potential use in tissue engineering applications. This coacervate represents a safe and tunable protein delivery system for biomedical applications. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Importance of dual delivery systems for bone tissue engineering.

PubMed

Farokhi, Mehdi; Mottaghitalab, Fatemeh; Shokrgozar, Mohammad Ali; Ou, Keng-Liang; Mao, Chuanbin; Hosseinkhani, Hossein

2016-03-10

Bone formation is a complex process that requires concerted function of multiple growth factors. For this, it is essential to design a delivery system with the ability to load multiple growth factors in order to mimic the natural microenvironment for bone tissue formation. However, the short half-lives of growth factors, their relatively large size, slow tissue penetration, and high toxicity suggest that conventional routes of administration are unlikely to be effective. Therefore, it seems that using multiple bioactive factors in different delivery systems can develop new strategies for improving bone tissue regeneration. Combination of these factors along with biomaterials that permit tunable release profiles would help to achieve truly spatiotemporal regulation during delivery. This review summarizes the various dual-control release systems that are used for bone tissue engineering. Copyright © 2015 Elsevier B.V. All rights reserved.

Development of drug-loaded polymer microcapsules for treatment of epilepsy.

PubMed

Chen, Yu; Gu, Qi; Yue, Zhilian; Crook, Jeremy M; Moulton, Simon E; Cook, Mark J; Wallace, Gordon G

2017-09-26

Despite significant progress in developing new drugs for seizure control, epilepsy still affects 1% of the global population and is drug-resistant in more than 30% of cases. To improve the therapeutic efficacy of epilepsy medication, a promising approach is to deliver anti-epilepsy drugs directly to affected brain areas using local drug delivery systems. The drug delivery systems must meet a number of criteria, including high drug loading efficiency, biodegradability, neuro-cytocompatibility and predictable drug release profiles. Here we report the development of fibre- and sphere-based microcapsules that exhibit controllable uniform morphologies and drug release profiles as predicted by mathematical modelling. Importantly, both forms of fabricated microcapsules are compatible with human brain derived neural stem cells and differentiated neurons and neuroglia, indicating clinical compliance for neural implantation and therapeutic drug delivery.

Innovative application of metal-organic frameworks for encapsulation and controlled release of allyl isothiocyanate

USDA-ARS?s Scientific Manuscript database

This research investigated the technical feasibility of metal-organic frameworks (MOFs) as novel delivery systems for encapsulation and controlled release of volatile allyl isothiocyanate (AITC) molecules. We hypothesized that water vapor molecules could act as an external stimulus to trigger the re...

Materials for pharmaceutical dosage forms: molecular pharmaceutics and controlled release drug delivery aspects.

PubMed

Mansour, Heidi M; Sohn, Minji; Al-Ghananeem, Abeer; Deluca, Patrick P

2010-09-15

Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development.

Materials for Pharmaceutical Dosage Forms: Molecular Pharmaceutics and Controlled Release Drug Delivery Aspects

PubMed Central

Mansour, Heidi M.; Sohn, MinJi; Al-Ghananeem, Abeer; DeLuca, Patrick P.

2010-01-01

Controlled release delivery is available for many routes of administration and offers many advantages (as microparticles and nanoparticles) over immediate release delivery. These advantages include reduced dosing frequency, better therapeutic control, fewer side effects, and, consequently, these dosage forms are well accepted by patients. Advances in polymer material science, particle engineering design, manufacture, and nanotechnology have led the way to the introduction of several marketed controlled release products and several more are in pre-clinical and clinical development. PMID:20957095

Bioerodible System for Sequential Release of Multiple Drugs

PubMed Central

Sundararaj, Sharath C.; Thomas, Mark V.; Dziubla, Thomas D.; Puleo, David A.

2013-01-01

Because many complex physiological processes are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the objective of the present research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. The polymers used were cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule. PMID:24096151

A low-voltage electrokinetic nanochannel drug delivery system.

PubMed

Fine, Daniel; Grattoni, Alessandro; Zabre, Erika; Hussein, Fazle; Ferrari, Mauro; Liu, Xuewu

2011-08-07

Recent work has elucidated the potential of important new therapeutic paradigms, including metronomic delivery and chronotherapy, in which the precise timing and location of therapeutic administration has a significant impact on efficacy and toxicity. New drug delivery architectures are needed to not only release drug continuously at precise rates, but also synchronize their release with circadian cycles. We present an actively controlled nanofluidic membrane that exploits electrophoresis to control the magnitude, duration, and timing of drug release. The membrane, produced using high precision silicon fabrication techniques, has platinum electrodes integrated at the inlet and outlet that allow both amplification and reversal of analyte delivery with low applied voltage (at or below 2 VDC). Device operation was demonstrated with solutions of both fluorescein isothiocyanate conjugated bovine serum albumin and lysozyme using fluorescence spectroscopy, fluorescence microscopy, and a lysozyme specific bio-assay and has been characterized for long-term molecular release and release reversibility. Through a combination of theoretical and experimental analysis, the relative contributions of electrophoresis and electroosmosis have been investigated. The membrane's clinically relevant electrophoretic release rate at 2 VDC exceeds the passive release by nearly one order of magnitude, demonstrating the potential to realize the therapeutic paradigm goal. This journal is © The Royal Society of Chemistry 2011

Polyvinyl alcohol hydrogels for iontohporesis

NASA Astrophysics Data System (ADS)

Bera, Prasanta; Alam, Asif Ali; Arora, Neha; Tibarewala, Dewaki Nandan; Basak, Piyali

2013-06-01

Transdermal therapeutic systems propound controlled release of active ingredients through the skin into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. The iontophoresis deal with the systemic delivery of the bioactive agents (drug) by applying an electric current. It is basically an injection without the needle. The iontophoretic system requires a gel-based matrix to accommodate the bioactive agent. Hydrogels have been used by many investigators in controlled-release drug delivery systems because of their good tissue compatibility and easy manipulation of swelling level and, thereby, solute permeability. In this work we have prepared polyvinyl alcohol (PVA) hydrogel. We have cross linked polyvinyl alcohol chemically with Glutaraldehyde with different wt%. FTIR study reveals the chemical changes during cross linking. Swelling in water, is done to have an idea about drug loading and drug release from the membrane. After drug loading to the hydrogels, we have studied the drug release property of the hydrogels using salicylic acid as a model drug.

Controlled growth factor release from synthetic extracellular matrices

NASA Astrophysics Data System (ADS)

Lee, Kuen Yong; Peters, Martin C.; Anderson, Kenneth W.; Mooney, David J.

2000-12-01

Polymeric matrices can be used to grow new tissues and organs, and the delivery of growth factors from these matrices is one method to regenerate tissues. A problem with engineering tissues that exist in a mechanically dynamic environment, such as bone, muscle and blood vessels, is that most drug delivery systems have been designed to operate under static conditions. We thought that polymeric matrices, which release growth factors in response to mechanical signals, might provide a new approach to guide tissue formation in mechanically stressed environments. Critical design features for this type of system include the ability to undergo repeated deformation, and a reversible binding of the protein growth factors to polymeric matrices to allow for responses to repeated stimuli. Here we report a model delivery system that can respond to mechanical signalling and upregulate the release of a growth factor to promote blood vessel formation. This approach may find a number of applications, including regeneration and engineering of new tissues and more general drug-delivery applications.

Controlled-release, pegylation, liposomal formulations: new mechanisms in the delivery of injectable drugs.

PubMed

Reddy, K R

2000-01-01

To review recent developments in novel injectable drug delivery mechanisms and outline the advantages and disadvantages of each. A MEDLINE (1995-January 2000) search using the terms polyethylene glycol, liposomes, polymers, polylactic acid, and controlled release was conducted. Additional references were identified by scanning bibliographies. All articles were considered for inclusion. Abstracts were included only if they were judged to add critical information not otherwise available in the medical literature. A number of systems that alter the delivery of injectable drugs have been developed in attempts to improve pharmacodynamic and pharmacokinetic properties of therapeutic agents. New drug delivery systems can be produced either through a change in formulation (e.g., continuous-release products, liposomes) or an addition to the drug molecule (e.g., pegylation). Potential advantages of new delivery mechanisms include an increased or prolonged duration of pharmacologic activity, a decrease in adverse effects, and increased patient compliance and quality of life. Injectable continuous-release systems deliver drugs in a controlled, predetermined fashion and are particularly appropriate when it is important to avoid large fluctuations in plasma drug concentrations. Encapsulating a drug within a liposome can produce a prolonged half-life and a shift of distribution toward tissues with increased capillary permeability (e.g., tumors, infected tissue). Pegylation provides a method for modification of therapeutic proteins to minimize many of the limitations (e.g., poor stability, short half-life, immunogenicity) associated with these agents. Pegylation of therapeutic proteins is an established process with new applications. However, not all pegylated proteins are alike, and each requires optimization on a protein-by-protein basis to derive maximum clinical benefit. The language required to describe each pegylated therapeutic protein must be more precise to accurately distinguish each protein's differential pharmacologic properties.

Bifunctional capsular dosage form: novel fanicular cylindrical gastroretentive system of clarithromycin and immediate release granules of ranitidine HCl for simultaneous delivery.

PubMed

Rajput, Pallavi; Singh, Deshvir; Pathak, Kamla

2014-01-30

The study was aimed to develop a bifunctional single unit capsular system containing gastroretentive funicular cylindrical system (FCS) for controlled local delivery of clarithromycin and immediate release of ranitidine HCl. A 2(3) full factorial design was used to prepare gastroretentive FCS of clarithromycin using polyacrylamide (PAM), HPMC E15LV and Carbopol 934 P. The FCSs were evaluated for % cumulative drug release, floating time and in vitro detachment stress. Among the eight formulations, FCS5 (containing PAM and Carbopol 934 P at high and HPMC E15LV at low levels) showed % cumulative drug release of 97.09±1.14% in 8 h, floating time of 3 h and detachment stress of 8303.64±0.34 dynes/cm(2). Evaluation of optimized FCS by novel dynamic in vitro test proved superior bioadhesivity than cylindrical system under aggressive simulated peristaltic activity. Magnetic resonance imaging elucidated zero order release via constant swelling and erosion of FCS5. In vitro permeability across gastric mucin ensured its potential for effective eradication of deep seated Helicobactor pylori in gastric linings. The optimized FCS was combined with immediate release granules of rantidine HCl to get a bifunctional capsular dosage form. In vitro simultaneous drug release of clarithromycin and rantidine estimated by Vierordt's method exhibited a controlled drug release of 97.72±0.4% in 8 h for clarithromycin through FCS5 and 98.8±1.2% in 60 min from IR granules of ranitidine HCl. The novel system thus established its capability of simultaneous variable delivery of acid suppression agent and macrolide antibiotic that can be advantageous in clinical setting. Copyright © 2013 Elsevier B.V. All rights reserved.

Autonomous Rhythmic Drug Delivery Systems Based on Chemical and Biochemomechanical Oscillators

NASA Astrophysics Data System (ADS)

Siegel, Ronald A.

While many drug delivery systems target constant, or zero-order drug release, certain drugs and hormones must be delivered in rhythmic pulses in order to achieve their optimal effect. Here we describe studies with two model autonomous rhythmic delivery systems. The first system is driven by a pH oscillator that modulates the ionization state of a model drug, benzoic acid, which can permeate through a lipophilic membrane when the drug is uncharged. The second system is based on a nonlinear negative feedback instability that arises from coupling of swelling of a hydrogel membrane to an enzymatic reaction, with the hydrogel controlling access of substrate to the enzyme, and the enzyme's product controlling the hydrogel's swelling state. The latter system, whose autonomous oscillations are driven by glucose at constant external activity, is shown to deliver gonadotropin releasing hormone (GnRH) in rhythmic pulses, with periodicity of the same order as observed in sexually mature adult humans. Relevant experimental results and some mathematical models are reviewed.

Design and characterization of Amoitone B-loaded nanostructured lipid carriers for controlled drug release.

PubMed

Luan, Jingjing; Zhang, Dianrui; Hao, Leilei; Li, Caiyun; Qi, Lisi; Guo, Hejian; Liu, Xinquan; Zhang, Qiang

2013-11-01

Amoitone B, a novel compound chemically synthesized as the analogue of cytosporone B, has been proved to own superior affinity with Nur77 than its parent compound and exhibit notable anticancer activity. However, its application is seriously restricted due to the water-insolubility and short biological half-time. The aim of this study was to construct an effective delivery system for Amoitone B to realize sustained release, thus prolong drug circulation time in body and improve the bioavailability. Nanostructured lipid carriers (NLC) act as a new type of colloidal drug delivery system, which offer the advantages of improved drug loading and sustained release. Amoitone B-loaded NLC (AmB-NLC) containing glyceryl monostearate (GMS) and various amounts of medium chain triglycerides (MCT) were successfully prepared by emulsion-evaporation and low temperature-solidification technology with a particle size of about 200 nm and a zeta potential value of about -20 mV. The results of X-ray diffraction and DSC analysis showed amorphous crystalline state of Amoitone B in NLC. Furthermore, the drug entrapment efficacy (EE) was improved compared with solid lipid nanoparticles (SLN). The EE range was from 71.1% to 84.7%, enhanced with the increase of liquid lipid. In vitro drug release studies revealed biphasic drug release patterns with burst release initially and prolonged release afterwards and the release was accelerated with augment of liquid lipid. These results demonstrated that AmB-NLC could be a promising delivery system to control drug release and improve loading capacity, thus prolong drug action time in body and enhance the bioavailability.

Microfabrication of a High-Throughput Nanochannel Delivery/Filtration System

NASA Technical Reports Server (NTRS)

Ferrari, Mauro; Liu, Xuewu; Grattoni, Alessandro; Fine, Daniel; Hosali, Sharath; Goodall, Randi; Medema, Ryan; Hudson, Lee

2011-01-01

A microfabrication process is proposed to produce a nanopore membrane for continuous passive drug release to maintain constant drug concentrations in the patient s blood throughout the delivery period. Based on silicon microfabrication technology, the dimensions of the nanochannel area, as well as microchannel area, can be precisely controlled, thus providing a steady, constant drug release rate within an extended time period. The multilayered nanochannel structures extend the limit of release rate range of a single-layer nanochannel system, and allow a wide range of pre-defined porosity to achieve any arbitrary drug release rate using any preferred nanochannel size. This membrane system could also be applied to molecular filtration or isolation. In this case, the nanochannel length can be reduced to the nanofabrication limit, i.e., 10s of nm. The nanochannel delivery system membrane is composed of a sandwich of a thin top layer, the horizontal nanochannels, and a thicker bottom wafer. The thin top layer houses an array of microchannels that offers the inlet port for diffusing molecules. It also works as a lid for the nanochannels by providing the channels a top surface. The nanochannels are fabricated by a sacrificial layer technique that obtains smooth surfaces and precisely controlled dimensions. The structure of this nanopore membrane is optimized to yield high mechanical strength and high throughput.

Combination of injectable ethinyl estradiol and drospirenone drug-delivery systems and characterization of their in vitro release.

PubMed

Nippe, Stefanie; General, Sascha

2012-11-20

Our aim was to investigate the in vitro release and combination of ethinyl estradiol (EE) and drospirenone (DRSP) drug-delivery systems. DRSP poly(lactic-co-glycolic acid) (PLGA) microparticles and organogels containing DRSP microcrystals were prepared and characterized with regard to properties influencing drug release. The morphology and release kinetics of DRSP PLGA microparticles indicated that DRSP is dispersed in the polymer. The in vitro release profiles correlated well with in vivo data. Although DRSP degradation is known to be acid-catalyzed, DRSP was relatively stable in the PLGA matrix. Aqueous DRSP PLGA microparticle suspensions were combinable with EE PLGA microparticles and EE poly(butylcyanoacrylate) (PBCA) microcapsules without interacting. EE release from PLGA microparticles was faster than DRSP release; EE release is assumed to be primarily controlled by drug diffusion. Liquid-filled EE PBCA microcapsules were shown to be more robust than air-filled EE PBCA microcapsules; the bursting of microcapsules accelerating the drug delivery was therefore delayed. The drug release profile for DRSP organogels was fairly linear with the square root of time. The system was not combinable with EE PBCA microcapsules. In contrast, incorporation of EE PLGA microparticles in organogels resulted in prolonged EE release. The drug release of EE and DRSP was thus approximated. Copyright © 2012 Elsevier B.V. All rights reserved.

Near-infrared remotely triggered drug-release strategies for cancer treatment

NASA Astrophysics Data System (ADS)

Goodman, Amanda M.; Neumann, Oara; Nørregaard, Kamilla; Henderson, Luke; Choi, Mi-Ran; Clare, Susan E.; Halas, Naomi J.

2017-11-01

Remotely controlled, localized drug delivery is highly desirable for potentially minimizing the systemic toxicity induced by the administration of typically hydrophobic chemotherapy drugs by conventional means. Nanoparticle-based drug delivery systems provide a highly promising approach for localized drug delivery, and are an emerging field of interest in cancer treatment. Here, we demonstrate near-IR light-triggered release of two drug molecules from both DNA-based and protein-based hosts that have been conjugated to near-infrared-absorbing Au nanoshells (SiO2 core, Au shell), each forming a light-responsive drug delivery complex. We show that, depending upon the drug molecule, the type of host molecule, and the laser illumination method (continuous wave or pulsed laser), in vitro light-triggered release can be achieved with both types of nanoparticle-based complexes. Two breast cancer drugs, docetaxel and HER2-targeted lapatinib, were delivered to MDA-MB-231 and SKBR3 (overexpressing HER2) breast cancer cells and compared with release in noncancerous RAW 264.7 macrophage cells. Continuous wave laser-induced release of docetaxel from a nanoshell-based DNA host complex showed increased cell death, which also coincided with nonspecific cell death from photothermal heating. Using a femtosecond pulsed laser, lapatinib release from a nanoshell-based human serum albumin protein host complex resulted in increased cancerous cell death while noncancerous control cells were unaffected. Both methods provide spatially and temporally localized drug-release strategies that can facilitate high local concentrations of chemotherapy drugs deliverable at a specific treatment site over a specific time window, with the potential for greatly minimized side effects.

HPMA-based block copolymers promote differential drug delivery kinetics for hydrophobic and amphiphilic molecules.

PubMed

Tomcin, Stephanie; Kelsch, Annette; Staff, Roland H; Landfester, Katharina; Zentel, Rudolf; Mailänder, Volker

2016-04-15

We describe a method how polymeric nanoparticles stabilized with (2-hydroxypropyl)methacrylamide (HPMA)-based block copolymers are used as drug delivery systems for a fast release of hydrophobic and a controlled release of an amphiphilic molecule. The versatile method of the miniemulsion solvent-evaporation technique was used to prepare polystyrene (PS) as well as poly-d/l-lactide (PDLLA) nanoparticles. Covalently bound or physically adsorbed fluorescent dyes labeled the particles' core and their block copolymer corona. Confocal laser scanning microscopy (CLSM) in combination with flow cytometry measurements were applied to demonstrate the burst release of a fluorescent hydrophobic drug model without the necessity of nanoparticle uptake. In addition, CLSM studies and quantitative calculations using the image processing program Volocity® show the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake. Our findings offer the possibility to combine the advantages of a fast release for hydrophobic and a controlled release for an amphiphilic molecule therefore pointing to the possibility to a 'multi-step and multi-site' targeting by one nanocarrier. We describe thoroughly how different components of a nanocarrier end up in cells. This enables different cargos of a nanocarrier having a consecutive release and delivery of distinct components. Most interestingly we demonstrate individual kinetics of distinct components of such a system: first the release of a fluorescent hydrophobic drug model at contact with the cell membrane without the necessity of nanoparticle uptake. Secondly, the intracellular detachment of the amphiphilic block copolymer from the particles' core after uptake occurs. This offers the possibility to combine the advantages of a fast release for a hydrophobic substance at the time of interaction of the nanoparticle with the cell surface and a controlled release for an amphiphilic molecule later on therefore pointing to the possibility to a 'multi-step and multisite' targeting by one nanocarrier. We therefore feel that this could be used for many cellular systems where the combined and orchestrated delivery of components is prerequisite in order to obtain the highest efficiency. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Novel concept of the smart NIR-light-controlled drug release of black phosphorus nanostructure for cancer therapy.

PubMed

Qiu, Meng; Wang, Dou; Liang, Weiyuan; Liu, Liping; Zhang, Yin; Chen, Xing; Sang, David Kipkemoi; Xing, Chenyang; Li, Zhongjun; Dong, Biqin; Xing, Feng; Fan, Dianyuan; Bao, Shiyun; Zhang, Han; Cao, Yihai

2018-01-16

A biodegradable drug delivery system (DDS) is one the most promising therapeutic strategies for cancer therapy. Here, we propose a unique concept of light activation of black phosphorus (BP) at hydrogel nanostructures for cancer therapy. A photosensitizer converts light into heat that softens and melts drug-loaded hydrogel-based nanostructures. Drug release rates can be accurately controlled by light intensity, exposure duration, BP concentration, and hydrogel composition. Owing to sufficiently deep penetration of near-infrared (NIR) light through tissues, our BP-based system shows high therapeutic efficacy for treatment of s.c. cancers. Importantly, our drug delivery system is completely harmless and degradable in vivo. Together, our work proposes a unique concept for precision cancer therapy by external light excitation to release cancer drugs. If these findings are successfully translated into the clinic, millions of patients with cancer will benefit from our work.

Noninvasive remote-controlled release of drug molecules in vitro using magnetic actuation of mechanized nanoparticles.

PubMed

Thomas, Courtney R; Ferris, Daniel P; Lee, Jae-Hyun; Choi, Eunjoo; Cho, Mi Hyeon; Kim, Eun Sook; Stoddart, J Fraser; Shin, Jeon-Soo; Cheon, Jinwoo; Zink, Jeffrey I

2010-08-11

Mesoporous silica nanoparticles are useful nanomaterials that have demonstrated the ability to contain and release cargos with mediation by gatekeepers. Magnetic nanocrystals have the ability to exhibit hyperthermic effects when placed in an oscillating magnetic field. In a system combining these two materials and a thermally sensitive gatekeeper, a unique drug delivery system can be produced. A novel material that incorporates zinc-doped iron oxide nanocrystals within a mesoporous silica framework that has been surface-modified with pseudorotaxanes is described. Upon application of an AC magnetic field, the nanocrystals generate local internal heating, causing the molecular machines to disassemble and allowing the cargos (drugs) to be released. When breast cancer cells (MDA-MB-231) were treated with doxorubicin-loaded particles and exposed to an AC field, cell death occurred. This material promises to be a noninvasive, externally controlled drug delivery system with cancer-killing properties.

Controlled porosity osmotic pump-based controlled release systems of pseudoephedrine. I. Cellulose acetate as a semipermeable membrane.

PubMed

Makhija, Sapna N; Vavia, Pradeep R

2003-04-14

A controlled porosity osmotic pump-based drug delivery system has been described in this study. Unlike the elementary osmotic pump (EOP) which consists of an osmotic core with the drug surrounded by a semipermeable membrane drilled with a delivery orifice, controlled porosity of the membrane is accomplished by the use of different channeling agents in the coating. The usual dose of pseudoephedrine is 60 mg to be taken three or four times daily. It has a short plasma half life of 5-8 h. Hence, pseudoephedrine was chosen as a model drug with an aim to develop a controlled release system for a period of 12 h. Sodium bicarbonate was used as the osmogent. The effect of different ratios of drug:osmogent on the in-vitro release was studied. Cellulose acetate (CA) was used as the semipermeable membrane. Different channeling agents tried were diethylphthalate (DEP), dibutylphthalate (DBP), dibutylsebacate (DBS) and polyethyleneglycol 400 (PEG 400). The effect of polymer loading on in-vitro drug release was studied. It was found that drug release rate increased with the amount of osmogent due to the increased water uptake, and hence increased driving force for drug release. This could be retarded by the proper choice of channeling agent in order to achieve the desired zero order release profile. Also the lag time seen with tablets coated using diethylphthalate as channeling agent was reduced by using a hydrophilic plasticizer like polyethyleneglycol 400 in combination with diethylphthalate. This system was found to deliver pseudoephedrine at a zero order rate for 12 h. The effect of pH on drug release was also studied. The optimized formulations were subjected to stability studies as per ICH guidelines at different temperature and humidity conditions.

Development and dissolution studies of bisphosphonate (clodronate)-containing hydroxyapatite-polylactic acid biocomposites for slow drug delivery.

PubMed

Macha, Innocent J; Cazalbou, Sophie; Shimmon, Ronald; Ben-Nissan, Besim; Milthorpe, Bruce

2017-06-01

An increase in clinical demand on the controlled release of bisphosphonates (BPs) due to complications associated with systemic administration, has been the current driving force on the development of BP drug-release systems. Bisphosphonates have the ability to bind to divalent metal ions, such as Ca 2+ , in bone mineral and prevent bone resorption by influencing the apoptosis of osteoclasts. Localized delivery using biodegradable materials, such as polylactic acid (PLA) and hydroxyapatite (HAp), which are ideal in this approach, have been used in this study to investigate the dissolution of clodronate (non-nitrogen-containing bisphosphonate) in a new release system. The effects of coral structure-derived HAp and the release kinetics of the composites were evaluated. The release kinetics of clodronate from PLA-BP and PLA-HAp-BP systems seemed to follow the power law model described by Korsmeyer-Peppas. Drug release was quantified by 31 P-NMR with detection and quantification limits of 9.2 and 30.7 mM, respectively. The results suggest that these biocomposite systems could be tuned to release clodronate for both relatively short and prolonged period of time. In addition to drug delivery, the degradation of HAp supplies both Ca 2+ and phosphate ions that can help in bone mineralization. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Food emulsions as delivery systems for flavor compounds: A review.

PubMed

Mao, Like; Roos, Yrjö H; Biliaderis, Costas G; Miao, Song

2017-10-13

Food flavor is an important attribute of quality food, and it largely determines consumer food preference. Many food products exist as emulsions or experience emulsification during processing, and therefore, a good understanding of flavor release from emulsions is essential to design food with desirable flavor characteristics. Emulsions are biphasic systems, where flavor compounds are partitioning into different phases, and the releases can be modulated through different ways. Emulsion ingredients, such as oils, emulsifiers, thickening agents, can interact with flavor compounds, thus modifying the thermodynamic behavior of flavor compounds. Emulsion structures, including droplet size and size distribution, viscosity, interface thickness, etc., can influence flavor component partition and their diffusion in the emulsions, resulting in different release kinetics. When emulsions are consumed in the mouth, both emulsion ingredients and structures undergo significant changes, resulting in different flavor perception. Special design of emulsion structures in the water phase, oil phase, and interface provides emulsions with great potential as delivery systems to control flavor release in wider applications. This review provides an overview of the current understanding of flavor release from emulsions, and how emulsions can behave as delivery systems for flavor compounds to better design novel food products with enhanced sensorial and nutritional attributes.

Recent advancement of gelatin nanoparticles in drug and vaccine delivery.

PubMed

Sahoo, Nityananda; Sahoo, Ranjan Ku; Biswas, Nikhil; Guha, Arijit; Kuotsu, Ketousetuo

2015-11-01

Novel drug delivery system using nanoscale materials with a broad spectrum of applications provides a new therapeutic foundation for technological integration and innovation. Nanoparticles are suitable drug carrier for various routes of administration as well as rapid recognition by the immune system. Gelatin, the biological macromolecule is a versatile drug/vaccine delivery carrier in pharmaceutical field due to its biodegradable, biocompatible, non-antigenicity and low cost with easy availability. The surface of gelatin nanoparticles can be modified with site-specific ligands, cationized with amine derivatives or, coated with polyethyl glycols to achieve targeted and sustained release drug delivery. Compared to other colloidal carriers, gelatin nanoparticles are better stable in biological fluids to provide the desired controlled and sustained release of entrapped drug molecules. The current review highlights the different formulation aspects of gelatin nanoparticles which affect the particle characteristics like zeta potential, polydispersity index, entrapment efficacy and drug release properties. It has also given emphasis on the major applications of gelatin nanoparticles in drug and vaccine delivery, gene delivery to target tissues and nutraceutical delivery for improving the poor bioavailabity of bioactive phytonutrients. Copyright © 2015 Elsevier B.V. All rights reserved.

Controlled-release systemic delivery - a new concept in cancer chemoprevention

PubMed Central

2012-01-01

Many chemopreventive agents have encountered bioavailability issues in pre-clinical/clinical studies despite high oral doses. We report here a new concept utilizing polycaprolactone implants embedded with test compounds to obtain controlled systemic delivery, circumventing oral bioavailability issues and reducing the total administered dose. Compounds were released from the implants in vitro dose dependently and for long durations (months), which correlated with in vivo release. Polymeric implants of curcumin significantly inhibited tissue DNA adducts following the treatment of rats with benzo[a]pyrene, with the total administered dose being substantially lower than typical oral doses. A comparison of bioavailability of curcumin given by implants showed significantly higher levels of curcumin in the plasma, liver and brain 30 days after treatment compared with the dietary route. Withaferin A implants resulted in a nearly 60% inhibition of lung cancer A549 cell xenografts, but no inhibition occurred when the same total dose was administered intraperitoneally. More than 15 phytochemicals have been tested successfully by this formulation. Together, our data indicate that this novel implant-delivery system circumvents oral bioavailability issues, provides continuous delivery for long durations and lowers the total administered dose, eliciting both chemopreventive/chemotherapeutic activities. This would also allow the assessment of activity of minor constituents and synthetic metabolites, which otherwise remain uninvestigated in vivo. PMID:22696595

Application of Chitosan and its Derivatives in Nanocarrier Based Pulmonary Drug Delivery Systems.

PubMed

Dua, Kamal; Bebawy, Mary; Awasthi, Rajendra; Tekade, Rakesh K; Tekade, Muktika; Gupta, Gaurav; De Jesus Andreoli Pinto, Terezinha; Hansbro, Philip M

2017-01-01

The respiratory tract as a non-invasive route of drug administration is gaining increasing attention in the present time on achieving both local and the systemic therapeutic effects. Success in achieving pulmonary delivery, requires overcoming barriers including mucociliary clearance and uptake by macrophages. An effective drug delivery system delivers the therapeutically active moieties at the right time and rate to target sites. A major limitation associated with most of the currently available conventional and controlled release drug delivery devices is that not all the drug candidates are well absorbed uniformly locally or systemically. We searched and reviewed the literature focusing on chitosan and chitosan derivative based nanocarrier systems used in pulmonary drug delivery. We focused on the applications of chitosan in the development of nanoparticles for this purpose. Chitosan, a natural linear bio-polyaminosaccharide is central in the development of novel drug delivery systems (NDDS) including nanoparticles for use in the treatment of various respiratory diseases. It achieves this through its unique properties of biodegradability, biocompatibility, mucoadhesivity and its ability to enhance macromolecule permeation across membranes. It also achieves sustained and targeted effects, primary requirements for an effective pulmonary drug delivery system. This review highlights the applications and importance of chitosan with special emphasis on nanotechnology, employed in the management of respiratory diseases such as asthma, Chronic Obstructive Pulmonary Disease (COPD), lung cancer and pulmonary fibrosis. This review will be of interest to both the biological and formulation scientists as it provides a summary on the utility of chitosan in pulmonary drug delivery systems. At present, there are no patented chitosan based controlled release products available for pulmonary drug delivery and so this area has enormous potential in the field of respiratory science. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Stimuli-Responsive Nanomaterials for Therapeutic Protein Delivery

PubMed Central

Lu, Yue; Sun, Wujin; Gu, Zhen

2014-01-01

Protein therapeutics have emerged as a significant role in treatment of a broad spectrum of diseases, including cancer, metabolic disorders and autoimmune diseases. The efficacy of protein therapeutics, however, is limited by their instability, immunogenicity and short half-life. In order to overcome these barriers, tremendous efforts have recently been made in developing controlled protein delivery systems. Stimuli-triggered release is an appealing and promising approach for protein delivery and has made protein delivery with both spatiotemporal- and dosage-controlled manners possible. This review surveys recent advances in controlled protein delivery of proteins or peptides using stimuli-responsive nanomaterials. Strategies utilizing both physiological and external stimuli are introduced and discussed. PMID:25151983

Modulating drug release from gastric-floating microcapsules through spray-coating layers.

PubMed

Lee, Wei Li; Tan, Jun Wei Melvin; Tan, Chaoyang Nicholas; Loo, Say Chye Joachim

2014-01-01

Floating dosage forms with prolonged gastric residence time have garnered much interest in the field of oral delivery. However, studies had shown that slow and incomplete release of hydrophobic drugs during gastric residence period would reduce drug absorption and cause drug wastage. Herein, a spray-coated floating microcapsule system was developed to encapsulate fenofibrate and piroxicam, as model hydrophobic drugs, into the coating layers with the aim of enhancing and tuning drug release rates. Incorporating fenofibrate into rubbery poly(caprolactone) (PCL) coating layer resulted in a complete and sustained release for up to 8 h, with outermost non-drug-holding PCL coating layer serving as a rate-controlling membrane. To realize a multidrug-loaded system, both hydrophilic metformin HCl and hydrophobic fenofibrate were simultaneously incorporated into these spray-coated microcapsules, with metformin HCl and fenofibrate localized within the hollow cavity of the capsule and coating layer, respectively. Both drugs were observed to be completely released from these coated microcapsules in a sustained manner. Through specific tailoring of coating polymers and their configurations, piroxicam loaded in both the outer polyethylene glycol and inner PCL coating layers was released in a double-profile manner (i.e. an immediate burst release as the loading dose, followed by a sustained release as the maintenance dose). The fabricated microcapsules exhibited excellent buoyancy in simulated gastric fluid, and provided controlled and sustained release, thus revealing its potential as a rate-controlled oral drug delivery system.

Delivery of doxorubicin and paclitaxel from double-layered microparticles: The effects of layer thickness and dual-drug vs. single-drug loading.

PubMed

Lee, Wei Li; Guo, Wei Mei; Ho, Vincent H B; Saha, Amitaksha; Chong, Han Chung; Tan, Nguan Soon; Tan, Ern Yu; Loo, Say Chye Joachim

2015-11-01

Double-layered microparticles composed of poly(d,l-lactic-co-glycolic acid, 50:50) (PLGA) and poly(l-lactic acid) (PLLA) were loaded with doxorubicin HCl (DOX) and paclitaxel (PCTX) through a solvent evaporation technique. DOX was localized in the PLGA shell, while PCTX was localized in the PLLA core. The aim of this study was to investigate how altering layer thickness of dual-drug, double-layered microparticles can influence drug release kinetics and their antitumor capabilities, and against single-drug microparticles. PCTX-loaded double-layered microparticles with denser shells retarded the initial release of PCTX, as compared with dual-drug-loaded microparticles. The DOX release from both DOX-loaded and dual-drug-loaded microparticles were observed to be similar with an initial burst. Through specific tailoring of layer thicknesses, a suppressed initial burst of DOX and a sustained co-delivery of two drugs can be achieved over 2months. Viability studies using spheroids of MCF-7 cells showed that controlled co-delivery of PCTX and DOX from dual-drug-loaded double-layered microparticles were better in reducing spheroid growth rate. This study provides mechanistic insights into how by tuning the layer thickness of double-layered microparticles the release kinetics of two drugs can be controlled, and how co-delivery can potentially achieve better anticancer effects. While the release of multiple drugs has been reported to achieve successful apoptosis and minimize drug resistance, most conventional particulate systems can only deliver a single drug at a time. Recently, although a number of formulations (e.g. micellar nanoparticles, liposomes) have been successful in delivering two or more anticancer agents, sustained co-delivery of these agents remains inadequate due to the complex agent loading processes and rapid release of hydrophilic agents. Therefore, the present work reports the multilayered particulate system that simultaneously hosts different drugs, while being able to tune their individual release over months. We believe that our findings would be of interest to the readers of Acta Biomaterialia because the proposed system could open a new avenue on how two drugs can be released, through rate-controlling carriers, for combination chemotherapy. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Current HPLC Methods for Assay of Nano Drug Delivery Systems.

PubMed

Tekkeli, Serife Evrim Kepekci; Kiziltas, Mustafa Volkan

2017-01-01

In nano drug formulations the mechanism of release is a critical process to recognize controlled and targeted drug delivery systems. In order to gain high bioavailability and specificity from the drug to reach its therapeutic goal, the active substance must be loaded into the nanoparticles efficiently. Therefore, the amount in biological fluids or tissues and the remaining amount in nano carriers are very important parameters to understand the potential of the nano drug delivery systems. For this aim, suitable and validated quantitation methods are required to determine released drug concentrations from nano pharmaceutical formulations. HPLC (High Performance Liquid Chromatography) is one of the most common techniques used for determination of released drug content out of nano drug formulations, in different physical conditions, over different periods of time. Since there are many types of HPLC methods depending on detector and column types, it is a challenge for the researchers to choose a suitable method that is simple, fast and validated HPLC techniques for their nano drug delivery systems. This review's goal is to compare HPLC methods that are currently used in different nano drug delivery systems in order to provide detailed and useful information for researchers. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Polymer based drug delivery systems for mycobacterial infections.

PubMed

Pandey, Rajesh; Khuller, G K

2004-07-01

In the last decade, polymer based technologies have found wide biomedical applications. Polymers, whether synthetic (e.g. polylactide-co-glycolide or PLG) or natural (e.g. alginate, chitosan etc.), have the property of encapsulating a diverse range of molecules of biological interest and bear distinct therapeutic advantages such as controlled release of drugs, protection against the premature degradation of drugs and reduction in drug toxicity. These are important considerations in the long-duration treatment of chronic infectious diseases such as tuberculosis in which patient non-compliance is the major obstacle to successful chemotherapy. Antitubercular drugs, singly or in combination, have been encapsulated in polymers to provide controlled drug release and the system also offers the flexibility of selecting various routes of administration such as oral, subcutaneous and aerosol. The present review highlights the approaches towards the preparation of polymeric antitubercular drug delivery systems, emphasizing how the route of administration may influence drug bioavailability as well as the chemotherapeutic efficacy. In addition, the pros and cons of the various delivery systems are also discussed.

In Vitro and In Vivo Investigation of the Potential of Amorphous Microporous Silica as a Protein Delivery Vehicle

PubMed Central

Vanmellaert, Lieve; Vermaelen, Peter; Deroose, Christophe M.; Naert, Ignace; Cardoso, Marcio Vivan; Martens, Johan A.

2013-01-01

Delivering growth factors (GFs) at bone/implant interface needs to be optimized to achieve faster osseointegration. Amorphous microporous silica (AMS) has a potential to be used as a carrier and delivery platform for GFs. In this work, adsorption (loading) and release (delivery) mechanism of a model protein, bovine serum albumin (BSA), from AMS was investigated in vitro as well as in vivo. In general, strong BSA adsorption to AMS was observed. The interaction was stronger at lower pH owing to favorable electrostatic interaction. In vitro evaluation of BSA release revealed a peculiar release profile, involving a burst release followed by a 6 h period without appreciable BSA release and a further slower release later. Experimental data supporting this observation are discussed. Apart from understanding protein/biomaterial (BSA/AMS) interaction, determination of in vivo protein release is an essential aspect of the evaluation of a protein delivery system. In this regard micropositron emission tomography (μ-PET) was used in an exploratory experiment to determine in vivo BSA release profile from AMS. Results suggest stronger in vivo retention of BSA when adsorbed on AMS. This study highlights the possible use of AMS as a controlled protein delivery platform which may facilitate osseointegration. PMID:23991413

Fabrication of core-shell micro/nanoparticles for programmable dual drug release by emulsion electrospraying

NASA Astrophysics Data System (ADS)

Wang, Yazhou; Zhang, Yiqiong; Wang, Bochu; Cao, Yang; Yu, Qingsong; Yin, Tieying

2013-06-01

The study aimed at constructing a novel drug delivery system for programmable multiple drug release controlled with core-shell structure. The core-shell structure consisted of chitosan nanoparticles as core and polyvinylpyrrolidone micro/nanocoating as shell to form core-shell micro/nanoparticles, which was fabricated by ionic gelation and emulsion electrospray methods. As model drug agents, Naproxen and rhodamine B were encapsulated in the core and shell regions, respectively. The core-shell micro/nanoparticles thus fabricated were characterized and confirmed by scanning electron microscope, transmission electron microscope, and fluorescence optical microscope. The core-shell micro/nanoparticles showed good release controllability through drug release experiment in vitro. It was noted that a programmable release pattern for dual drug agents was also achieved by adjusting their loading regions in the core-shell structures. The results indicate that emulsion electrospraying technology is a promising approach in fabrication of core-shell micro/nanoparticles for programmable dual drug release. Such a novel multi-drug delivery system has a potential application for the clinical treatment of cancer, tuberculosis, and tissue engineering.

Ingenious pH-sensitive dextran/mesoporous silica nanoparticles based drug delivery systems for controlled intracellular drug release.

PubMed

Zhang, Min; Liu, Jia; Kuang, Ying; Li, Qilin; Zheng, Di-Wei; Song, Qiongfang; Chen, Hui; Chen, Xueqin; Xu, Yanglin; Li, Cao; Jiang, Bingbing

2017-05-01

In this work, dextran, a polysaccharide with excellent biocompatibility, is applied as the "gatekeeper" to fabricate the pH-sensitive dextran/mesoporous silica nanoparticles (MSNs) based drug delivery systems for controlled intracellular drug release. Dextran encapsulating on the surface of MSNs is oxidized by NaIO 4 to obtain three kinds of dextran dialdehydes (PADs), which are then coupled with MSNs via pH-sensitive hydrazone bond to fabricate three kinds of drug carriers. At pH 7.4, PADs block the pores to prevent premature release of anti-cancer drug doxorubicin hydrochloride (DOX). However, in the weakly acidic intracellular environment (pH∼5.5) the hydrazone can be ruptured; and the drug can be released from the carriers. The drug loading capacity, entrapment efficiency and release rates of the drug carriers can be adjusted by the amount of NaIO 4 applied in the oxidation reaction. And from which DOX@MSN-NH-N=C-PAD 10 is chosen as the most satisfactory one for the further in vitro cytotoxicity studies and cellular uptake studies. The results demonstrate that DOX@MSN-NH-N=C-PAD 10 with an excellent pH-sensitivity can enter HeLa cells to release DOX intracellular due to the weakly acidic pH intracellular and kill the cells. In our opinion, the ingenious pH-sensitive drug delivery systems have application potentials for cancer therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

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.

In situ monitoring of intracellular controlled drug release from mesoporous silica nanoparticles coated with pH-responsive charge-reversal polymer.

PubMed

Zhang, Peng; Wu, Tong; Kong, Ji-Lie

2014-10-22

Therapeutic platforms such as chemotherapy that respond to physical and biological stimuli are highly desirable for effective cancer therapy. In this study, pH-responsive charge-reversal, polymer-coated mesoporous silica nanoparticles [PAH-cit/APTES-MSNs; PAH-cit refers to poly(allylamine)-citraconic anhydride; APTES refers to (3-aminopropyl)triethoxysilane] were synthesized for application as drug-delivery systems for the treatment of malignant cells. Confocal laser scanning microscopy (CLSM) revealed that the PAH-cit/APTES-MSNs nanocomposite effectively delivered and released doxorubicin hydrochloride to the nucleus of HeLa (human cervical carcinoma) cells. Additionally, the real-time dynamic drug-release process was monitored by CLSM. The current pH-controlled-smart-release platform holds promise in drug-delivery and cancer therapy-related applications.

Calcium Binding-Mediated Sustained Release of Minocycline from Hydrophilic Multilayer Coatings Targeting Infection and Inflammation

PubMed Central

Zhang, Zhiling; Nix, Camilla A.; Ercan, Utku K.; Gerstenhaber, Jonathan A.; Joshi, Suresh G.; Zhong, Yinghui

2014-01-01

Infection and inflammation are common complications that seriously affect the functionality and longevity of implanted medical implants. Systemic administration of antibiotics and anti-inflammatory drugs often cannot achieve sufficient local concentration to be effective, and elicits serious side effects. Local delivery of therapeutics from drug-eluting coatings presents a promising solution. However, hydrophobic and thick coatings are commonly used to ensure sufficient drug loading and sustained release, which may limit tissue integration and tissue device communications. A calcium-mediated drug delivery mechanism was developed and characterized in this study. This novel mechanism allows controlled, sustained release of minocycline, an effective antibiotic and anti-inflammatory drug, from nanoscale thin hydrophilic polyelectrolyte multilayers for over 35 days at physiologically relevant concentrations. pH-responsive minocycline release was observed as the chelation between minocycline and Ca2+ is less stable at acidic pH, enabling ‘smart’ drug delivery in response to infection and/or inflammation-induced tissue acidosis. The release kinetics of minocycline can be controlled by varying initial loading, Ca2+ concentration, and Ca2+ incorporation into different layers, enabling facile development of implant coatings with versatile release kinetics. This drug delivery platform can potentially be used for releasing any drug that has high Ca2+ binding affinity, enabling its use in a variety of biomedical applications. PMID:24409292

Injectable, in situ forming poly(propylene fumarate)-based ocular drug delivery systems.

PubMed

Ueda, H; Hacker, M C; Haesslein, A; Jo, S; Ammon, D M; Borazjani, R N; Kunzler, J F; Salamone, J C; Mikos, A G

2007-12-01

This study sought to develop an injectable formulation for long-term ocular delivery of fluocinolone acetonide (FA) by dissolving the anti-inflammatory drug and the biodegradable polymer poly(propylene fumarate) (PPF) in the biocompatible, water-miscible, organic solvent N-methyl-2-pyrrolidone (NMP). Upon injection of the solution into an aqueous environment, a FA-loaded PPF matrix is precipitated in situ through the diffusion/extraction of NMP into surrounding aqueous fluids. Fabrication of the matrices and in vitro release studies were performed in phosphate buffered saline at 37 degrees C. Drug loadings up to 5% were achieved. High performance liquid chromatography was employed to determine the released amount of FA. The effects of drug loading, PPF content of the injectable formulation, and additional photo-crosslinking of the matrix surface were investigated. Overall, FA release was sustained in vitro over up to 400 days. After an initial burst release of 22 to 68% of initial FA loading, controlled drug release driven by diffusion and bulk erosion was observed. Drug release rates in a therapeutic range were demonstrated. Release kinetics were found to be dependent on drug loading, formulation PPF content, and extent of surface crosslinking. The results suggest that injectable, in situ formed PPF matrices are promising candidates for the formulation of long-term, controlled delivery devices for intraocular drug delivery. Copyright 2007 Wiley Periodicals, Inc.

Biomaterials and biotechnology: from the discovery of the first angiogenesis inhibitors to the development of controlled drug delivery systems and the foundation of tissue engineering.

PubMed

Langer, Robert

2013-09-01

This paper describes the discovery of the first inhibitors of angiogenesis; the discoveries that led to the development of the first biocompatible controlled release systems for macromolecules, and findings that helped to create the field of tissue engineering. In addition, new paradigms for creating biomaterials, early work on nanotechnology in medicine and intelligent drug delivery systems are discussed. Copyright © 2013 Wiley Periodicals, Inc.

Design strategies and applications of circulating cell-mediated drug delivery systems.

PubMed

Su, Yixue; Xie, Zhiwei; Kim, Gloria B; Dong, Cheng; Yang, Jian

2015-01-01

Drug delivery systems, particularly nanomaterial-based drug delivery systems, possess a tremendous amount of potential to improve diagnostic and therapeutic effects of drugs. Controlled drug delivery targeted to a specific disease is designed to significantly improve the pharmaceutical effects of drugs and reduce their side effects. Unfortunately, only a few targeted drug delivery systems can achieve high targeting efficiency after intravenous injection, even with the development of numerous surface markers and targeting modalities. Thus, alternative drug and nanomedicine targeting approaches are desired. Circulating cells, such as erythrocytes, leukocytes, and stem cells, present innate disease sensing and homing properties. Hence, using living cells as drug delivery carriers has gained increasing interest in recent years. This review highlights the recent advances in the design of cell-mediated drug delivery systems and targeting mechanisms. The approaches of drug encapsulation/conjugation to cell-carriers, cell-mediated targeting mechanisms, and the methods of controlled drug release are elaborated here. Cell-based "live" targeting and delivery could be used to facilitate a more specific, robust, and smart payload distribution for the next-generation drug delivery systems.

A Novel Theranostic Platform for Targeted Cancer Therapy and Treatment Monitoring | Division of Cancer Prevention

Cancer.gov

DESCRIPTION (provided by applicant): Cancer treatment currently relies heavily upon administration of cytotoxic drugs that attack both cancerous and healthy cells due to limited selectivity of drugs. Therapeutic efficacy and systemic toxicity can be improved by employing a multifunctional drug delivery system that allows targeted drug delivery, controlled drug release and

Formulation, release characteristics, and bioavailability study of gastroretentive floating matrix tablet and floating raft system of Mebeverine HCl

PubMed Central

El Nabarawi, Mohamed A; Teaima, Mahmoud H; Abd El-Monem, Rehab A; El Nabarawy, Nagla A; Gaber, Dalia A

2017-01-01

To prolong the residence time of dosage forms within the gastrointestinal tract until all drug is released at the desired rate is one of the real challenges for oral controlled-release drug delivery systems. This study was designed to develop a controlled-release floating matrix tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the optimum matrix tablet, raft system formula, and marketed Duspatalin® 200 mg retard as reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively, and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K100M 1:1) showed the slowest drug release among all prepared tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K100M 1%/Precirol 2%) had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with the marketed MbH product, the Cmax of FT-10 was almost the same, while FRS-11 maximum concentration was higher. The tmax was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10 and FRS-11, respectively, compared to marketed product. These results demonstrated that both controlled-released floating matrix tablet and raft system would be promising gastroretentive delivery systems for prolonging drug action. PMID:28435220

Formulation, release characteristics, and bioavailability study of gastroretentive floating matrix tablet and floating raft system of Mebeverine HCl.

PubMed

El Nabarawi, Mohamed A; Teaima, Mahmoud H; Abd El-Monem, Rehab A; El Nabarawy, Nagla A; Gaber, Dalia A

2017-01-01

To prolong the residence time of dosage forms within the gastrointestinal tract until all drug is released at the desired rate is one of the real challenges for oral controlled-release drug delivery systems. This study was designed to develop a controlled-release floating matrix tablet and floating raft system of Mebeverine HCl (MbH) and evaluate different excipients for their floating behavior and in vitro controlled-release profiles. Oral pharmacokinetics of the optimum matrix tablet, raft system formula, and marketed Duspatalin ® 200 mg retard as reference were studied in beagle dogs. The optimized tablet formula (FT-10) and raft system formula (FRS-11) were found to float within 34±5 sec and 15±7 sec, respectively, and both remain buoyant over a period of 12 h in simulated gastric fluid. FT-10 (Compritol/HPMC K100M 1:1) showed the slowest drug release among all prepared tablet formulations, releasing about 80.2% of MbH over 8 h. In contrast, FRS-11 (Sodium alginate 3%/HPMC K100M 1%/Precirol 2%) had the greatest retardation, providing sustained release of 82.1% within 8 h. Compared with the marketed MbH product, the C max of FT-10 was almost the same, while FRS-11 maximum concentration was higher. The t max was 3.33, 2.167, and 3.0 h for marketed MbH product, FT-10, and FRS-11, respectively. In addition, the oral bioavailability experiment showed that the relative bioavailability of the MbH was 104.76 and 116.01% after oral administration of FT-10 and FRS-11, respectively, compared to marketed product. These results demonstrated that both controlled-released floating matrix tablet and raft system would be promising gastroretentive delivery systems for prolonging drug action.

Controlled release of bupivacaine using hybrid thermoresponsive nanoparticles activated via photothermal heating.

PubMed

Alejo, Teresa; Andreu, Vanesa; Mendoza, Gracia; Sebastian, Victor; Arruebo, Manuel

2018-08-01

Near-infrared (NIR) responsive nanoparticles are of great interest in the biomedical field as antennas for photothermal therapy and also as triggers for on-demand drug delivery. The present work reports the preparation of hollow gold nanoparticles (HGNPs) with plasmonic absorption in the NIR region covalently bound to a thermoresponsive polymeric shell that can be used as an on-demand drug delivery system for the release of analgesic drugs. The photothermal heating induced by the nanoparticles is able to produce the collapse of the polymeric shell thus generating the release of the local anesthetic bupivacaine in a spatiotemporally controlled way. Those HGNPs contain a 10 wt.% of polymer and present excellent reversible heating under NIR light excitation. Bupivacaine released at physiological temperature (37 °C) showed a pseudo-zero order release that could be spatiotemporally modified on-demand after applying several pulses of light/temperature above and below the lower critical solution temperature (LCST) of the polymeric shell. Furthermore, the nanomaterials obtained did not displayed detrimental effects on four mammalian cell lines at doses up to 0.2 mg/mL. From the results obtained it can be concluded than this type of hybrid thermoresponsive nanoparticle can be used as an externally activated on-demand drug delivery system. Copyright © 2018 Elsevier Inc. All rights reserved.

Modulation of electrostatic interactions to improve controlled drug delivery from nanogels.

PubMed

Mauri, Emanuele; Chincarini, Giulia M F; Rigamonti, Riccardo; Magagnin, Luca; Sacchetti, Alessandro; Rossi, Filippo

2017-03-01

The synthesis of nanogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy in controlled drug delivery. However, with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small hydrophilic molecules through polymeric network pores. For these reasons research community is pointing toward the use of click strategies to reduce release rates of the linked drugs to the polymer chains. Here we propose an alternative method that considers the electrostatic interactions between polymeric chains and drugs to tune the release kinetics from nanogel network. The main advantage of these systems lies in the fact that the carried drugs are not modified and no chemical reactions take place during their loading and release. In this work we synthesized PEG-PEI based nanogels with different protonation degrees and the release kinetics with charged and uncharged drug mimetics (sodium fluorescein, SF, and rhodamine B, RhB) were studied. Moreover, also the effect of counterion used to induce protonation was taken into account in order to build a tunable drug delivery system able to provide multiple release rates with the same device. Copyright © 2016 Elsevier B.V. All rights reserved.

pH-Cleavable Nucleoside Lipids: A New Paradigm for Controlling the Stability of Lipid-Based Delivery Systems.

PubMed

Oumzil, Khalid; Benizri, Sébastien; Tonelli, Giovanni; Staedel, Cathy; Appavoo, Ananda; Chaffanet, Max; Navailles, Laurence; Barthélémy, Philippe

2015-11-01

Lipid-based delivery systems are an established technology with considerable clinical acceptance and several applications in human. Herein, we report the design, synthesis and evaluation of novel orthoester nucleoside lipids (ONLs) for the modulation of liposome stability. The ONLs contain head groups with 3'-orthoester nucleoside derivatives featuring positive or negative charges. The insertion of the orthoester function in the NL structures allows the formation of pH-sensitive liposomes. ONL-based liposomes can be hydrolyzed to provide nontoxic products, including nucleoside derivatives and hexadecanol. To allow the release to be tunable at different hydrolysis rates, the charge of the polar head structure is modulated, and the head group can be released at a biologically relevant pH. Crucially, when ONLs are mixed with natural phosphocholine lipids (PC), the resultant liposome evolves toward the formation of a hexadecanol/PC lamellar system. Biological evaluation shows that stable nucleic acid lipid particles (SNALPs) formulated with ONLs and siRNAs can effectively enter into tumor cells and release their nucleic acid payload in response to an intracellular acidic environment. This results in a much higher antitumor activity than conventional SNALPs. The ability to use pH-cleavable nucleolipids to control the stability of lipid-based delivery systems represents a promising approach for the intracellular delivery of drug cargos. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Magnetically guided release of ciprofloxacin from superparamagnetic polymer nanocomposites.

PubMed

Gupta, Rashmi; Bajpai, A K

2011-01-01

Tailored with superparamagnetic properties the magnetic nanocomposites have been thoroughly investigated in recent past because of their potential applications in the fields of biomedicine and bioengineering such as protein detection, magnetic targeted drug carriers, bioseparation, magnetic resonance imaging contrast agents and hyperthermia. Magnetic drug targeting has come up as a safe and effective drug-delivery technology, i.e., with the least amount of magnetic particles a maximum of drug may be easily administered and transported to the site of choice. In the present work novel magnetic drug-targeting carriers consisting of magnetic nanoparticles encapsulated within a smart polymer matrix with potential of controlled drug release is described. To make such magnetic polymeric drug-delivery systems, both the magnetic nanoparticles and antibiotic drug (ciprofloxacin) were incorporated into the hydrogel. The controlled release process and release profiles were investigated as a function of experimental protocols such as percent loading of drug, chemical composition of the nanocomposite, pH of release media and strength of magnetic field on the release profiles. The structure, morphology and compositions of magnetic hydrogel nanocomposites were characterized by FT-IR, TEM, XRD and VSM techniques. It was found that magnetic nanocomposites were biocompatible and superparamagnetic in nature and could be used as a smart drug carrier for controlled and targeted drug delivery.

Regenerated cellulose capsules for controlled drug delivery: Part III. Developing a fabrication method and evaluating extemporaneous utility for controlled-release.

PubMed

Bhatt, Bhavik; Kumar, Vijay

2016-08-25

In this article, we describe a method to utilize cellulose dissolved in dimethyl sulfoxide and paraformaldehyde solvent system to fabricate two-piece regenerated cellulose hard shell capsules for their potential use as an oral controlled drug delivery a priori vehicle. A systematic evaluation of solution rheology as well as resulting capsule mechanical, visual and thermal analysis was performed to develop a suitable method to repeatedly fabricate RC hard shell capsule halves. Because of the viscoelastic nature of the cellulose solution, a combination of dip-coating and casting method, herein referred to as dip-casting method, was developed. The dip-casting method was formalized by utilizing two-stage 2(2) full factorial design approach in order to determine a suitable approach to fabricate capsules with minimal variability. Thermal annealing is responsible for imparting shape rigidity of the capsules. Proof-of-concept analysis for the utility of these capsules in controlled drug delivery was performed by evaluating the release of KCl from them as well as from commercially available USP equivalent formulations. Release of KCl from cellulose capsules was comparable to extended release capsule formulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Porous Carriers for Controlled/Modulated Drug Delivery

PubMed Central

Ahuja, G.; Pathak, K.

2009-01-01

Considerable research efforts have been directed in recent years towards the development of porous carriers as controlled drug delivery matrices because of possessing several features such as stable uniform porous structure, high surface area, tunable pore size and well-defined surface properties. Owing to wide range of useful properties porous carriers have been used in pharmaceuticals for many purposes including development of floating drug delivery systems, sustained drug delivery systems. Various types of pores like open, closed, transport and blind pores in the porous solid allow them to adsorb drugs and release them in a more reproducible and predictable manner. Pharmaceutically exploited porous adsorbents includes, silica (mesoporous), ethylene vinyl acetate (macroporous), polypropylene foam powder (microporous), titanium dioxide (nanoporous). When porous polymeric drug delivery system is placed in contact with appropriate dissolution medium, release of drug to medium must be preceded by the drug dissolution in the water filled pores or from surface and by diffusion through the water filled channels. The porous carriers are used to improve the oral bioavailability of poorly water soluble drugs, to increase the dissolution of relatively insoluble powders and conversion of crystalline state to amorphous state. PMID:20376211

Advances in the Applications of Polyhydroxyalkanoate Nanoparticles for Novel Drug Delivery System

PubMed Central

Shrivastav, Anupama; Kim, Hae-Yeong; Kim, Young-Rok

2013-01-01

Drug delivery technology is emerging as an interdisciplinary science aimed at improving human health. The controlled delivery of pharmacologically active agents to the specific site of action at the therapeutically optimal rate and dose regimen has been a major goal in designing drug delivery systems. Over the past few decades, there has been considerable interest in developing biodegradable drug carriers as effective drug delivery systems. Polymeric materials from natural sources play an important role in controlled release of drug at a particular site. Polyhydroxyalkanoates, due to their origin from natural sources, are given attention as candidates for drug delivery materials. Biodegradable and biocompatible polyhydroxyalkanoates are linear polyesters produced by microorganisms under unbalanced growth conditions, which have emerged as potential polymers for use as biomedical materials for drug delivery due to their unique physiochemical and mechanical properties. This review summarizes many of the key findings in the applications of polyhydroxyalkanoates and polyhydroxyalkanoate nanoparticles for drug delivery system. PMID:23984383

Stimuli-free programmable drug release for combination chemo-therapy

NASA Astrophysics Data System (ADS)

Fan, Li; Jin, Boquan; Zhang, Silu; Song, Chaojun; Li, Quan

2016-06-01

Combinational chemotherapy capable of targeted delivery and programmable multi-drug release leads to enhanced drug efficacy, and is highly desired for cancer treatment. However, effective approaches for achieving both features in a single treatment are limited. In the present work, we demonstrated programmed delivery of both chemotherapeutic and immunotherapeutic agents with tumor cell targeting capability by using SiO2 based self-decomposable nanoparticulate systems. The programmable drug delivery is realized by manipulating drug loading configurations instead of relying on external stimuli. Both in vitro and in vivo results showed specific drug binding to FAT1-expressing colon cancer cells. The loaded dual drugs were demonstrated to be delivered in a sequential manner with specific time intervals between their peak releases, which maximize the synergistic effect of the chemotherapeutics. These features led to significantly enhanced drug efficacy and reduced system toxicity. The tumor weight decreased by 1/350, together with a moderate increase in rats' body weight, which were observed when adopting the dual drug loaded nanoparticles, as compared to those of the control groups. The present system provides a simple and feasible method for the design of targeting and combination chemotherapy with programmed drug release.Combinational chemotherapy capable of targeted delivery and programmable multi-drug release leads to enhanced drug efficacy, and is highly desired for cancer treatment. However, effective approaches for achieving both features in a single treatment are limited. In the present work, we demonstrated programmed delivery of both chemotherapeutic and immunotherapeutic agents with tumor cell targeting capability by using SiO2 based self-decomposable nanoparticulate systems. The programmable drug delivery is realized by manipulating drug loading configurations instead of relying on external stimuli. Both in vitro and in vivo results showed specific drug binding to FAT1-expressing colon cancer cells. The loaded dual drugs were demonstrated to be delivered in a sequential manner with specific time intervals between their peak releases, which maximize the synergistic effect of the chemotherapeutics. These features led to significantly enhanced drug efficacy and reduced system toxicity. The tumor weight decreased by 1/350, together with a moderate increase in rats' body weight, which were observed when adopting the dual drug loaded nanoparticles, as compared to those of the control groups. The present system provides a simple and feasible method for the design of targeting and combination chemotherapy with programmed drug release. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr06305a

An oral colon-targeting controlled release system based on resistant starch acetate: synthetization, characterization, and preparation of film-coating pellets.

PubMed

Pu, Huayin; Chen, Ling; Li, Xiaoxi; Xie, Fengwei; Yu, Long; Li, Lin

2011-05-25

An oral colon-targeting controlled release system based on resistant starch acetate (RSA) as a film-coating material was developed. The RSA was successfully synthesized, and its digestion resistibility could be improved by increasing the degree of substitution (DS), which was favorable for the colon-targeting purpose. As a delivery carrier material, the characteristics of RSA were investigated by polarized light microscopy, FTIR spectroscopy, and X-ray diffraction. The results revealed a decrease of the crystallinity of RSA and a change of its crystalline structure from B + V hydrid type to V type. To evaluate the colon-targeting release performance, the RSA film-coated pellets loaded with different bioactive components were prepared by extrusion-spheronization and then by fluid bed coating. The effects of the DS, plasticizer content, and coating thickness of the RSA film and those of the content and molecular weight of the loaded bioactive component on the colon-targeting release performance of the resulting delivery system were investigated. By adjusting the DS, the coating thickness, and the plasticizer content of the RSA film, either the pellets loaded with a small molecular bioactive component such as 5-aminosalicylic acid or those with a macromolecular bioactive peptide or protein such as bovine serum albumin, hepatocyte growth-promoting factor, or insulin showed a desirable colon-targeting release performance. The release percentage was less than 12% in simulated upper gastrointestinal tract and went up to 70% over a period of 40 h in simulated colonic fluid. This suggests that the delivery system based on RSA film has an excellent colon-targeting release performance and the universality for a wide range of bioactive components.

In vitro performance of lipid-PLGA hybrid nanoparticles as an antigen delivery system: lipid composition matters.

PubMed

Hu, Yun; Ehrich, Marion; Fuhrman, Kristel; Zhang, Chenming

2014-01-01

Due to the many beneficial properties combined from both poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and liposomes, lipid-PLGA hybrid NPs have been intensively studied as cancer drug delivery systems, bio-imaging agent carriers, as well as antigen delivery vehicles. However, the impact of lipid composition on the performance of lipid-PLGA hybrid NPs as a delivery system has not been well investigated. In this study, the influence of lipid composition on the stability of the hybrid NPs and in vitro antigen release from NPs under different conditions was examined. The uptake of hybrid NPs with various surface charges by dendritic cells (DCs) was carefully studied. The results showed that PLGA NPs enveloped by a lipid shell with more positive surface charges could improve the stability of the hybrid NPs, enable better controlled release of antigens encapsulated in PLGA NPs, as well as enhance uptake of NPs by DC.

Elution characteristics of teicoplanin-loaded biodegradable borate glass/chitosan composite.

PubMed

Jia, Wei-Tao; Zhang, Xin; Zhang, Chang-Qing; Liu, Xin; Huang, Wen-Hai; Rahaman, Mohamed N; Day, Delbert E

2010-03-15

Local antibiotic delivery system has an advantage over systemic antibiotic for osteomyelitis treatment due to the delivery of high local antibiotic concentration while avoiding potential systemic toxicity. Composite biomaterials with multifunctional roles, consisting of a controlled antibiotic release, a mechanical (load-bearing) function, and the ability to promote bone regeneration, gradually become the most active area of investigation and development of local antibiotic delivery vehicles. In the present study, a composite of borate glass and chitosan (designated BG/C) was developed as teicoplanin delivery vehicle. The in vitro elution kinetics and antibacterial activity of teicoplanin released from BG/C composite as a function of immersion time were determined. Moreover, the pH changes of eluents and the bioactivity of the composite were characterized using scanning electron microscopy coupled with energy-dispersive spectroscopy and X-ray diffraction analysis. 2009 Elsevier B.V. All rights reserved.

pH responsive controlled release of anti-cancer hydrophobic drugs from sodium alginate and hydroxyapatite bi-coated iron oxide nanoparticles.

PubMed

Manatunga, Danushika C; de Silva, Rohini M; de Silva, K M Nalin; de Silva, Nuwan; Bhandari, Shiva; Yap, Yoke Khin; Costha, N Pabakara

2017-08-01

Developing a drug carrier system which could perform targeted and controlled release over a period of time is utmost concern in the pharmaceutical industry. This is more relevant when designing drug carriers for poorly water soluble drug molecules such as curcumin and 6-gingerol. Development of a drug carrier system which could overcome these limitations and perform controlled and targeted drug delivery is beneficial. This study describes a promising approach for the design of novel pH sensitive sodium alginate, hydroxyapatite bilayer coated iron oxide nanoparticle composite (IONP/HAp-NaAlg) via the co-precipitation approach. This system consists of a magnetic core for targeting and a NaAlg/HAp coating on the surface to accommodate the drug molecules. The nanocomposite was characterized using FT-IR spectroscopy, X-ray diffraction, scanning electron microscopy, transmission electron microscopy and thermogravimetric analysis. The loading efficiency and loading capacity of curcumin and 6-gingerol were examined. In vitro drug releasing behavior of curcumin and 6-gingerol was studied at pH 7.4 and pH 5.3 over a period of seven days at 37°C. The mechanism of drug release from the nanocomposite of each situation was studied using kinetic models and the results implied that, the release is typically via diffusion and a higher release was observed at pH 5.3. This bilayer coated system can be recognized as a potential drug delivery system for the purpose of curcumin and 6-gingerol release in targeted and controlled manner to treat diseases such as cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Sensor-integrated polymer actuators for closed-loop drug delivery system

NASA Astrophysics Data System (ADS)

Xu, Han; Wang, Chunlei; Kulinsky, Lawrence; Zoval, Jim; Madou, Marc

2006-03-01

This work presents manufacturing and testing of a closed-loop drug delivery system where drug release is achieved by an electrochemical actuation of an array of polymeric valves on a set of drug reservoirs. The valves are based on bi-layer structures made of polypyrrole/gold in the shape of a flap that is hinged on one side of a valve seat. Drugs stored in the underlying chambers are released by bending the bi-layer flaps back with a small applied bias. These polymeric valves simultaneously function as both drug release components and biological/chemical sensors responding to a specific biological or environmental stimulus. The sensors may send signals to the control module to realize closed-loop control of the drug release. In this study a glucose sensor has been integrated with the polymeric actuators through immobilization of glucose oxidase(GOx) within polypyrrole(PPy) valves. Sensitivities per unit area of the integrated glucose sensor have been measured and compared before and after the actuation of the sensor/actuator PPy/DBS/GOx film. Other sensing parameters such as linear range and response time were discussed as well. Using an array of these sensor/actuator cells, the amount of released drug, e.g. insulin, can be precisely controlled according to the surrounding glucose concentration detected by the glucose sensor. Activation of these reservoirs can be triggered either by the signal from the sensor, or by the signal from the operator. This approach also serves as the initial step to use the proposed system as an implantable drug delivery platform in the future.

Reservoir-Based Drug Delivery Systems Utilizing Microtechnology

PubMed Central

Stevenson, Cynthia L.; Santini, John T.; Langer, Robert

2012-01-01

This review covers reservoir-based drug delivery systems that incorporate microtechnology, with an emphasis on oral, dermal, and implantable systems. Key features of each technology are highlighted such as working principles, fabrication methods, dimensional constraints, and performance criteria. Reservoir-based systems include a subset of microfabricated drug delivery systems and provide unique advantages. Reservoirs, whether external to the body or implanted, provide a well-controlled environment for a drug formulation, allowing increased drug stability and prolonged delivery times. Reservoir systems have the flexibility to accommodate various delivery schemes, including zero order, pulsatile, and on demand dosing, as opposed to a standard sustained release profile. Furthermore, the development of reservoir-based systems for targeted delivery for difficult to treat applications (e.g., ocular) has resulted in potential platforms for patient therapy. PMID:22465783

Controlled extended octenidine release from a bacterial nanocellulose/Poloxamer hybrid system.

PubMed

Alkhatib, Y; Dewaldt, M; Moritz, S; Nitzsche, R; Kralisch, D; Fischer, D

2017-03-01

Although bacterial nanocellulose (BNC) has been widely investigated in the last 10years as drug delivery system, up to now no long-term controlled release of drugs could be realized. Therefore, the aim of the present work was the development of a BNC-based drug delivery system that provides prolonged retention time for the antiseptic octenidine up to one week with improved mechanical and antimicrobial properties as well as a high biocompatibility. BNC was modified by incorporation of differently concentrated Poloxamers 338 and 407 as micelles and gels that were extensively investigated regarding size, surface charge, and dynamic viscosity. Depending on type and concentration of the Poloxamer, a retarded octenidine release up to one week could be accomplished. Additionally, superior material properties such as high compression stability and water binding could be achieved. The antimicrobial activity of octenidine against Staphylococcus aureus and Pseudomonas aeruginosa was not changed by the use of Poloxamers. Excellent biocompatibility of the Poloxamer loaded BNC could be demonstrated after local administration in a shell-less hen's egg model. In conclusion, a long-term delivery system consisting of BNC and Poloxamer could be developed for octenidine as a ready-to-use system e.g. for long-term dermal wound treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

Nanogel-based natural polymers as smart carriers for the controlled delivery of Timolol Maleate through the cornea for glaucoma.

PubMed

Ilka, Roya; Mohseni, Mojdeh; Kianirad, Mehran; Naseripour, Masood; Ashtari, Khadijeh; Mehravi, Bita

2018-04-01

Despite frequent scientific efforts, efficient ocular drug delivery is a major challenge for pharmaceutical scientists. Poor bioavailability of ophthalmic solutions can be overcome by using smart ophthalmic drug-delivery systems. In this research, loading and delivery of Timolol Maleate (TM) through the cornea by synthesized nanoparticles based on biopolymers (chitosan-alginate) were studied. The physico-chemical properties of these nanoparticles were characterized using scanning electron microscopy (SEM), transmission electron microscopy (TEM) and dynamic light scattering (DLS). Loading and release were evaluated by a UV-vis spectrometer and the ex vivo permeation study was carried out using the Franz Diffusion Cell and fluorescent microscopy studies. The results indicated that morphology and size of nanoparticles were spherical and in the range of 80-100nm. The loading capacity and encapsulation efficiency were about 42% and 94% respectively. They illustrated a burst release in the first hour followed by a slower and more sustained drug release during the next 24h. Also, the results indicated that the cornea penetration of TM loaded in nanoparticles was twice than that of TM. Hence, this nanocarrier can be considered as a suitable candidate for controlled TM delivery and release through the cornea. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug release from nanoparticles embedded in four different nanofibrillar cellulose aerogels.

PubMed

Valo, Hanna; Arola, Suvi; Laaksonen, Päivi; Torkkeli, Mika; Peltonen, Leena; Linder, Markus B; Serimaa, Ritva; Kuga, Shigenori; Hirvonen, Jouni; Laaksonen, Timo

2013-09-27

Highly porous nanocellulose aerogels prepared by freeze-drying from various nanofibrillar cellulose (NFC) hydrogels are introduced as nanoparticle reservoirs for oral drug delivery systems. Here we show that beclomethasone dipropionate (BDP) nanoparticles coated with amphiphilic hydrophobin proteins can be well integrated into the NFC aerogels. NFCs from four different origins are introduced and compared to microcrystalline cellulose (MCC). The nanocellulose aerogel scaffolds made from red pepper (RC) and MCC release the drug immediately, while bacterial cellulose (BC), quince seed (QC) and TEMPO-oxidized birch cellulose-based (TC) aerogels show sustained drug release. Since the release of the drug is controlled by the structure and interactions between the nanoparticles and the cellulose matrix, modulation of the matrix formers enable a control of the drug release rate. These nanocomposite structures can be very useful in many pharmaceutical nanoparticle applications and open up new possibilities as carriers for controlled drug delivery. Copyright © 2013 Elsevier B.V. All rights reserved.

Design and evaluation of hydrophobic coated buoyant core as floating drug delivery system for sustained release of cisapride

PubMed Central

Jacob, Shery; Nair, Anroop B; Patil, Pandurang N

2010-01-01

An inert hydrophobic buoyant coated–core was developed as floating drug delivery system (FDDS) for sustained release of cisapride using direct compression technology. Core contained low density, porous ethyl cellulose, which was coated with an impermeable, insoluble hydrophobic coating polymer such as rosin. It was further seal coated with low viscosity hydroxypropyl methyl cellulose (HPMC E15) to minimize moisture permeation and better adhesion with an outer drug layer. It was found that stable buoyant core was sufficient to float the tablet more than 8 h without the aid of sodium bicarbonate and citric acid. Sustained release of cisapride was achieved with HPMC K4M in the outer drug layer. The floating lag time required for these novel FDDS was found to be zero, however it is likely that the porosity or density of the core is critical for floatability of these tablets. The in vitro release pattern of these tablets in simulated gastric fluid showed the constant and controlled release for prolonged time. It can be concluded that the hydrophobic coated buoyant core could be used as FDDS for gastroretentive delivery system of cisapride or other suitable drugs. PMID:24825997

Influence of surfactants on the release behaviour and structural properties of sol-gel derived silica xerogels embedded with metronidazole.

PubMed

Czarnobaj, Katarzyna; Sawicki, Wiesław

2013-01-01

The aim of this study was to obtain stable and controlled release silica xerogels containing metronidazole (MT) prepared with surfactants with different charges: cetyltrimethylammonium bromide (CTAB), sodium dodecyl sulphate (SDS) and hydroxypropyl cellulose (HPC), which could be the promising carrier materials used as the implantable drug delivery systems. The xerogels were prepared by the sol-gel method. The influence of various formulation precursors on porosity parameters and drug release were investigated. Addition of surfactants showed a promising result in controlling the MT release. Dissolution study revealed increased release of MT from silica modified SDS and CTAB, whereas the release of MT from silica modified HPC considerably decreased, in comparison with unmodified silica. The addition of surfactants showed slight changes in porosity parameters. All xerogels are characterized by a highly developed surface area (701-642 m(2) g(-1)) and mesoporous structure. The correlation between pore size obtained matrices and release rate of drug was also observed. Based on the presented results of this study, it may be stated that applied xerogel matrices: pure silica and surfactants-modified silica could be promising candidates for the formulation in local delivery systems.

Review Article: Fabricated Microparticles: An Innovative Method to Minimize the Side Effects of NSAIDs in Arthritis.

PubMed

Abadi, Shaivad Shabee Hulhasan; Moin, Afrasim; Veerabhadrappa, Gangadharappa Hosahalli

2016-01-01

Microparticles are polymeric bodies ranging 1-1000 µm that constitute a variety of forms such as microcapsules, microspheres, microcages, microshells, microrods, biosensors microparticles, radiolabeled microparticles, and so forth. This review focuses on general microparticles, mainly microcapsules and microspheres. Nonsteriodal anti-inflammatory drugs (NSAIDs) are one of the mostcommonly prescribed medications in the world. Most of the NSAIDs available have severe side effects. With increased awareness of NSAID-induced gastrointestinal (GI) side effects, safety has become a priority in treatment of arthritis and other inflammatory diseases with NSAIDs. A trend in NSAID development has been to improve therapeutic efficacy while reducing the severity of GI side effects by altering dosage through modified release to optimize drug delivery. One such approach is the use of fabricated microparticles such as microcapsules and microspheres as carriers of drugs. Microparticles provide delivery of macromolecules and micromolecules via different routes and effectively control the release profile of such drugs. Microcapsules and microspheres are compatible with most natural and synthetic polymers and can be used for several routes of administration, including parenteral, oral, nasal, intra-ocular, topical, and the like. Because of greater stability and multiple manufacturing techniques, microspheres and microcapsules are preferred as drug carriers over other colloidal drug delivery systems. Microparticles provide effective protection of the encapsulated agent against degradation by enzymatic activities, controlled and confined delivery of drugs from a few hours to months, and ingenious administration compared to alternative forms of controlled-release parenteral dosages, such as macro-sized implants. This comprehensive overview of fabricated microparticles describes microencapsulation technologies to produce microparticles for targeted therapy of arthritis and other inflammatory diseases which provide constant and prolonged therapeutic effects that reduce dosing frequency and thereby minimize potential adverse effects of NSAIDs such as GI irritation and insufficient patient compliance. The present review describes the latest developments in microparticulate drug delivery systems and the best alternatives for safe and effective microcapsular systems in a controlled manner for the delivery of NSAIDs.

Spatiotemporal Programing for the On-Demand Release of Bupivacaine Based on an Injectable Composite Hydrogel.

PubMed

Dinh, Van Vuong; Suh, Yun-Suhk; Yang, Han-Kwang; Lim, Yong Taik

2016-12-01

We report a programed drug delivery system that can tailor the release of anesthetic bupivacaine in a spatiotemporally controlled manner. The drug delivery system was developed through the combination of a collagen-based injectable hydrogel and 2 types of poly(lactic-co-glycolic acid) (PLGA) particles. As a rapid-release platform (90% release after 24 h), bupivacaine hydrochloride was incorporated into collagen/poly(γ-glutamic acid) hydrogel, which exhibited gel formation at body temperature. PLGA microparticles (diameter 1-3 μm) containing bupivacaine base showed a very slow release of bupivacaine (95% after 240 h), whereas PLGA nanoparticles (124 ± 30 nm) containing bupivacaine base demonstrated an intermediate release rate (95% after 160 h). By changing the relative composition ratio between the 3 components in these injectable composite hydrogels, the release of bupivacaine could be easily controlled from very rapid (within 1 day) to very delayed (up to 9 days). The experimental results on the release data (cumulative release, time point release, average release rate) were coincident with the release profile generated by computer simulation. These injectable composite hydrogels with systematically tunable mixing ratios are expected to serve as a promising technology for the on-demand release of bupivacaine in pain management. Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

A novel delivery system of doxorubicin with high load and pH-responsive release from the nanoparticles of poly (α,β-aspartic acid) derivative.

PubMed

Wang, Xiaojuan; Wu, Guolin; Lu, Caicai; Zhao, Weipeng; Wang, Yinong; Fan, Yunge; Gao, Hui; Ma, Jianbiao

2012-08-30

A poly (amino acid)-based amphiphilic copolymer was utilized to fabricate a better micellar drug delivery system (DDS) with improved compatibility and sustained release of doxorubicin (DOX). First, poly (ethylene glycol) monomethyl ether (mPEG) and DOX were conjugated onto polyasparihyazide (PAHy), prepared by hydrazinolysis of the poly (succinimide) (PSI), to afford an amphiphilic polymer [PEG-hyd-P (AHy-hyd-DOX)] with acid-liable hydrazone bonds. The DOX, chemically conjugated to the PAHy, was designed to supply hydrophobic segments. PEGs were also grafted to the polymer via hydrazone bonds to supply hydrophiphilic segments and prolong its lifetime in blood circulation. Free DOX molecules could be entrapped into the nanoparticles fabricated by such an amphiphilic polymer (PEG-hyd-P (AHy-hyd-DOX)), via hydrophobic interaction and π-π stacking between the conjugated and free DOX molecules to obtain a pH responsive drug delivery system with high DOX loaded. The drug loading capacity, drug release behavior, and morphology of the micelles were investigated. The biological activity of micelles was evaluated in vitro. The drug loading capacity was intensively augmented by adjusting the feed ratio, and the maximum loading capacity was as high as 38%. Besides, the DOX-loaded system exhibited pH-dependent drug release profiles in vitro. The cumulative release of DOX was much faster at pH 5.0 than that at pH 7.4. The DOX-loaded system kept highly antitumor activity for a long time, compared with free DOX. This easy-prepared DDS, with features of biocompatibility, biodegradability, high drug loading capacity and pH-responsiveness, was a promising controlled release delivery system for DOX. Copyright © 2012 Elsevier B.V. All rights reserved.

Stimuli-responsive nanomaterials for therapeutic protein delivery.

PubMed

Lu, Yue; Sun, Wujin; Gu, Zhen

2014-11-28

Protein therapeutics have emerged as a significant role in treatment of a broad spectrum of diseases, including cancer, metabolic disorders and autoimmune diseases. The efficacy of protein therapeutics, however, is limited by their instability, immunogenicity and short half-life. In order to overcome these barriers, tremendous efforts have recently been made in developing controlled protein delivery systems. Stimuli-triggered release is an appealing and promising approach for protein delivery and has made protein delivery with both spatiotemporal- and dosage-controlled manners possible. This review surveys recent advances in controlled protein delivery of proteins or peptides using stimuli-responsive nanomaterials. Strategies utilizing both physiological and external stimuli are introduced and discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

Influence of hydroxypropyl methylcellulose on drug release pattern of a gastroretentive floating drug delivery system using a 3(2) full factorial design.

PubMed

Swain, Kalpana; Pattnaik, Satyanarayan; Mallick, Subrata; Chowdary, Korla Appana

2009-01-01

In the present investigation, controlled release gastroretentive floating drug delivery system of theophylline was developed employing response surface methodology. A 3(2) randomized full factorial design was developed to study the effect of formulation variables like various viscosity grades and contents of hydroxypropyl methylcellulose (HPMC) and their interactions on response variables. The floating lag time for all nine experimental trial batches were less than 2 min and floatation time of more than 12 h. Theophylline release from the polymeric matrix system followed non-Fickian anomalous transport. Multiple regression analysis revealed that both viscosity and content of HPMC had statistically significant influence on all dependent variables but the effect of these variables found to be nonlinear above certain threshold values.

Nanoparticle bioconjugate for controlled cellular delivery of doxorubicin

NASA Astrophysics Data System (ADS)

Sangtani, Ajmeeta; Petryayeva, Eleonora; Wu, Miao; Susumu, Kimihiro; Oh, Eunkeu; Huston, Alan L.; Lasarte-Aragones, Guillermo; Medintz, Igor L.; Algar, W. Russ; Delehanty, James B.

2018-02-01

Nanoparticle (NP)-mediated drug delivery offers the potential to overcome limitations of systemic delivery, including the ability to specifically target cargo and control release of NP-associated drug cargo. Doxorubicin (DOX) is a widely used FDA-approved cancer therapeutic; however, multiple side effects limit its utility. Thus, there is wide interest in modulating toxicity after cell delivery. Our goal here was to realize a NP-based DOX-delivery system that can modulate drug toxicity by controlling the release kinetics of DOX from the surface of a hard NP carrier. To achieve this, we employed a quantum dot (QD) as a central scaffold which DOX was appended via three different peptidyl linkages (ester, disulfide, hydrazone) that are cleavable in response to various intracellular conditions. Attachment of a cell penetrating peptide (CPP) containing a positively charged polyarginine sequence facilitates endocytosis of the ensemble. Polyhistidine-driven metal affinity coordination was used to self-assemble both peptides to the QD surface, allowing for fine control over both the ratio of peptides attached to the QD as well as DOX dose delivered to cells. Microplate-based Förster resonance energy transfer assays confirmed the successful ratiometric assembly of the conjugates and functionality of the linkages. Cell delivery experiments and cytotoxicity assays were performed to compare the various cleavable linkages to a control peptide where DOX is attached through an amide bond. The role played by various attachment chemistries used in QD-peptide-drug assemblies and their implications for the rationale in design of NPbased constructs for drug delivery is described here.

Targeting homeostasis in drug delivery using bioresponsive hydrogel microforms.

PubMed

Wilson, A Nolan; Guiseppi-Elie, Anthony

2014-01-30

A drug delivery platform comprising a biocompatible, bioresponsive hydrogel and possessing a covalently tethered peptide-drug conjugate was engineered to achieve stasis, via a closed control loop, of the external biochemical activity of the actuating protease. The delivery platform contains a peptide-drug conjugate covalently tethered to the hydrogel matrix, which in the presence of the appropriate protease, was cleaved and the drug released into the bathing environment. This platform was developed and investigated in silico using a finite element modeling (FEM) approach. Firstly, the primary governing phenomena guiding drug release profiles were investigated, and it was confirmed that under transport-limited conditions, the diffusion of the enzyme within the hydrogel and the coupled enzyme kinetics accurately model the system and are in agreement with published results. Secondly, the FEM model was used to investigate the release of a competitive protease inhibitor, MAG283, via cleavage of Acetyl-Pro-Leu-Gly|Leu-MAG-283 by MMP9 in order to achieve targeted homeostasis of MMP-9 activity, such as in the pathophysiology of chronic wounds, via closed-loop feedback control. The key engineering parameters for the delivery device are the radii of the hydrogel microspheres and the concentration of the peptide-inhibitor conjugate. Homeostatic drug delivery, where the focus turns away from the drug release rate and turns toward achieving targeted control of biochemical activity within a biochemical pathway, is an emerging approach in drug delivery methodologies for which the potential has not yet been fully realized. Copyright © 2013 Elsevier B.V. All rights reserved.

Design and characterization of calcium alginate microparticles coated with polycations as protein delivery system.

PubMed

Zarate, J; Virdis, L; Orive, G; Igartua, M; Hernández, R M; Pedraz, J L

2011-01-01

Bovine serum albumin (BSA) loaded calcium alginate microparticles (MPs) produced in this study by a w/o emulsification and external gelation method exhibited spherical and fairly smooth and porous morphology with 1.052 ± 0.057 µm modal particle size. The high permeability of the calcium alginate hydrogel lead to a potent burst effect and too fast protein release. To overcome these problems, MPs were coated with polycations, such as chitosan, poly-L-lysine and DEAE-dextran. Our results demonstrated that coated MPs showed slower release and were able to significantly reduce the release of BSA in the first hour. Therefore, this method can be applied to prepare coated alginate MPs which could be an optimal system for the controlled release of biotherapeutic molecules. Nevertheless, further studies are needed to optimize delivery properties which could provide a sustained release of proteins.

Controlled Endolysosomal Release of Agents by pH-responsive Polymer Blend Particles.

PubMed

Zhan, Xi; Tran, Kenny K; Wang, Liguo; Shen, Hong

2015-07-01

A key step of delivering extracellular agents to its intracellular target is to escape from endosomal/lysosomal compartments, while minimizing the release of digestive enzymes that may compromise cellular functions. In this study, we examined the intracellular distribution of both fluorecent cargoes and enzymes by a particle delivery platform made from the controlled blending of poly(lactic-co-glycolic acid) (PLGA) and a random pH-sensitive copolymer. We utilized both microscopic and biochemical methods to semi-quantitatively assess how the composition of blend particles affects the level of endosomal escape of cargos of various sizes and enzymes into the cytosolic space. We demonstrated that these polymeric particles enabled the controlled delivery of cargos into the cytosolic space that was more dependent on the cargo size and less on the composition of blend particles. Blend particles did not induce the rupture of endosomal/lysosomal compartments and released less than 20% of endosomal/lysosomal enzymes. This study provides insight into understanding the efficacy and safety of a delivery system for intracellular delivery of biologics and drugs. Blend particles offer a potential platform to target intracellular compartments while potentially minimizing cellular toxicity.

Controlled endolysosomal release of agents by pH-responsive polymer blend particles

PubMed Central

Zhan, Xi; Tran, Kenny K.; Wang, Liguo; Shen, Hong

2015-01-01

Purpose A key step of delivering extracellular agents to its intracellular target is to escape from endosomal/lysosomal compartments, while minimizing the release of digestive enzymes that may compromise cellular functions. In this study, we examined the intracellular distribution of both fluorecent cargoes and enzymes by a particle delivery platform made from the controlled blending of poly (lactic-co-glycolic acid) (PLGA) and a random pH-sensitive copolymer. Methods We utilized both microscopic and biochemical methods to semi-quantitatively assess how the composition of blend particles affects the level of endosomal escape of cargos of various sizes and enzymes into the cytosolic space. Results We demonstrated that these polymeric particles enabled the controlled delivery of cargos into the cytosolic space that was more dependent on the cargo size and less on the composition of blend particles. Blend particles did not induce the rupture of endosomal/lysosomal compartments and released less than 20% of endosomal/lysosomal enzymes. Conclusions This study provides insight into understanding the efficacy and safety of a delivery system for intracellular delivery of biologics and drugs. Blend particles offer a potential platform to target intracellular compartments while potentially minimizing cellular toxicity. PMID:25592550

A multifunctional β-CD-modified Fe3O4@ZnO:Er(3+),Yb(3+) nanocarrier for antitumor drug delivery and microwave-triggered drug release.

PubMed

Peng, Hongxia; Cui, Bin; Li, Guangming; Wang, Yingsai; Li, Nini; Chang, Zhuguo; Wang, Yaoyu

2015-01-01

We constructed a novel core-shell structured Fe3O4@ZnO:Er(3+),Yb(3+)@(β-CD) nanoparticles used as drug carrier to investigate the loading and controllable release properties of the chemotherapeutic drug etoposide (VP-16). The cavity of β-cyclodextrin is chemically inert, it can store etoposide molecules by means of hydrophobic interactions. The Fe3O4 core and ZnO:Er(3+),Yb(3+) shell functioned successfully for magnetic targeting and up-conversion fluorescence imaging, respectively. In addition, the ZnO:Er(3+),Yb(3+) shell acts as a good microwave absorber with excellent microwave thermal response property for microwave triggered drug release (the VP-16 release of 18% under microwave irradiation for 15 min outclass the 2% within 6h without microwave irradiation release). The release profile could be controlled by the duration and number of cycles of microwave application. This material therefore promises to be a useful noninvasive, externally controlled drug-delivery system in cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Controlling drug delivery kinetics from mesoporous titania thin films by pore size and surface energy.

PubMed

Karlsson, Johan; Atefyekta, Saba; Andersson, Martin

2015-01-01

The osseointegration capacity of bone-anchoring implants can be improved by the use of drugs that are administrated by an inbuilt drug delivery system. However, to attain superior control of drug delivery and to have the ability to administer drugs of varying size, including proteins, further material development of drug carriers is needed. Mesoporous materials have shown great potential in drug delivery applications to provide and maintain a drug concentration within the therapeutic window for the desired period of time. Moreover, drug delivery from coatings consisting of mesoporous titania has shown to be promising to improve healing of bone-anchoring implants. Here we report on how the delivery of an osteoporosis drug, alendronate, can be controlled by altering pore size and surface energy of mesoporous titania thin films. The pore size was varied from 3.4 nm to 7.2 nm by the use of different structure-directing templates and addition of a swelling agent. The surface energy was also altered by grafting dimethylsilane to the pore walls. The drug uptake and release profiles were monitored in situ using quartz crystal microbalance with dissipation (QCM-D) and it was shown that both pore size and surface energy had a profound effect on both the adsorption and release kinetics of alendronate. The QCM-D data provided evidence that the drug delivery from mesoporous titania films is controlled by a binding-diffusion mechanism. The yielded knowledge of release kinetics is crucial in order to improve the in vivo tissue response associated to therapeutic treatments.

Synthetic Zeolites as Controlled-Release Delivery Systems for Anti-Inflammatory Drugs.

PubMed

Khodaverdi, Elham; Soleimani, Hossein Ali; Mohammadpour, Fatemeh; Hadizadeh, Farzin

2016-06-01

Scientists have always been trying to use artificial zeolites to make modified-release drug delivery systems in the gastrointestinal tract. An ideal carrier should have the capability to release the drug in the intestine, which is the main area of absorption. Zeolites are mineral aluminosilicate compounds with regular structure and huge porosity, which are available in natural and artificial forms. In this study, soaking, filtration and solvent evaporation methods were used to load the drugs after activation of the zeolites. Weight measurement, spectroscopy FTIR, thermogravimetry and scanning electronic microscope were used to determine drug loading on the systems. Finally, consideration of drug release was made in a simulated gastric fluid and a simulated intestinal fluid for all matrixes (zeolites containing drugs) and drugs without zeolites. Diclofenac sodium (D) and piroxicam (P) were used as the drug models, and zeolites X and Y as the carriers. Drug loading percentage showed that over 90% of drugs were loaded on zeolites. Dissolution tests in stomach pH environment showed that the control samples (drug without zeolite) released considerable amount of drugs (about 90%) within first 15 min when it was about 10-20% for the matrixes. These results are favorable as NSAIDs irritate the stomach wall and it is ideal not to release much drugs in the stomach. Furthermore, release rate of drugs from matrixes has shown slower rate in comparison with control samples in intestine pH environment. © 2016 John Wiley & Sons A/S.

Evaluation of Calendula mucilage as a mucoadhesive and controlled release component in buccal tablets.

PubMed

Sabale, V; Patel, V; Paranjape, A

2014-01-01

Mucoadhesive drug delivery systems were developed to sustain drug delivery via various mucus membranes for either local or systemic delivery of poorly absorbed drugs such as peptides and proteins as well as drugs that are subjected to high first-pass metabolism. The present study was undertaken to use isolated Calendula mucilage as a mucoadhesive agent and to formulate controlled release buccoadhesive tablets with an intention to avoid hepatic first-pass metabolism as well as to enhance residence time of drug in the buccal cavity. The mucilage was isolated from the Calendula petals by aqueous extraction method and characterized for various physiochemical parameters as well as for its adhesive properties. By using direct compression technique, tablets were prepared containing dried mucilage and chlorpheniramine maleate (CPM) as a model drug. Three batches of tablets were prepared and evaluated containing three mucoadhesive components namely Methocel K4M, Carbopol 974P and isolated Calendula mucilage in 16.66%, 33.33 % and 50 % (1:2:3 ratio) resulting in 9 different formulations. FTIR studies between mucilage and CPM suggested the absence of a chemical interaction between CPM and Calendula mucilage. The results of the study showed that the isolated mucilage had good physicochemical and morphological characteristics and tablets conformed to the pharmacopoeial specifications. Also in vitro release studies showed controlled action of drug with increasing the concentration of the isolated Calendula mucilage as a mucoadhesive agent in the formulations. Permeability studies indicated that permeability behavior was not statistically different (P>0.05) by changing the mucoadhesive component. The formulated mucoadhesive tablets for buccal administration containing 75 mg Calendula mucilage showed controlled drug release. Thus, mucoadhesive natural Calendula mucilage based buccal tablets for controlled release were successfully formulated.

Evaluation of Calendula mucilage as a mucoadhesive and controlled release component in buccal tablets

PubMed Central

Sabale, V.; Patel, V.; Paranjape, A.

2014-01-01

Mucoadhesive drug delivery systems were developed to sustain drug delivery via various mucus membranes for either local or systemic delivery of poorly absorbed drugs such as peptides and proteins as well as drugs that are subjected to high first-pass metabolism. The present study was undertaken to use isolated Calendula mucilage as a mucoadhesive agent and to formulate controlled release buccoadhesive tablets with an intention to avoid hepatic first-pass metabolism as well as to enhance residence time of drug in the buccal cavity. The mucilage was isolated from the Calendula petals by aqueous extraction method and characterized for various physiochemical parameters as well as for its adhesive properties. By using direct compression technique, tablets were prepared containing dried mucilage and chlorpheniramine maleate (CPM) as a model drug. Three batches of tablets were prepared and evaluated containing three mucoadhesive components namely Methocel K4M, Carbopol 974P and isolated Calendula mucilage in 16.66%, 33.33 % and 50 % (1:2:3 ratio) resulting in 9 different formulations. FTIR studies between mucilage and CPM suggested the absence of a chemical interaction between CPM and Calendula mucilage. The results of the study showed that the isolated mucilage had good physicochemical and morphological characteristics and tablets conformed to the pharmacopoeial specifications. Also in vitro release studies showed controlled action of drug with increasing the concentration of the isolated Calendula mucilage as a mucoadhesive agent in the formulations. Permeability studies indicated that permeability behavior was not statistically different (P>0.05) by changing the mucoadhesive component. The formulated mucoadhesive tablets for buccal administration containing 75 mg Calendula mucilage showed controlled drug release. Thus, mucoadhesive natural Calendula mucilage based buccal tablets for controlled release were successfully formulated. PMID:25598798

Bioactive factor delivery strategies from engineered polymer hydrogels for therapeutic medicine

PubMed Central

Nguyen, Minh Khanh; Alsberg, Eben

2014-01-01

Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural-(e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic-(e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years. PMID:25242831

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

PubMed Central

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.; Cristini, Vittorio; Brinker, Lina M.; Staquicini, Fernanda I.; Cardó-Vila, Marina; D’Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R.; Dogra, Prashant; Melancon, Marites P.; Stafford, R. Jason; Miyazono, Kohei; Gelovani, Juri G.; Kataoka, Kazunori; Brinker, C. Jeffrey; Sidman, Richard L.; Arap, Wadih; Pasqualini, Renata

2016-01-01

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications. PMID:26839407

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.

PubMed

Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P; Cristini, Vittorio; Brinker, Lina M; Staquicini, Fernanda I; Cardó-Vila, Marina; D'Angelo, Sara; Ferrara, Fortunato; Proneth, Bettina; Lin, Yu-Shen; Dunphy, Darren R; Dogra, Prashant; Melancon, Marites P; Stafford, R Jason; Miyazono, Kohei; Gelovani, Juri G; Kataoka, Kazunori; Brinker, C Jeffrey; Sidman, Richard L; Arap, Wadih; Pasqualini, Renata

2016-02-16

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

DOE PAGES

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.; ...

2016-02-02

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared,more » thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. We conclude that these results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.« less

Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release

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

Hosoya, Hitomi; Dobroff, Andrey S.; Driessen, Wouter H. P.

A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared,more » thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. We conclude that these results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.« less

Preparation and evaluation of injectable Rasagiline mesylate dual-controlled drug delivery system for the treatment of Parkinson's disease.

PubMed

Jiang, Ying; Zhang, Xuemei; Mu, Hongjie; Hua, Hongchen; Duan, Dongyu; Yan, Xiuju; Wang, Yiyun; Meng, Qingqing; Lu, Xiaoyan; Wang, Aiping; Liu, Wanhui; Li, Youxin; Sun, Kaoxiang

2018-11-01

A microsphere-gel in situ forming implant (MS-Gel ISFI) dual-controlled drug delivery system was applied to a high water-soluble small-molecule compound Rasagiline mesylate (RM) for effective treatment of Parkinson's disease. This injectable complex depot system combined an in situ phase transition gel with high drug-loading and encapsulation efficiency RM-MS prepared by a modified emulsion-phase separation method and optimized by Box-Behnken design. It was evaluated for in vitro drug release, in vivo pharmacokinetics, and in vivo pharmacodynamics. We found that the RM-MS-Gel ISFI system showed no initial burst release and had a long period of in vitro drug release (60 days). An in vivo pharmacokinetic study indicated a significant reduction (p < .01) in the initial high plasma drug concentration of the RM-MS-Gel ISFI system compared to that of the single RM-MS and RM-in situ gel systems after intramuscular injection to rats. A pharmacodynamic study demonstrated a significant reduction (p < .05) in 6-hydroxydopamine-induced contralateral rotation behavior and an effective improvement (p < .05) in dopamine levels in the striatum of the lesioned side after 28 days in animals treated with the RM-MS-Gel ISFI compared with that of animals treated with saline. MS-embedded in situ phase transition gel is superior for use as a biodegradable and injectable sustained drug delivery system with a low initial burst and long period of drug release for highly hydrophilic small molecule drugs.

The ability of retention, drug release and rheological properties of nanogel bioadhesives based on cellulose derivatives.

PubMed

Keshavarz, M; Kaffashi, B

2014-12-01

The rheological and drug release behavior of biopolymer nanocomposite gels based on the cellulose derivatives, formulated as the bioadhesive drug delivery platforms, were investigated. The bioadhesive gel is composed of the microcrystalline cellulose, sodium carboxymethyl cellulose and phosphate buffered saline (pH = 7.4 at 20 °C) as the dissolution and release medium. The reinforcing nanofillers such as MMT-clay, fumed porous silica and porous starch were used as additives in the nanogel bioadhesive. The constant steady state viscosities of this nanogels upon incorporation of various nanofillers into the systems is the sign of structural stability. Hence, this system is suitable for use in the controlled drug delivery systems in contact with the biological tissues. Based on the rheological measurements, the shear flow properties (i.e. zero shear viscosity and yield stress) were influenced by the concentration of polymers and nanoparticles. The results indicate that the nonlinear rheological data are fitted properly by the Giesekus model. Furthermore, the results showed that the nonlinear viscoelastic parameters (λ and α) are highly affected by the biogel and nanoparticles concentrations. Finally, the drug release was measured, and the results indicated that the biopolymer-clay nanocomposites have appropriate release pattern as the release is better controlled compared to the other nanogel formulations.

Synchronized and sustained release of multiple components in silymarin from erodible glyceryl monostearate matrix system.

PubMed

Lu, Cheng; Lu, Yi; Chen, Jian; Zhang, Wentong; Wu, Wei

2007-05-01

Development of sustained delivery systems for herbal medicines was very difficult because of their complexity in composition. The concept of synchronized release from sustained release systems, which is characterized by release of multiple components in their original ratio that defines a herbal medicine, served as the basis for keeping the original pharmacological activity. In this study, erodible matrix systems based on glyceryl monostearate and polyethylene glycol 6000 or poloxamer 188 were prepared to perform strict control on synchronized release of the five active components of silymarin, i.e. taxifolin, silychrystin, silydianin, isosilybin and silybin. The matrix system was prepared by a melt fusion method. Synchronized release was achieved with high similarity factor f(2) values between each two of the five components. Erosion profiles of the matrix were in good correlation with release profiles of the five components, showing erosion-controlled release mechanisms. Through tuning some of the formulation variables, the system can be adjusted for synchronized and sustained release of silymarin for oral administration. In vitro hemolysis study indicated that the synchronized release samples showed a much better stabilizing effect on erythrocyte membrane.

Boar semen controlled delivery system: storage and in vitro spermatozoa release.

PubMed

Torre, M L; Faustini, M; Norberti, R; Stacchezzini, S; Maggi, L; Maffeo, G; Conte, U; Vigo, D

2002-12-13

Swine spermatozoa were encapsulated in barium alginate and protamine-barium alginate membranes to lengthen their preservation time and to provide a means of controlling their release. Precocious acrosome reactions and secondary anomalies were measured as indices of semen quality. These characteristics were observed for two forms of encapsulated spermatozoa when stored at 18 and 38 degrees C for 24 h and for semen diluted in a classical extender at both temperatures. The results indicate that encapsulation enhances semen preservation, providing protection against membrane damage upon dilution. The effect is even more evident at the higher temperature (38 degrees C), where cell metabolism is higher. An in vitro release test of spermatozoa showed a massive cell delivery from barium alginate capsules within 6 h, and a slow release from protamine-barium alginate capsules. The properties of spermatozoa 24 h after release did not differ from the semen stored at the same temperature in capsules, indicating that the release process does not impair semen quality.

Development of a chitosan based double layer-coated tablet as a platform for colon-specific drug delivery

PubMed Central

Kim, Min Soo; Yeom, Dong Woo; Kim, Sung Rae; Yoon, Ho Yub; Kim, Chang Hyun; Son, Ho Yong; Kim, Jin Han; Lee, Sangkil; Choi, Young Wook

2017-01-01

A double layer-coated colon-specific drug delivery system (DL-CDDS) was developed, which consisted of chitosan (CTN) based polymeric subcoating of the core tablet containing citric acid for microclimate acidification, followed by an enteric coating. The polymeric composition ratio of Eudragit E100 and ethyl cellulose and amount of subcoating were optimized using a two-level factorial design method. Drug-release characteristics in terms of dissolution efficiency and controlled-release duration were evaluated in various dissolution media, such as simulated colonic fluid in the presence or absence of CTNase. Microflora activation and a stepwise mechanism for drug release were postulated. Consequently, the optimized DL-CDDS showed drug release in a controlled manner by inhibiting drug release in the stomach and intestine, but releasing the drug gradually in the colon (approximately 40% at 10 hours and 92% at 24 hours in CTNase-supplemented simulated colonic fluid), indicating its feasibility as a novel platform for CDD. PMID:28053506

Thiolated polymers as mucoadhesive drug delivery systems.

PubMed

Duggan, Sarah; Cummins, Wayne; O' Donovan, Orla; Hughes, Helen; Owens, Eleanor

2017-03-30

Mucoadhesion is the process of binding a material to the mucosal layer of the body. Utilising both natural and synthetic polymers, mucoadhesive drug delivery is a method of controlled drug release which allows for intimate contact between the polymer and a target tissue. It has the potential to increase bioavailability, decrease potential side effects and offer protection to more sensitive drugs such as proteins and peptide based drugs. The thiolation of polymers has, in the last number of years, come to the fore of mucoadhesive drug delivery, markedly improving mucoadhesion due to the introduction of free thiol groups onto the polymer backbone while also offering a more cohesive polymeric matrix for the slower and more controlled release of drug. This review explores the concept of mucoadhesion and the recent advances in both the polymers and the methods of thiolation used in the synthesis of mucoadhesive drug delivery devices. Copyright © 2017 Elsevier B.V. All rights reserved.

Mesoporous silicate nanoparticles/3D nanofibrous scaffold-mediated dual-drug delivery for bone tissue engineering.

PubMed

Yao, Qingqing; Liu, Yangxi; Selvaratnam, Balaranjan; Koodali, Ranjit T; Sun, Hongli

2018-04-09

Controlled delivery systems play a critical role in the success of bone morphogenetic proteins (i.e., BMP2 and BMP7) for challenged bone repair. Instead of single-drug release that is currently and commonly prevalent, dual-drug delivery strategies are highly desired to achieve effective bone regeneration because natural bone repair process is driven by multiple factors. Particularly, angiogenesis is essential for osteogenesis and requires more than just one factor (e.g., Vascular Endothelial Growth Factor, VEGF). Therefore, we developed a novel mesoporous silicate nanoparticles (MSNs) incorporated-3D nanofibrous gelatin (GF) scaffold for dual-delivery of BMP2 and deferoxamine (DFO). DFO is a hypoxia-mimetic drug that can activate hypoxia-inducible factor-1 alpha (HIF-1α), and trigger subsequent angiogenesis. Sustained BMP2 release system was achieved through encapsulation into large-pored MSNs, while the relative short-term release of DFO was engineered through covalent conjugation with chitosan to reduce its cytotoxicity and elongate its half-life. Both MSNs and DFO were incorporated onto a porous 3D GF scaffold to serve as a biomimetic osteogenic microenvironment. Our data indicated that DFO and BMP2 were released from a scaffold at different release rates (10 vs 28 days) yet maintained their angiogenic and osteogenic ability, respectively. Importantly, our data indicated that the released DFO significantly improved BMP2-induced osteogenic differentiation where the dose/duration was important for its effects in both mouse and human stem cell models. Thus, we developed a novel and tunable MSNs/GF 3D scaffold-mediated dual-drug delivery system and studied the potential application of the both FDA-approved DFO and BMP2 for bone tissue engineering. Copyright © 2018 Elsevier B.V. All rights reserved.

Double loaded self-decomposable SiO2 nanoparticles for sustained drug release

NASA Astrophysics Data System (ADS)

Zhao, Saisai; Zhang, Silu; Ma, Jiang; Fan, Li; Yin, Chun; Lin, Ge; Li, Quan

2015-10-01

Sustained drug release for a long duration is a desired feature of modern drugs. Using double-loaded self-decomposable SiO2 nanoparticles, we demonstrated sustained drug release in a controllable manner. The double loading of the drugs was achieved using two different mechanisms--the first one via a co-growth mechanism, and the second one by absorption. A two-phase sustained drug release was firstly revealed in an in vitro system, and then further demonstrated in mice. After a single intravenous injection, the drug was controllably released from the nanoparticles into blood circulation with a Tmax of about 8 h, afterwards a long lasting release pattern was achieved to maintain drug systemic exposure with a plasma elimination half-life of approximately 28 h. We disclosed that the absorbed drug molecules contributed to the initial fast release for quickly reaching the therapeutic level with relatively higher plasma concentrations, while the ``grown-in'' drugs were responsible for maintaining the therapeutic level via the later controlled slow and sustained release. The present nanoparticle carrier drug configuration and the loading/maintenance release mechanisms provide a promising platform that ensures a prolonged therapeutic effect by controlling drug concentrations within the therapeutic window--a sustained drug delivery system with a great impact on improving the management of chronic diseases.Sustained drug release for a long duration is a desired feature of modern drugs. Using double-loaded self-decomposable SiO2 nanoparticles, we demonstrated sustained drug release in a controllable manner. The double loading of the drugs was achieved using two different mechanisms--the first one via a co-growth mechanism, and the second one by absorption. A two-phase sustained drug release was firstly revealed in an in vitro system, and then further demonstrated in mice. After a single intravenous injection, the drug was controllably released from the nanoparticles into blood circulation with a Tmax of about 8 h, afterwards a long lasting release pattern was achieved to maintain drug systemic exposure with a plasma elimination half-life of approximately 28 h. We disclosed that the absorbed drug molecules contributed to the initial fast release for quickly reaching the therapeutic level with relatively higher plasma concentrations, while the ``grown-in'' drugs were responsible for maintaining the therapeutic level via the later controlled slow and sustained release. The present nanoparticle carrier drug configuration and the loading/maintenance release mechanisms provide a promising platform that ensures a prolonged therapeutic effect by controlling drug concentrations within the therapeutic window--a sustained drug delivery system with a great impact on improving the management of chronic diseases. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr03029c

A 3D-printed local drug delivery patch for pancreatic cancer growth suppression.

PubMed

Yi, Hee-Gyeong; Choi, Yeong-Jin; Kang, Kyung Shin; Hong, Jung Min; Pati, Ruby Gupta; Park, Moon Nyeo; Shim, In Kyong; Lee, Chan Mi; Kim, Song Cheol; Cho, Dong-Woo

2016-09-28

Since recurrence and metastasis of pancreatic cancer has a worse prognosis, chemotherapy has been typically performed to attack the remained malignant cells after resection. However, it is difficult to achieve the therapeutic concentration at the tumor site with systemic chemotherapy. Numerous local drug delivery systems have been studied to overcome the shortcomings of systemic delivery. However, because most systems involve dissolution of the drug within the carrier, the concentration of the drug is limited to the saturation solubility, and consequently cannot reach the sufficient drug dose. Therefore, we hypothesized that 3D printing of a biodegradable patch incorporated with a high drug concentration would provide a versatile shape to be administered at the exact tumor site as well as an appropriate therapeutic drug concentration with a controlled release. Here, we introduce the 3D-printed patches composed of a blend of poly(lactide-co-glycolide), polycaprolactone, and 5-fluorouracil for delivering the anti-cancer drug in a prolonged controlled manner and therapeutic dose. 3D printing technology can manipulate the geometry of the patch and the drug release kinetics. The patches were flexible, and released the drug over four weeks, and thereby suppressed growth of the subcutaneous pancreatic cancer xenografts in mice with minimized side effects. Our approach reveals that 3D printing of bioabsorbable implants containing anti-cancer drugs could be a powerful method for an effective local delivery of chemotherapeutic agents to treatment of cancers. Copyright © 2016 Elsevier B.V. All rights reserved.

Development and characterization of polymer-oil nanostructured carrier (PONC) for controlled delivery of all-trans retinoic acid (ATRA)

NASA Astrophysics Data System (ADS)

Narvekar, Mayuri M.

The commonly used PLGA-based delivery systems are often limited by their inadequate drug loading and release properties. This study reports the integration of oil into PLGA to form the prototype of a hybrid drug carrier PONC. Our primary goal is to confer the key strength of lipid-based drug carriers, i.e. efficient encapsulation of lipophilic compounds, to a PLGA system without taking away its various useful qualities. The PONC were formulated by emulsification solvent evaporation technique, which were then characterized for particle size, encapsulation efficiency, drug release and anticancer efficacy. The ATRA loaded PONC showed excellent encapsulation efficiency and release kinetics. Even after surface functionalization with PEG , controlled drug release kinetics was maintained, with 88.5% of the encapsulated ATRA released from the PEG-PONC in a uniform manner over 120 hours. It also showed favorable physicochemical properties and serum stability. PEG-PONC has demonstrated substantially superior activity over the free ATRA in ovarian cancer cells that are non-responsive to the standard chemotherapy. The newly developed PEG-PONC significantly reduced the IC50 values (p<0.05) in the chemoresistant cells in both MTT and colony formation assays. Hence, this new ATRA-nanoformulation may offer promising means for the delivery of lipophilic compounds like all-trans retinoic acid to treat highly resistant ovarian cancer.

Smart Electrospun Nanofibers for Controlled Drug Release: Recent Advances and New Perspectives

PubMed Central

Weng, Lin; Xie, Jingwei

2017-01-01

In biological systems, chemical molecules or ions often release upon certain conditions, at a specific location, and over a desired period of time. Electrospun nanofibers that undergo alterations in the physicochemical characteristics corresponding to environmental changes have gained considerable interest for various applications. Inspired by biological systems, therapeutic molecules have been integrated with these smart electrospun nanofibers, presenting activation-modulated or feedback-regulated control of drug release. Compared to other materials like smart hydrogels, environment-responsive nanofiber-based drug delivery systems are relatively new but possess incomparable advantages due to their greater permeability, which allows shorter response time and more precise control over the release rate. In this article, we review the mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers. We also illustrate several typical examples in specific applications. We conclude this article with a discussion on perspectives and future possibilities in this field. PMID:25732665

Smart electrospun nanofibers for controlled drug release: recent advances and new perspectives.

PubMed

Weng, Lin; Xie, Jingwei

2015-01-01

In biological systems, chemical molecules or ions often release upon certain conditions, at a specific location, and over a desired period of time. Electrospun nanofibers that undergo alterations in the physicochemical characteristics corresponding to environmental changes have gained considerable interest for various applications. Inspired by biological systems, therapeutic molecules have been integrated with these smart electrospun nanofibers, presenting activation-modulated or feedback-regulated control of drug release. Compared to other materials like smart hydrogels, environment-responsive nanofiber-based drug delivery systems are relatively new but possess incomparable advantages due to their greater permeability, which allows shorter response time and more precise control over the release rate. In this article, we review the mechanisms of various environmental parameters functioning as stimuli to tailor the release rates of smart electrospun nanofibers. We also illustrate several typical examples in specific applications. We conclude this article with a discussion on perspectives and future possibilities in this field.

Controlled release of silyl ether camptothecin from thiol-ene click chemistry-functionalized mesoporous silica nanoparticles.

PubMed

Yan, Yue; Fu, Jie; Wang, Tianfu; Lu, Xiuyang

2017-03-15

As efficient drug carriers, stimuli-responsive mesoporous silica nanoparticles are at the forefront of research on drug delivery systems. An acid-responsive system based on silyl ether has been applied to deliver a hybrid prodrug. Thiol-ene click chemistry has been successfully utilized for tethering this prodrug to mesoporous silica nanoparticles. Here, by altering the steric bulk of the substituent on the silicon atom, the release rate of a model drug, camptothecin, was controlled. The synthesized drug delivery system was investigated by analytical methods to confirm the functionalization and conjugation of the mesoporous silica nanoparticles. Herein, trimethyl silyl ether and triethyl silyl ether were selected to regulate the release rate. Under normal plasma conditions (pH 7.4), both types of camptothecin-loaded mesoporous silica nanoparticles (i.e., MSN-Me-CPT and MSN-Et-CPT) did not release the model drug. However, under in vitro acidic conditions (pH 4.0), based on a comparison of the release rates, camptothecin was released from MSN-Me-CPT more rapidly than from MSN-Et-CPT. To determine the biocompatibility of the modified mesoporous silica nanoparticles and the in vivo camptothecin uptake behavior, MTT assays with cancer cells and confocal microscopy observations were conducted, with positive results. These functionalized nanoparticles could be useful in clinical treatments requiring controlled drug release. As the release rate of drug from drug-carrier plays important role in therapy effects, trimethyl silyl ether (TMS) and triethyl silyl ether (TES) were selected as acid-sensitive silanes to control the release rates of model drugs conjugated from MSNs by thiol-ene click chemistry. The kinetic profiles of TMS and TES materials have been studied. At pH 4.0, the release of camptothecin from MSN-Et-CPT occurred after 2h, whereas MSN-Me-CPT showed immediate drug release. The results showed that silyl ether could be used to control release rates of drugs from MSNs under acid environment, which could be useful in clinical treatments requiring controlled drug release. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Predictable pulsatile release of tramadol hydrochloride for chronotherapeutics of arthritis.

PubMed

Dabhi, Chandu; Randale, Shivsagar; Belgamwar, Veena; Gattani, Surendra; Tekade, Avinash

2010-07-01

The present investigation deals with the development of a pH and time-dependent press-coated pulsatile drug delivery system for delivering drugs into the colon. The system consists of a drug containing core, coated by a combination of natural polymer Delonix regia gum (DRG) and hydroxypropyl methylcellulose (HPMC K4M) in various proportions, which controls the onset of release. The whole system was coated with methacrylic acid copolymers, which not only prevents the drug release in the stomach, but also prolongs the lag time. Tramadol HCl was used as a model drug and varying combinations of DRG and HPMC K4M were used to achieve the desired lag time before rapid and complete release of the drug in the colon. It was observed that the lag time depends on the coating ratio of DRG to HPMC and also on press coating weight. Drug release was found to be increased by 15-30% in the presence of colonic microbial flora. The results showed the capability of the system in achieving pulsatile release for a programmable period of time and pH-dependent release to attain colon-targeted delivery.

Enzymatic- and temperature-sensitive controlled release of ultrasmall superparamagnetic iron oxides (USPIOs).

PubMed

Yu, Shann S; Scherer, Randy L; Ortega, Ryan A; Bell, Charleson S; O'Neil, Conlin P; Hubbell, Jeffrey A; Giorgio, Todd D

2011-02-27

Drug and contrast agent delivery systems that achieve controlled release in the presence of enzymatic activity are becoming increasingly important, as enzymatic activity is a hallmark of a wide array of diseases, including cancer and atherosclerosis. Here, we have synthesized clusters of ultrasmall superparamagnetic iron oxides (USPIOs) that sense enzymatic activity for applications in magnetic resonance imaging (MRI). To achieve this goal, we utilize amphiphilic poly(propylene sulfide)-bl-poly(ethylene glycol) (PPS-b-PEG) copolymers, which are known to have excellent properties for smart delivery of drug and siRNA. Monodisperse PPS polymers were synthesized by anionic ring opening polymerization of propylene sulfide, and were sequentially reacted with commercially available heterobifunctional PEG reagents and then ssDNA sequences to fashion biofunctional PPS-bl-PEG copolymers. They were then combined with hydrophobic 12 nm USPIO cores in the thin-film hydration method to produce ssDNA-displaying USPIO micelles. Micelle populations displaying complementary ssDNA sequences were mixed to induce crosslinking of the USPIO micelles. By design, these crosslinking sequences contained an EcoRV cleavage site. Treatment of the clusters with EcoRV results in a loss of R2 negative contrast in the system. Further, the USPIO clusters demonstrate temperature sensitivity as evidenced by their reversible dispersion at ~75°C and re-clustering following return to room temperature. This work demonstrates proof of concept of an enzymatically-actuatable and thermoresponsive system for dynamic biosensing applications. The platform exhibits controlled release of nanoparticles leading to changes in magnetic relaxation, enabling detection of enzymatic activity. Further, the presented functionalization scheme extends the scope of potential applications for PPS-b-PEG. Combined with previous findings using this polymer platform that demonstrate controlled drug release in oxidative environments, smart theranostic applications combining drug delivery with imaging of platform localization are within reach. The modular design of these USPIO nanoclusters enables future development of platforms for imaging and drug delivery targeted towards proteolytic activity in tumors and in advanced atherosclerotic plaques.

Controlled long-term release of small peptide hormones using a new microporous polypropylene polymer: its application for vasopressin in the Brattleboro rat and potential perinatal use

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

Kruisbrink, J.; Boer, G.J.

1984-12-01

Based on drug release by microporous hollow fibers and the recent introduction of microporous polymers, a new technique was developed for controlled delivery of peptides. Small-diameter microporous polypropylene tubing, lumen-loaded with microgram quantities of vasopressin, and coated with collodion, releases vasopressin after in vitro immersion slowly (1-100 ng/d) and constantly for months. The mechanism of pseudo-zero-order delivery is based on high adsorption of vasopressin, keeping the void volume concentration of dissolved vasopressin constant, which is consequently a constant driving force of outward diffusion. The collodion coating prevents the entry of proteinaceous compounds which would result in rapid desorption of vasopressin.more » The present delivery module provides a lasting release for other peptides as well (lysine-vasopressin, oxytocin, alpha-melanocyte-stimulating hormone and, to a lesser extent, Met-enkephalin). The microporous polymer-collodion device is biocompatible and, loaded with vasopressin, successfully alleviates the diabetes insipidus of Brattleboro rats deficient for vasopressin. Subcutaneous implantation normalized diuresis for a period of 60 d and constant urine vasopressin excretion is observed. When the commercially available osmotic minipump is too large for implantation, the small size of the present controlled-delivery system allows peptide treatment of young and immature laboratory rats, even if located in utero.« less

The potential of polymeric film-forming systems as sustained delivery platforms for topical drugs.

PubMed

Frederiksen, Kit; Guy, Richard H; Petersson, Karsten

2016-01-01

Dosing regimens requiring multiple daily applications frequently result in poor patient compliance, especially in the treatment of chronic skin diseases. Consequently, development of sustained delivery systems for topical drugs permitting less frequent dosing is of continuing interest for dermatological therapy. This potential of polymeric film-forming systems (FFS), created in situ on the skin, as sustained delivery platforms for topical drug delivery is reviewed. Key formulation parameters that determine delivery efficiency are considered focussing on those that permit a drug reservoir to be established in the upper layers of the skin and/or on the skin surface from which release can be sustained over a prolonged period. The advantageous and superior cosmetic attributes of FFS (compared to conventional semi-solid formulations) that offer significantly improved patient compliance are also addressed. The promise of polymeric FFS as convenient and aesthetic platforms for sustained topical drug delivery is clear. Manipulation of the formulation allows the delivery profile to be customized and optimized to take advantage of both a rapid, initial input of drug into the skin (likely due to a transient period of supersaturation) and a slower, controlled release over an extended time from the residual film created thereafter.

Levodopa delivery systems: advancements in delivery of the gold standard.

PubMed

Ngwuluka, Ndidi; Pillay, Viness; Du Toit, Lisa C; Ndesendo, Valence; Choonara, Yahya; Modi, Girish; Naidoo, Dinesh

2010-02-01

Despite the fact that Parkinson's disease (PD) was discovered almost 200 years ago, its treatment and management remain immense challenges because progressive loss of dopaminergic nigral neurons, motor complications experienced by the patients as the disease progresses and drawbacks of pharmacotherapeutic management still persist. Various therapeutic agents have been used in the management of PD, including levodopa (l-DOPA), selegiline, amantadine, bromocriptine, entacapone, pramipexole dihydrochloride and more recently istradefylline and rasagiline. Of all agents, l-DOPA although the oldest, remains the most effective. l-DOPA is easier to administer, better tolerated, less expensive and is required by almost all PD patients. However, l-DOPA's efficacy in advanced PD is significantly reduced due to metabolism, subsequent low bioavailability and irregular fluctuations in its plasma levels. Significant strides have been made to improve the delivery of l-DOPA in order to enhance its bioavailability and reduce plasma fluctuations as well as motor complications experienced by patients purportedly resulting from pulsatile stimulation of the striatal dopamine receptors. Drug delivery systems that have been instituted for the delivery of l-DOPA include immediate release formulations, liquid formulations, dispersible tablets, controlled release formulations, dual-release formulations, microspheres, infusion and transdermal delivery, among others. In this review, the l-DOPA-loaded drug delivery systems developed over the past three decades are elaborated. The ultimate aim was to assess critically the attempts made thus far directed at improving l-DOPA absorption, bioavailability and maintenance of constant plasma concentrations, including the drug delivery technologies implicated. This review highlights the fact that neuropharmaceutics is at a precipice, which is expected to spur investigators to take that leap to enable the generation of innovative delivery systems for the effective management of PD.

Water soluble nanoporous nanoparticle for in vivo targeted drug delivery and controlled release in B cells tumor context

NASA Astrophysics Data System (ADS)

de Angelis, F.; Pujia, A.; Falcone, C.; Iaccino, E.; Palmieri, C.; Liberale, C.; Mecarini, F.; Candeloro, P.; Luberto, L.; de Laurentiis, A.; Das, G.; Scala, G.; di Fabrizio, E.

2010-10-01

Multitasking nanoparticles are gaining great attention for smart drug delivery systems. The exploration of the nano-scale opens new concrete opportunities for revealing new properties and undiscovered cell-particle interactions. Here we present a biodegradable nanoporous silicon nanoparticle that can be successfully employed for in vivo targeted drug delivery and sustained release. The bare nanoporous nanocarriers can be accurately designed and fabricated with an effective control of porosity, surface chemistry and particle size, up to a few nm. The proposed nanoparticles exhibit several remarkable features including high payload, biodegradability, no toxicity, and multiple loading in water without the need of additional chemical reagents at room temperature. The targeting strategy is based on phage display technology that was successfully used to discover cell surface binding peptide for murine B lymphoma A20 cell line. The peptide used in combination with the nanoporous nanoparticles allows an efficient in vivo targeting, a sustained release and a sensible therapeutic effect.Multitasking nanoparticles are gaining great attention for smart drug delivery systems. The exploration of the nano-scale opens new concrete opportunities for revealing new properties and undiscovered cell-particle interactions. Here we present a biodegradable nanoporous silicon nanoparticle that can be successfully employed for in vivo targeted drug delivery and sustained release. The bare nanoporous nanocarriers can be accurately designed and fabricated with an effective control of porosity, surface chemistry and particle size, up to a few nm. The proposed nanoparticles exhibit several remarkable features including high payload, biodegradability, no toxicity, and multiple loading in water without the need of additional chemical reagents at room temperature. The targeting strategy is based on phage display technology that was successfully used to discover cell surface binding peptide for murine B lymphoma A20 cell line. The peptide used in combination with the nanoporous nanoparticles allows an efficient in vivo targeting, a sustained release and a sensible therapeutic effect. Electronic supplementary information (ESI) available: Nanoparticles fabrication; payload evaluation; dissolution and release profiles; multivalent loading; targeting specifity on A20 Cells; cell cycle analysis; in vitro cytotoxicity assay; in vivo cytotoxicity assay. See DOI: 10.1039/c0nr00161a

Implementation of wireless power transfer and communications for an implantable ocular drug delivery system.

PubMed

Tang, T B; Smith, S; Flynn, B W; Stevenson, J T M; Gundlach, A M; Reekie, H M; Murray, A F; Renshaw, D; Dhillon, B; Ohtori, A; Inoue, Y; Terry, J G; Walton, A J

2008-09-01

A wireless power transfer and communication system based on near-field inductive coupling has been designed and implemented. The feasibility of using such a system to remotely control drug release from an implantable drug delivery system is addressed. The architecture of the wireless system is described and the signal attenuation over distance in both water and phosphate buffered saline is studied. Additionally, the health risk due to exposure to radio frequency (RF) radiation is examined using a biological model. The experimental results demonstrate that the system can trigger the release of drug within 5 s, and that such short exposure to RF radiation does not produce any significant (

The effectiveness of the controlled release of simvastatin from β-TCP macrosphere in the treatment of OVX mice.

PubMed

Chou, Joshua; Ito, Tomoko; Otsuka, Makoto; Ben-Nissan, Besim; Milthorpe, Bruce

2016-03-01

Simvastatin, a cholesterol treatment drug, has been shown to stimulate bone regeneration. As such, there has been an increase interest in the development of suitable materials and systems for the delivery of simvastatin. Without the appropriate dosage of simvastatin, the therapeutic effects on bone growth will be significantly reduced. Furthermore, similar to many pharmaceutical compounds, at high concentration simvastatin can cause various adverse side-effects. Given the associated side-effects with the usage of simvastatin, the development of suitable controlled drug release system is pertinent. Calcium phosphate in particularly beta-tricalcium phosphate (β-TCP) has been extensively studied and used as a carrier material for drug delivery system. In this study, Foraminifera exoskeletons were used as calcium carbonate precursor materials, which were hydrothermally converted to β-TCP as a carrier material for simvastatin. Natural marine exoskeletons posses interconnected and uniformly porous network capable of improving drug loading and release rate. To prolong the release of simvastatin, an apatite coating was made around the β-TCP sample and in vitro release studies in simulated body fluid (SBF) showed a significant decrease in release rate. Osteoporotic mice were used to examine the compare therapeutic effectiveness of β-TCP, β-TCP with simvastatin, apatite-coated β-TCP with simvastatin and direct injection of simvastatin near the right femur of the mice. Localized and systemic effect were compared with the femur of the non-implanted side (left) and showed that β-TCP with or without simvastatin was able to induce significant bone formation over 6 weeks. Mechanical analysis showed that apatite-coated β-TCP with simvastatin produced significantly stronger bones compared with other experimental groups. This study shows that natural exoskeletons with the appropriate structure can be successfully used as a drug delivery system for simvastatin and can its release can be prolonged with an apatite coating to significantly promote relevant bone formation. Copyright © 2013 John Wiley & Sons, Ltd.

A model system for targeted drug release triggered by biomolecular signals logically processed through enzyme logic networks.

PubMed

Mailloux, Shay; Halámek, Jan; Katz, Evgeny

2014-03-07

A new Sense-and-Act system was realized by the integration of a biocomputing system, performing analytical processes, with a signal-responsive electrode. A drug-mimicking release process was triggered by biomolecular signals processed by different logic networks, including three concatenated AND logic gates or a 3-input OR logic gate. Biocatalytically produced NADH, controlled by various combinations of input signals, was used to activate the electrochemical system. A biocatalytic electrode associated with signal-processing "biocomputing" systems was electrically connected to another electrode coated with a polymer film, which was dissolved upon the formation of negative potential releasing entrapped drug-mimicking species, an enzyme-antibody conjugate, operating as a model for targeted immune-delivery and consequent "prodrug" activation. The system offers great versatility for future applications in controlled drug release and personalized medicine.

A Controlled Drug-Delivery Experiment Using Alginate Beads

ERIC Educational Resources Information Center

Farrell, Stephanie; Vernengo, Jennifer

2012-01-01

This paper describes a simple, cost-effective experiment which introduces students to drug delivery and modeling using alginate beads. Students produce calcium alginate beads loaded with drug and measure the rate of release from the beads for systems having different stir rates, geometries, extents of cross-linking, and drug molecular weight.…

[Use of a novel polymer, the in-situ gelling mucoadhesive thiolated poly(aspartic acid) in ophthalmic drug delivery].

PubMed

Horvát, Gabriella; Budai-Szűcs, Mária; Berkó, Szilvia; Szabóné-Révész, Piroska; Gyarmati, Benjámin; Szilágyi, Barnabas Áron; Szilágyi, András; Csányi Erzsébet

2015-01-01

The bioavailability of drugs used on mucosal surfaces can be increased by the use of mucoadhesive polymers. A new type of mucoadhesive polymers is the group of thiolated polymers with thiol group containing side chains. These polymers are able to form covalent bonds (disulphide linkages) with the mucin glycoproteins. For the formulation of an ocular drug delivery system (DDS) thiolated poly(aspartic acid) polymer (ThioPASP) was used. Our aim was to determine their biocompatibility, mucoadhesion and drug release property. According to the results it can be established that the thiolated poly(aspartic acid) polymers can be a potential vehicle of an ocular drug delivery system due to their biocompatibility, good mucoadhesive property and drug release profile. Thanks to their properties controlled drug delivery can be achieved and bioavailability of the ophthalmic formulation can be increased, while the usage frequency can be decreased.

Colloidal drug delivery systems: current status and future directions.

PubMed

Garg, Tarun; Rath, Goutam; Goyal, Amit Kumar

2015-01-01

In this paper, we provide an overview an extensive range of colloidal drug delivery systems with special focus on vesicular and particulates systems that are being used in research or might be potentially useful as carriers systems for drug or active biomolecules or as cell carriers with application in the therapeutic field. We present some important examples of commercially available drug delivery systems with applications in research or in clinical fields. This class of systems is widely used due to excellent drug targeting, sustained and controlled release behavior, higher entrapment efficiency of drug molecules, prevention of drug hydrolysis or enzymatic degradation, and improvement of therapeutic efficacy. These characteristics help in the selection of suitable carrier systems for drug, cell, and gene delivery in different fields.

Plasmon resonant liposomes for controlled drug delivery

NASA Astrophysics Data System (ADS)

Knights-Mitchell, Shellie S.; Romanowski, Marek

2015-03-01

Nanotechnology use in drug delivery promotes a reduction in systemic toxicity, improved pharmacokinetics, and better drug bioavailability. Liposomes continue to be extensively researched as drug delivery systems (DDS) with formulations such as Doxil® and Ambisome® approved by FDA and successfully marketed in the United States. However, the limited ability to precisely control release of active ingredients from these vesicles continues to challenge the broad implementation of this technology. Moreover, the full potential of the carrier to sequester drugs until it can reach its intended target has yet to be realized. Here, we describe a liposomal DDS that releases therapeutic doses of an anticancer drug in response to external stimulus. Earlier, we introduced degradable plasmon resonant liposomes. These constructs, obtained by reducing gold on the liposome surface, facilitate spatial and temporal release of drugs upon laser light illumination that ultimately induces an increase in temperature. In this work, plasmon resonant liposomes have been developed to stably encapsulate and retain doxorubicin at physiological conditions represented by isotonic saline at 37o C and pH 7.4. Subsequently, they are stimulated to release contents either by a 5o C increase in temperature or by laser illumination (760 nm and 88 mW/cm2 power density). Successful development of degradable plasmon resonant liposomes responsive to near-infrared light or moderate hyperthermia can provide a new delivery method for multiple lipophilic and hydrophilic drugs with pharmacokinetic profiles that limit clinical utility.

Diffusion-Based Design of Multi-Layered Ophthalmic Lenses for Controlled Drug Release

PubMed Central

Pimenta, Andreia F. R.; Serro, Ana Paula; Paradiso, Patrizia; Saramago, Benilde

2016-01-01

The study of ocular drug delivery systems has been one of the most covered topics in drug delivery research. One potential drug carrier solution is the use of materials that are already commercially available in ophthalmic lenses for the correction of refractive errors. In this study, we present a diffusion-based mathematical model in which the parameters can be adjusted based on experimental results obtained under controlled conditions. The model allows for the design of multi-layered therapeutic ophthalmic lenses for controlled drug delivery. We show that the proper combination of materials with adequate drug diffusion coefficients, thicknesses and interfacial transport characteristics allows for the control of the delivery of drugs from multi-layered ophthalmic lenses, such that drug bursts can be minimized, and the release time can be maximized. As far as we know, this combination of a mathematical modelling approach with experimental validation of non-constant activity source lamellar structures, made of layers of different materials, accounting for the interface resistance to the drug diffusion, is a novel approach to the design of drug loaded multi-layered contact lenses. PMID:27936138

Osmotic pellet system comprising osmotic core and in-process amorphized drug in polymer-surfactant layer for controlled delivery of poorly water-soluble drug.

PubMed

Saindane, Nilesh; Vavia, Pradeep

2012-09-01

The aim of the present investigation was to develop controlled porosity osmotic system for poorly water-soluble drug based on drug in polymer-surfactant layer technology. A poorly water-soluble drug, glipizide (GZ), was selected as the model drug. The technology involved core of the pellets containing osmotic agent coated with drug dispersed in polymer and surfactant layer, finally coated with release-retardant layer with pore former. The optimized drug-layer-coated pellets were evaluated for solubility of GZ at different pH conditions and characterized for amorphous nature of the drug by differential scanning calorimetry and X-ray powder diffractometry. The optimized release-retardant layer pellets were evaluated for in vitro drug release at different pH, hydrodynamic, and osmolality conditions. The optimized drug layer showed improvement in solubility (10 times in pH 1.2, 11 times in pH 4.5, and 21 times in pH 6.8), whereas pellets coated with cellulose acetate (15.0%, w/w, weight gain) with pore former triethyl citrate (10.0%, w/w, of polymer) demonstrated zero-order drug release for 24 h at different pH conditions; moreover, retardation of drug release was observed with increment of osmolality. This system could be a platform technology for controlled delivery of poorly water-soluble drugs. Copyright © 2012 Wiley Periodicals, Inc.

Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.

PubMed

Nakano, Takashi; Chin, Catherine; Myint, David Mo Aung; Tan, Eng Wui; Hale, Peter John; Krishna M, Bala Murali; Reynolds, John N J; Wickens, Jeff; Dani, Keshav M

2014-06-23

Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine--a key neurotransmitter of the central nervous system--thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

Current status and approaches to developing press-coated chronodelivery drug systems.

PubMed

Lin, Shan-Yang; Kawashima, Yoshiaki

2012-02-10

The past several decades have seen the development of many controlled-release preparations featuring constant release rates to maintain drug concentrations in the human body, regardless of the patient's physiological condition. However, long-term constant drug concentrations in the blood and tissue can cause problems such as resistance, tolerability, and drug side effects. People vary considerably in their physiological and biochemical conditions during any 24 h period, due to the circadian rhythm, and thus, the constant delivery of a drug into the body seems both unnecessary and undesirable. If the drug release profile mimics a living system's pulsatile hormone secretion, then it may improve drug efficacy, and reduce the toxicity of a specific drug administration schedule. Medication and treatments provided according to the body's circadian rhythms will result in better outcomes. This may be provided by a chronopharmaceutical dosage regimen with pulsatile release that matches the circadian rhythm resulting from a disease state, so optimizing the therapeutic effect while minimizing side effects. The press coating technique is a simple and unique technology used to provide tablets with a programmable lag phase, followed by a fast, or rate-controlled, drug release after administration. The technique offers many advantages, and no special coating solvent or coating equipment is required for manufacturing this type of tablet. The present review article introduces chronopharmaceutical press-coated products from a patient physiological needs perspective. The contents of this article include biological rhythms and pulsatile hormone secretion in humans, the reasons for using pulsatile drug delivery for disease treatment, recent chronopharmaceutical preparations appearing on the market, updated compilation of all research articles and press-coated delivery techniques, factors affecting the performance and drug release characteristics of press-coated delivery systems, and recent challenges for the press coating technique. We also provide a brief overview of press-coating approaches intended for chronotherapy. Copyright © 2011 Elsevier B.V. All rights reserved.

Advanced drug and gene delivery systems based on functional biodegradable polycarbonates and copolymers.

PubMed

Chen, Wei; Meng, Fenghua; Cheng, Ru; Deng, Chao; Feijen, Jan; Zhong, Zhiyuan

2014-09-28

Biodegradable polymeric nanocarriers are one of the most promising systems for targeted and controlled drug and gene delivery. They have shown several unique advantages such as excellent biocompatibility, prolonged circulation time, passive tumor targeting via the enhanced permeability and retention (EPR) effect, and degradation in vivo into nontoxic products after completing their tasks. The current biodegradable drug and gene delivery systems exhibit, however, typically low in vivo therapeutic efficacy, due to issues of low loading capacity, inadequate in vivo stability, premature cargo release, poor uptake by target cells, and slow release of therapeutics inside tumor cells. To overcome these problems, a variety of advanced drug and gene delivery systems has recently been designed and developed based on functional biodegradable polycarbonates and copolymers. Notably, polycarbonates and copolymers with diverse functionalities such as hydroxyl, carboxyl, amine, alkene, alkyne, halogen, azido, acryloyl, vinyl sulfone, pyridyldisulfide, and saccharide, could be readily obtained by controlled ring-opening polymerization. In this paper, we give an overview on design concepts and recent developments of functional polycarbonate-based nanocarriers including stimuli-sensitive, photo-crosslinkable, or active targeting polymeric micelles, polymersomes and polyplexes for enhanced drug and gene delivery in vitro and in vivo. These multifunctional biodegradable nanosystems might be eventually developed for safe and efficient cancer chemotherapy and gene therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Microemulsion-Based Mucoadhesive Buccal Wafers: Wafer Formation, In Vitro Release, and Ex Vivo Evaluation.

PubMed

Pham, Minh Nguyet; Van Vo, Toi; Tran, Van-Thanh; Tran, Phuong Ha-Lien; Tran, Thao Truong-Dinh

2017-10-01

Microemulsion has the potentials to enhance dissolution as well as facilitate absorption and permeation of poorly water-soluble drugs through biological membranes. However, its application to govern a controlled release buccal delivery for local treatment has not been discovered. The aim of this study is to develop microemulsion-based mucoadhesive wafers for buccal delivery based on an incorporation of the microemulsion with mucoadhesive agents and mannitol. Ratio of oil to surfactant to water in the microemulsion significantly impacted quality of the wafers. Furthermore, the combination of carbopol and mannitol played a key role in forming the desired buccal wafers. The addition of an extra 50% of water to the formulation was suitable for wafer formation by freeze-drying, which affected the appearance and distribution of carbopol in the wafers. The amount of carbopol was critical for the enhancement of mucoadhesive properties and the sustained drug release patterns. Release study presented a significant improvement of the drug release profile following sustained release for 6 h. Ex vivo mucoadhesive studies provided decisive evidence to the increased retention time of wafers along with the increased carbopol content. The success of this study indicates an encouraging strategy to formulate a controlled drug delivery system by incorporating microemulsions into mucoadhesive wafers.

Synthesis of pH-sensitive poly(β-amino ester)-coated mesoporous silica nanoparticles for the controlled release of drugs

NASA Astrophysics Data System (ADS)

Talavera-Pech, William A.; Esparza-Ruiz, Adriana; Quintana-Owen, Patricia; Vilchis-Nestor, Alfredo R.; Barrón-Zambrano, Jesus A.; Ávila-Ortega, Alejandro

2018-03-01

This report describes the synthesis of a controlled drug delivery system that was obtained by coating mesoporous silica nanoparticles (MSNs) with poly(β-amino ester) (PbAE), which is a solid and stable material at physiological pH, but is dissolved at acidic pH values, such as those in tumor tissues (from 5.0 to 6.5). To synthesize the system, PbAE chains were grafted onto amino-functionalized MSNs through a reaction between the surface amino groups of MSNs and the ends of acrylate chains of a PbAE. The system was physicochemically characterized by dynamic light scattering (DLS), Fourier transform infrared spectroscopy, transmission electron microscopy, thermogravimetric analysis, X-ray photoelectron spectrometry, and X-ray diffraction analyses. In addition, the in vitro release of doxorubicin (DOX) and doxycycline (DXY) in acidic and physiological media was evaluated. It was observed that the PbAE modification did not affect the mesoporous structure of MSNs. When the amount of 3-aminopropyltriethoxysilane was increased during functionalization, the amount of PbAE binding to MSNs increased as well. With respect to drug release, the sample with the highest amount of PbAE showed better control in the delivery of DXY and DOX in acidic media, because at pH 5.5, the release of both drugs was 40% higher than that at pH 7.4. These results reveal two aspects about the presence of PbAE in MSNs: PbAE does not affect the mesoporous structure of the nanoparticles, and PbAE is the main factor controlling the delivery of drugs in acidic media.

A squeeze-type osmotic tablet for controlled delivery of nifedipine.

PubMed

Park, Jung Soo; Shin, Jun Hyun; Lee, Dong Hun; Kim, Moon Suk; Rhee, John M; Lee, Hai Bang; Khang, Gilson

2008-01-01

Osmotic delivery systems are based on osmotic driving force. Nifedipine tablets, available under the trade names Procardia XL (Pfizer) and Adalat (Bayer), are commercialized drug-delivery systems of an elemental osmotic pump that the push-pull osmotic tablet operates successfully in delivering water-insoluble drugs. For the improvement of the release pattern and the solubility of the drug, we developed a squeeze-type osmotic tablet (SQT) for nifedipine as a model drug. The SQT was composed of one or more ring type of squeeze-push layer (squeeze-disc) and a centered drug core. Squeeze-discs were stacked up with different physicochemical properties with gradient such as viscosity, swelling ratio and water absorption ratio using the osmotic agents from a disc of bottom to top. The present work investigated the effect of different preparation factors, such as hydrophilic polymers, the molecular weight of polymers, coating process, orifice size and types of excipient on release performance of nifedipine. With the purpose of delivering water-insoluble nifedipine at an approximate zero-order rate and step-function rate for 24 h, SQT has been successfully prepared, and significantly improved in the release rate and patterns in comparison with the Adalat push-pull system in vitro release features.

Carrier Mediated Systemic Delivery of Protein and Peptide Therapeutics.

PubMed

Zaman, Rahela; Othman, Iekhan; Chowdhury, Ezharul Hoque

2016-01-01

Over the last few decades proteins and peptide therapeutics have occupied an enormous fraction of pharmaceutical industry. Despite their high potential as therapeutics, the big challenge often encountered is the effective administration and bioavailability of protein therapeutics in vivo system. Peptide molecules are well known for their in vivo short half-lives. In addition, due to high molecular weight and susceptibility to enzymatic degradation, often it is not easy to administer peptides and proteins orally or through any other noninvasive routes. Conventional drug management system often demands for frequent and regular interval intravenous/subcutaneous administration, which decreases overall patient compliance and increases chances of side-effects related to dose-fluctuation in systemic circulation. A controlled mode of delivery system could address all these short-comings at a time. Therefore, long-acting sustained release formulations for both invasive and noninvasive routes are under rigorous study currently. Long-acting formulations through invasive routes can address patient compliance and dose-fluctuation issues by less frequent administration. Also, any new route of administration other than invasive routes will address cost-effectiveness of the therapeutic by lessening the need to deal with health professional and health care facility. Although a vast number of studies are dealing with novel drug delivery systems, till now only a handful of controlled release formulations for proteins and peptides have been approved by FDA. This study therefore focuses on current and perspective controlled release formulations of existing and novel protein/peptide therapeutics via conventional invasive routes as well as potential novel non-invasive routes of administration, e.g., oral, buccal, sublingual, nasal, ocular, rectal, vaginal and pulmonary.

Acoustically-Responsive Scaffolds: Control of Growth Factor Release for Tissue Regeneration Using Ultrasound

NASA Astrophysics Data System (ADS)

Moncion, Alexander

Administration of exogenous growth factors (GFs) is a proposed method of stimulating tissue regeneration. Conventional administration routes, such as at-site or systemic injections, have yielded problems with efficacy and/or safety, thus hindering the translation of GF-based regenerative techniques. Hydrogel scaffolds are commonly used as biocompatible delivery vehicles for GFs. Yet hydrogels do not afford spatial or temporal control of GF release - two critical parameters for tissue regeneration. Controlled delivery of GFs is critical for angiogenesis, which is a crucial process in tissue engineering that provides oxygen and nutrients to cells within an implanted hydrogel scaffold. Angiogenesis requires multiple GFs that are presented with distinct spatial and temporal profiles. Thus, controlled release of GFs with spatiotemporal modulation would significantly improve tissue regeneration by recapitulating endogenous GF presentation. In order to achieve this goal, we have developed acoustically-responsive scaffolds (ARSs), which are fibrin hydrogels doped with sonosensitive perfluorocarbon (PFC) emulsions capable of encapsulating various payloads. Focused, mega-Hertz range, ultrasound (US) can modulate the release of a payload non-invasively and in an on-demand manner from ARSs via physical mechanisms termed acoustic droplet vaporization (ADV) and inertial cavitation (IC). This work presents the relationship between the ADV/IC thresholds and various US and hydrogel parameters. These physical mechanisms were used for the controlled release of fluorescent dextran in vitro and in vivo to determine the ARS and US parameters that yielded optimal payload release. The optimal ARS and US parameters were used to demonstrate the controlled release of basic fibroblast growth factor from an in vivo subcutaneous implant model - leading to enhanced angiogenesis and perfusion. Additionally, different acoustic parameters and PFCs were tested and optimized to demonstrate the controlled release of two encapsulated payloads within an ARS. Overall, ARSs are a promising platform for GF delivery in tissue regeneration applications.

Biodegradable nano-micro carrier systems for sustained pulmonary drug delivery: (I) Self-assembled nanoparticles encapsulated in respirable/swellable semi-IPN microspheres

PubMed Central

El-Sherbiny, I. M.; Smyth, H. D. C.

2012-01-01

Design of appropriate inhaled carriers with adequate aerodynamic properties, drug release, biodegradation and evasion of macrophage uptake is a major challenge for controlled release pulmonary drug delivery. In this study, PEG graft copolymerized onto N-phthaloyl chitosan (NPHCs) was synthesized then characterized using FTIR, EA, DSC and 2D-XRD. The resulting PEG-g-NPHCs copolymers were self-assembled into drug loaded nanoparticles and encapsulated in respirable/swellable sodium alginate semi-IPN hydrogel microspheres as novel biodegradable carriers for controlled release pulmonary drug delivery. The developed nano-/microspheres carrier systems were formed via spray drying followed by ionotropic crosslinking in mild aqueous medium. The size of the developed self-assembled nanoparticles and the microspheres was measured using dynamic light scattering and laser diffraction, respectively. Morphology, moisture content, in-vitro biodegradation and dynamic swelling studies were also investigated for the developed carriers. A model protein was entrapped and the in-vitro release profiles were determined in PBS, pH 7.4 at 37°C. A dry powder aerosolization study was conducted using a Next Generation Impactor (NGI). The developed microspheres had suitable aerodynamic diameters (1.02–2.63 μm) and an excellent fine particle fraction, FPF of 31.52%. The microspheres showed also a very fast initial swelling within the first 2 min and started to enzymatically degrade within the first two hours. Moreover, the microspheres entrapped up 90% of the model drug and showed promising in-vitro sustained release profiles as compared to the control formulation. PMID:20580794

Effect of ca2+ to salicylic acid release in pectin based controlled drug delivery system

NASA Astrophysics Data System (ADS)

Kistriyani, L.; Wirawan, S. K.; Sediawan, W. B.

2016-01-01

Wastes from orange peel are potentially be utilized to produce pectin, which are currently an import commodity. Pectin can be used in making edible film. Edible films are potentially used as a drug delivery system membrane after a tooth extraction. Drug which is used in the drug delivery system is salicylic acid. It is an antiseptic. In order to control the drug release rate, crosslinking process is added in the manufacturing of membrane with CaCl2.2H2O as crosslinker. Pectin was diluted in water and mixed with a plasticizer and CaCl2.2H2O solution at 66°C to make edible film. Then the mixture was dried in an oven at 50 °C. After edible film was formed, it was coated using plasticizer and CaCl2.2H2O solution with various concentration 0, 0.015, 0.03 and 0.05g/mL. This study showed that the more concentration of crosslinker added, the slower release of salicylic acid would be. This was indicated by the value of diffusivites were getting smaller respectively. The addition of crosslinker also caused smaller gels swelling value,which made the membrane is mechanically stronger

A novel osmotic pump-based controlled delivery system consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen: in vitro and in vivo evaluation.

PubMed

Li, Shujuan; Wang, Xiaoyu; Wang, Yingying; Zhao, Qianqian; Zhang, Lina; Yang, Xinggang; Liu, Dandan; Pan, Weisan

2015-01-01

In this study, a novel controlled release osmotic pump capsule consisting of pH-modulated solid dispersion for poorly soluble drug flurbiprofen (FP) was developed to improve the solubility and oral bioavailability of FP and to minimize the fluctuation of plasma concentration. The pH-modulated solid dispersion containing FP, Kollidon® 12 PF and Na2CO3 at a weight ratio of 1/4.5/0.02 was prepared using the solvent evaporation method. The osmotic pump capsule was assembled by semi-permeable capsule shell of cellulose acetate (CA) prepared by the perfusion method. Then, the solid dispersion, penetration enhancer, and suspending agents were tableted and filled into the capsule. Central composite design-response surface methodology was used to evaluate the influence of factors on the responses. A second-order polynomial model and a multiple linear model were fitted to correlation coefficient of drug release profile and ultimate cumulative release in 12 h, respectively. The actual response values were in good accordance with the predicted ones. The optimized formulation showed a complete drug delivery and zero-order release rate. Beagle dogs were used to be conducted in the pharmacokinetic study. The in vivo study indicated that the relative bioavailability of the novel osmotic pump system was 133.99% compared with the commercial preparation. The novel controlled delivery system with combination of pH-modulated solid dispersion and osmotic pump system is not only a promising strategy to improve the solubility and oral bioavailability of poorly soluble ionizable drugs but also an effective way to reduce dosing frequency and minimize the plasma fluctuation.

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.

Microgels produced using microfluidic on-chip polymer blending for controlled released of VEGF encoding lentivectors.

PubMed

Madrigal, Justin L; Sharma, Shonit N; Campbell, Kevin T; Stilhano, Roberta S; Gijsbers, Rik; Silva, Eduardo A

2018-03-15

Alginate hydrogels are widely used as delivery vehicles due to their ability to encapsulate and release a wide range of cargos in a gentle and biocompatible manner. The release of encapsulated therapeutic cargos can be promoted or stunted by adjusting the hydrogel physiochemical properties. However, the release from such systems is often skewed towards burst-release or lengthy retention. To address this, we hypothesized that the overall magnitude of burst release could be adjusted by combining microgels with distinct properties and release behavior. Microgel suspensions were generated using a process we have termed on-chip polymer blending to yield composite suspensions of a range of microgel formulations. In this manner, we studied how alginate percentage and degradation relate to the release of lentivectors. Whereas changes in alginate percentage had a minimal impact on lentivector release, microgel degradation led to a 3-fold increase, and near complete release, over 10 days. Furthermore, by controlling the amount of degradable alginate present within microgels the relative rate of release can be adjusted. A degradable formulation of microgels was used to deliver vascular endothelial growth factor (VEGF)-encoding lentivectors in the chick chorioallantoic membrane (CAM) assay and yielded a proangiogenic response in comparison to the same lentivectors delivered in suspension. The utility of blended microgel suspensions may provide an especially appealing platform for the delivery of lentivectors or similarly sized therapeutics. Genetic therapeutics hold considerable potential for the treatment of diseases and disorders including ischemic cardiovascular diseases. To realize this potential, genetic vectors must be precisely and efficiently delivered to targeted regions of the body. However, conventional methods of delivery do not provide sufficient spatial and temporal control. Here, we demonstrate how alginate microgels provide a basis for developing systems for controlled genetic vector release. We adjust the physiochemical properties of alginate for quicker or slower release, and we demonstrate how combining distinct formulations of microgels can tune the release of the overall composite microgel suspension. These composite suspensions are generated using a straightforward and powerful application of droplet microfluidics which allows for the real-time generation of a composite suspension. Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

A Microparticle/Hydrogel Combination Drug-Delivery System for Sustained Release of Retinoids

PubMed Central

Gao, Song-Qi; Maeda, Tadao; Okano, Kiichiro; Palczewski, Krzysztof

2012-01-01

Purpose. To design and develop a drug-delivery system containing a combination of poly(d,l-lactide-co-glycolide) (PLGA) microparticles and alginate hydrogel for sustained release of retinoids to treat retinal blinding diseases that result from an inadequate supply of retinol and generation of 11-cis-retinal. Methods. To study drug release in vivo, either the drug-loaded microparticle–hydrogel combination was injected subcutaneously or drug-loaded microparticles were injected intravitreally into Lrat−/− mice. Orally administered 9-cis-retinoids were used for comparison and drug concentrations in plasma were determined by HPLC. Electroretinography (ERG) and both chemical and histologic analyses were used to evaluate drug effects on visual function and morphology. Results. Lrat−/− mice demonstrated sustained drug release from the microparticle/hydrogel combination that lasted 4 weeks after subcutaneous injection. Drug concentrations in plasma of the control group treated with the same oral dose rose to higher levels for 6−7 hours but then dropped markedly by 24 hours. Significantly increased ERG responses and a markedly improved retinal pigmented epithelium (RPE)–rod outer segment (ROS) interface were observed after subcutaneous injection of the drug-loaded delivery combination. Intravitreal injection of just 2% of the systemic dose of drug-loaded microparticles provided comparable therapeutic efficacy. Conclusions. Sustained release of therapeutic levels of 9-cis-retinoids was achieved in Lrat−/− mice by subcutaneous injection in a microparticle/hydrogel drug-delivery system. Both subcutaneous and intravitreal injections of drug-loaded microparticles into Lrat−/− mice improved visual function and retinal structure. PMID:22918645

Formulation, in vitro evaluation and study of variables on tri-layered gastro-retentive delivery system of diltiazem HCl.

PubMed

Raut Desai, Shilpa; Rohera, Bhagwan D

2014-03-01

Tri-layered floating tablets using only one grade of polyethylene oxide (PEO) would enable easy manufacturing, reproducibility and controlled release for highly soluble drugs. To evaluate the potential of PEO as a sole polymer for the controlled release and to study the effect of formulation variables on release and gastric retention of highly soluble Diltiazem hydrochloride (DTZ). Tablets were compressed with middle layer consisting of drug and polymer while outer layers consisted of polymer with sodium bicarbonate. Design of formulation to obtain 12 h, zero-order release and rapid floatation was done by varying the grades, quantity of PEO and sodium bicarbonate. Dissolution data were fitted in drug release models and swelling/erosion studies were undertaken to verify the drug release mechanism. Effect of formulation variables and tablet surface morphology using scanning electron microscopy were studied. The optimized formula passed the criteria of USP dissolution test I and exhibited floating lag-time of 3-4 min. Drug release was faster from low molecular weight (MW) PEO as compared to high MW. With an increase in the amount of sodium bicarbonate, faster buoyancy was achieved due to the increased CO2 gas formation. Drug release followed zero-order and gave a good fit to the Korsmeyer-Peppas model, which suggested that drug release was due to diffusion through polymer swelling. Zero-order, controlled release profile with the desired buoyancy can be achieved by using optimum formula quantities of sodium bicarbonate and polymer. The tri-layered system shows promising delivery of DTZ, and possibly other water-soluble drugs.

Light-triggerable formulations for the intracellular controlled release of biomolecules.

PubMed

Lino, Miguel M; Ferreira, Lino

2018-05-01

New therapies based on the use of biomolecules [e.g., proteins, peptides, and non-coding (nc)RNAs] have emerged during the past few years. Given their instability, adverse effects, and limited ability to cross cell membranes, delivery systems are required to fully reveal their biological potential. Sophisticated nanoformulations responsive to light offer an excellent opportunity for the controlled release of these biomolecules, enabling the control of timing, duration, location, and dosage. In this review, we discuss the design principles for the delivery of biomolecules, in particular proteins and RNA-based therapeutics, by light-triggerable formulations. We further discuss the opportunities offered by these formulations in terms of endosomal escape, as well as their limitations. Copyright © 2018 Elsevier Ltd. All rights reserved.

Implantable microencapsulated dopamine (DA): prolonged functional release of DA in denervated striatal tissue.

PubMed

McRae, A; Hjorth, S; Mason, D; Dillon, L; Tice, T

1990-01-01

Biodegradable controlled-release microcapsule systems made with the biocompatible biodegradable polyester excipient poly [DL-lactide-co-gly-colide] constitute an exciting new technology for drug delivery to the central nervous system (CNS). The present study describes functional observations indicating that implantation of dopamine (DA) microcapsules encapsulated within two different polymer excipients into denervated striatal tissue assures a prolonged release of the transmitter in vivo. This technology has a considerable potential for basic and possibly clinical research.

Porous PLGA microspheres tailored for dual delivery of biomolecules via layer-by-layer assembly.

PubMed

Go, Dewi P; Palmer, Jason A; Mitchell, Geraldine M; Gras, Sally L; O'Connor, Andrea J

2015-05-01

Tissue engineering is a complex and dynamic process that requires varied biomolecular cues to promote optimal tissue growth. Consequently, the development of delivery systems capable of sequestering more than one biomolecule with controllable release profiles is a key step in the advancement of this field. This study develops multilayered polyelectrolyte films incorporating alpha-melanocyte stimulating hormone (α-MSH), an anti-inflammatory molecule, and basic fibroblast growth factor (bFGF). The layers were successfully formed on macroporous poly lactic-co-glycolic acid microspheres produced using a combined inkjet and thermally induced phase separation technique. Release profiles could be varied by altering layer properties including the number of layers and concentrations of layering molecules. α-MSH and bFGF were released in a sustained manner and the bioactivity of α-MSH was shown to be preserved using an activated macrophage cell assay in vitro. The system performance was also tested in vivo subcutaneously in rats. The multilayered microspheres reduced the inflammatory response induced by a carrageenan stimulus 6 weeks after implantation compared to the non-layered microspheres without the anti-inflammatory and growth factors, demonstrating the potential of such multilayered constructs for the controlled delivery of bioactive molecules. © 2014 Wiley Periodicals, Inc.

Micro-porous surfaces in controlled drug delivery systems: design and evaluation of diltiazem hydrochloride controlled porosity osmotic pump using non-ionic surfactants as pore-former.

PubMed

Adibkia, Khosro; Ghanbarzadeh, Saeed; Shokri, Mohammad Hosein; Arami, Zahra; Arash, Zeinab; Shokri, Javad

2014-06-01

The major problem associated with conventional drug delivery systems is unpredictable plasma concentrations. The aim of this study was to design a controlled porosity osmotic pump (CPOP) of diltiazem hydrochloride to deliver the drug in a controlled manner. CPOP tablets were prepared by incorporation of drug in the core and subsequent coating with cellulose acetate as semi-permeable membrane. Non-ionic surfactants were applied as pore-formers as well. The effect of pore-formers concentration on the in vitro release of diltiazem was also studied. The formulations were compared based on four comparative parameters, namely, total drug released after 24 h (D24 h), lag-time (tL), squared correlation coefficient of zero order equation (RSQzero) and mean percent deviation from zero order kinetic (MPDzero). Results of scanning electron microscopy studies exhibited formation of pores in the membrane from where the drug release occurred. It was revealed that drug release rate was directly proportional to the concentration of the pore-formers. The value of D24 h in the formulations containing Tween 80 (10%) and Brij 35 (5%) were found to be more than 94.9%, and drug release followed zero order kinetic (RSQzero > 0.99 and MPDzero < 8%) with acceptable tL (lower than 1 h).

Glutathione- and pH-responsive nonporous silica prodrug nanoparticles for controlled release and cancer therapy

NASA Astrophysics Data System (ADS)

Xu, Zhigang; Liu, Shiying; Kang, Yuejun; Wang, Mingfeng

2015-03-01

A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were covalently encapsulated into silica matrices through glutathione (GSH)-responsive disulfide and pH-responsive hydrazone bonds, respectively, resulting in NPs with sizes tunable in the range of 50-200 nm. Both silica prodrug NPs showed stimuli-responsive controlled release upon exposure to a GSH-rich or acidic environment, resulting in improved anticancer efficacy. Notably, two prodrug NPs simultaneously taken up by HeLa cells showed a remarkable combinatorial efficacy compared to free drug pairs. These results suggest that the stimuli-responsive silica prodrug NPs are promising anticancer drug carriers for efficient cancer therapy.A myriad of drug delivery systems such as liposomes, micelles, polymers and inorganic nanoparticles (NPs) have been developed for cancer therapy. Very few of them, however, have the ability to integrate multiple functionalities such as specific delivery, high circulation stability, controllable release and good biocompatibility and biodegradability in a single system to improve the therapeutic efficacy. Herein, we report two types of stimuli-responsive nonporous silica prodrug NPs towards this goal for controlled release of anticancer drugs and efficient combinatorial cancer therapy. As a proof of concept, anticancer drugs camptothecin (CPT) and doxorubicin (DOX) were covalently encapsulated into silica matrices through glutathione (GSH)-responsive disulfide and pH-responsive hydrazone bonds, respectively, resulting in NPs with sizes tunable in the range of 50-200 nm. Both silica prodrug NPs showed stimuli-responsive controlled release upon exposure to a GSH-rich or acidic environment, resulting in improved anticancer efficacy. Notably, two prodrug NPs simultaneously taken up by HeLa cells showed a remarkable combinatorial efficacy compared to free drug pairs. These results suggest that the stimuli-responsive silica prodrug NPs are promising anticancer drug carriers for efficient cancer therapy. Electronic supplementary information (ESI) available: Experimental details of SSP-CPT and SSP-DOX; 1H NMR and FT-IR spectra; DLS, TEM and SEM images of prodrug NPs; the TEM image, UV-vis absorption and photoluminescence spectra of CPT/DOX NPs; the TEM images of prodrug NPs incubated under physiological conditions; the reaction conditions and structure information of size-controlled prodrug NPs; the IC50 value of free drug and prodrug NPs at different times. See DOI: 10.1039/c5nr00297d

Magnetic alginate microspheres: system for the position controlled delivery of nerve growth factor.

PubMed

Ciofani, Gianni; Raffa, Vittoria; Menciassi, Arianna; Cuschieri, Alfred; Micera, Silvestro

2009-04-01

The use of polymeric carriers containing dispersed magnetic nanocrystalline particles for targeted delivery of drugs in clinical practice has attracted the interest of the scientific community. In this paper a system comprised of alginate microparticles with a core of magnetite and carrying nerve growth factor (NGF) is described. The magnetic properties of these microspheres, typical of superparamagnetic materials, allow precise and controlled delivery to the intended tissue environment. Experiments carried out on PC12 cells with magnetic alginate microspheres loaded with NGF have confirmed the induction of cell differentiation which is strongly dependent on the distance from the microsphere cluster. In addition, finite element modelling (FEM) of the release profile from the microspheres in culture, indicated the possibility of creating defined and predictable NGF gradients from the loaded microspheres. These observations on the carriage and release of growth factors by the proposed microparticles open new therapeutic options for both neuronal regeneration and of the development of effective neuronal interfaces.

Polymer-based delivery systems for support and delivery of bacteriophages

NASA Astrophysics Data System (ADS)

Brown, Alyssa Marie

One of the most urgent problems in the fields of medicine and agriculture is the decreasing effectiveness of antibiotics. Once a miracle drug, antibiotics have recently become associated with the creation of antibiotic-resistant bacteria. The main limitations of these treatments include lack of both adaptability and specificity. To overcome these shortcomings of current antibiotic treatments, there has been a renewed interest in bacteriophage research. Bacteriophages are naturally-occurring viruses that lyse bacteria. They are highly specific, with each bacteriophage type lysing a narrow range of bacteria strains. Bacteriophages are also ubiquitous biological entities, populating environments where bacterial growth is supported. Just as humans are exposed to bacteria in their daily lives, we are exposed to bacteriophages as well. To use bacteriophages in practical applications, they must be delivered to the site of an infection in a controlled-release system. Two systems were studied to observe their support of bacteriophage lytic activity, as well as investigate the possibility of controlling bacteriophage release rates. First, hydrogels were studied, using crosslinking and blending techniques to achieve a range of release profiles. Second, polyanhydride microparticles were studied, evaluating release rates as a function of monomer chemistries.

Mesoporous silica nanoparticle-based intelligent drug delivery system for bienzyme-responsive tumour targeting and controlled release.

PubMed

Zhang, Yang; Xu, Juan

2018-01-01

This paper proposes a novel type of multifunctional envelope-type mesoporous silica nanoparticle (MSN) to achieve cancer cell targeting and drug-controlled release. In this system, MSNs were first modified by active targeting moiety hyaluronic acid (HA) for breast cancer cell targeting and hyaluronidases (Hyal)-induced intracellular drug release. Then gelatin, a proteinaceous biopolymer, was grafted onto the MSNs to form a capping layer via glutaraldehyde-mediated cross-linking. To shield against unspecific uptake of cells and prolong circulation time, the nanoparticles were further decorated with poly(ethylene glycol) polymers (PEG) to obtain MSN@HA-gelatin-PEG (MHGP). Doxorubicin (DOX), as a model drug, was loaded into PEMSN to assess the breast cancer cell targeting and drug release behaviours. In vitro study revealed that PEG chains protect the targeting ligand and shield against normal cells. After reaching the breast cancer cells, MMP-2 overpressed by cells hydrolyses gelatin layer to deshield PEG and switch on the function of HA. As a result, DOX-loaded MHGP was selectively trapped by cancer cells through HA receptor-mediated endocytosis and subsequently release DOX due to Hyal-catalysed degradation of HA. This system presents successful bienzyme-responsive targeting drug delivery in an optimal fashion and provides potential applications for targeted cancer therapy.

The use of thiolated polymers as carrier matrix in oral peptide delivery--proof of concept.

PubMed

Bernkop-Schnürch, Andreas; Pinter, Yvonne; Guggi, Davide; Kahlbacher, Hermann; Schöffmann, Gudrun; Schuh, Maximilian; Schmerold, Ivo; Del Curto, Maria Dorly; D'Antonio, Mauro; Esposito, Pierandrea; Huck, Christian

2005-08-18

It was the aim of this study to develop an oral delivery system for the peptide drug antide. The stability of the therapeutic peptide towards gastrointestinal peptidases was evaluated. The therapeutic agent and the permeation mediator glutathione were embedded in the thiolated polymer chitosan-4-thio-butylamidine conjugate (chitosan-TBA conjugate) and compressed to tablets. Drug release studies were performed in the dissolution test apparatus according to the Pharmacopoeia Europea using the paddle method and demineralized water as release medium. In order to avoid mucoadhesion of these delivery systems already in the oral cavity and oesophagus tablets were coated with a triglyceride. These tablets were orally given to pigs (weight: 50+/-2 kg; Edelschwein Pietrain). Moreover, antide was administered intravenously, subcutaneously and orally in solution. Results showed stability of antide towards pepsin, trypsin and chymotrypsin. In contrast, antide was rapidly degraded by elastase. Consequently a stomach-targeted delivery system was designed. Drug release studies demonstrated an almost zero-order controlled release of antide over 8 h. In vivo studies demonstrated a relative bioavailability of 34.4% for the subcutaneous administration. Oral administration of antide in solution led to no detectable concentrations of the drug in plasma at all. In contrast, administering antide being incorporated in the thiolated polymer resulted in a significant uptake of the peptide. The absolute and relative bioavailability was determined to be 1.1% and 3.2%, respectively.

Drug Release Kinetics and Transport Mechanisms of Non-degradable and Degradable Polymeric Delivery Systems

PubMed Central

Fu, Yao; Kao, Weiyuan John

2010-01-01

Importance of the field The advancement in material design and engineering has led to the rapid development of novel materials with increasing complexity and functions. Both non-degradable and degradable polymers have found wide applications in the controlled delivery field. Studies on drug release kinetics provide important information into the function of material systems. To elucidate the detailed transport mechanism and the structure-function relationship of a material system, it is critical to bridge the gap between the macroscopic data and the transport behavior at the molecular level. Areas covered in this review The structure and function information of selected non-degradable and degradable polymers have been collected and summarized from literatures published after 1990s. The release kinetics of selected drug compounds from various material systems will be discussed in case studies. Recent progresses in the mathematical models based on different transport mechanisms will be highlighted. What the reader will gain This article aims to provide an overview of structure-function relationships of selected non-degradable and degradable polymers as drug delivery matrices. Take home message Understanding the structure-function relationship of the material system is key to the successful design of a delivery system for a particular application. Moreover, developing complex polymeric matrices requires more robust mathematical models to elucidate the solute transport mechanisms. PMID:20331353

Controlled release of bioactive PDGF-AA from a hydrogel/nanoparticle composite.

PubMed

Elliott Donaghue, Irja; Shoichet, Molly S

2015-10-01

Polymer excipients, such as low molar mass poly(ethylene glycol) (PEG), have shown contradictory effects on protein stability when co-encapsulated in polymeric nanoparticles. To gain further insight into these effects, platelet-derived growth factor (PDGF-AA) was encapsulated in polymeric nanoparticles with vs. without PEG. PDGF-AA is a particularly compelling protein, as it has been demonstrated to promote cell survival and induce the oligodendrocyte differentiation of neural stem/progenitor cells (NSPCs) both in vitro and in vivo. Here we show, for the first time, the controlled release of bioactive PDGF-AA from an injectable nanoparticle/hydrogel drug delivery system (DDS). PDGF-AA was encapsulated, with high efficiency, in poly(lactide-co-glycolide) nanoparticles, and its release from the drug delivery system was followed over 21 d. Interestingly, the co-encapsulation of low molecular weight poly(ethylene glycol) increased the PDGF-AA loading but, unexpectedly, accelerated the aggregation of PDGF-AA, resulting in reduced activity and detection by enzyme-linked immunosorbent assay (ELISA). In the absence of PEG, released PDGF-AA remained bioactive as demonstrated with NSPC oligodendrocyte differentiation, similar to positive controls, and significantly different from untreated controls. This work presents a novel delivery method for differentiation factors, such as PDGF-AA, and provides insights into the contradictory effects reported in the literature of excipients, such as PEG, on the loading and release of proteins from polymeric nanoparticles. Previously, the polymer poly(ethylene glycol) (PEG) has been used in many biomaterials applications, from surface coatings to the encapsulation of proteins. In this work, we demonstrate that, unexpectedly, low molecular weight PEG has a deleterious effect on the release of the encapsulated protein platelet-derived growth factor AA (PDGF-AA). We also demonstrate release of bioactive PDGF-AA (in the absence of PEG). Specifically, we demonstrate the differentiation of neural stem and progenitor cells to oligodendrocytes, similar to what is observed with the addition of fresh PDGFAA. A differentiated oligodendrocyte population is a key strategy in central nervous system regeneration. This work is the first demonstration of controlled PDGF-AA release, and also brings new insights to the broader field of protein encapsulation. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Development and Characterization of Liquid Crystal-Gold Nanoparticle Hybrid Materials for Optical Applications

NASA Astrophysics Data System (ADS)

Quint, Makiko T.

Hybrid material, mixtures of two or more materials with new properties, represents an exciting class of new materials for a variety of potential applications such as displays, optoelectronics, and sensors due to their unique physical and optical properties. The scope of this dissertation is to produce two new plasmonic applications by combining liquid crystals with gold nanoparticles. The first application is gold nanoparticle coated liquid crystal thin film. Most liquid crystal (LC) thin films require external voltage to reorient LC molecules. Recent advances in optical controlling technology of LC molecule behavior, resulting in the reduction of energy consumption, have stimulated research and development of new LC thin films. In order to re-orient LC molecules by just using light, the common approach is to include either a photo-responsive LC host, one that require high power light and severely narrows the range of usable materials, or add photo-active dye or polymer layer, photodegradation over time. Our work designing an all-optical method for LC re-orientation that overcomes all the limitations mentioned above. We have successfully both in- and out-of-plane spatial orientation of nematic liquid crystal (LC) molecules by leveraging the highly localized electric fields produced in the near-field regime of a gold nanoparticle (AuNP) layer. This re-orientation of LC molecules in thin LC-AuNP film is all-optical, driven by a small resonance excitation power with the localized surface plasmon absorption of the AuNPs at room temperature. The second application is LC mediated nano-assembled gold microcapsules. This application has a potential in controlled-release cargo-style delivery system. Targeted delivery systems with controlled release mechanisms have been the subject of extensive research more than fifty years. One is to control the release process remotely by using optical excitation. Optical actuation of delivery capsules, which plasmonic nanoparticle such as gold, allows rapid release at specific locations and uses the photothermal effect to unload contents. Almost all gold-based delivery applications including Au coated nanocrystals or AuNPs with soft materials like gels and polymers are not suitable for control release applications in real life since these applications do not provide robust leakage-free containment lower than the American National Standards Institute (ANSI) maximum permissible light exposure limit. We have successfully managed the difficulties mentioned above and produced a new gold-based delivery application. The application is spherical capsules with a densely packed wall of AuNPs. The rigid capsule wall allows encapsulation of cargo that can be contained, virtually leakage-free, over several months. Further, by leveraging LSPR of AuNPs, we can rupture the microshells using optical excitation with ultralow power (< 2 mW), controllably and rapidly releasing the encapsulated contents in less than 5 seconds. Our results exhibiting the capture and optically regulated release of encapsulated substances are a novel platform that combines controlled-release cargo-style delivery and photothermal therapy in one versatile and multifunctional unit. Both our applications are overcoming current limitations and promising future research directions towards the next generation of LC-AuNPs hybrid material research and developments.

Technologies for Controlled, Local Delivery of siRNA

PubMed Central

Sarett, Samantha M.; Nelson, Christopher E.; Duvall, Craig L.

2015-01-01

The discovery of RNAi in the late 1990s unlocked a new realm of therapeutic possibilities by enabling potent and specific silencing of theoretically any desired genetic target. Better elucidation of the mechanism of action, the impact of chemical modifications that stabilize and reduce nonspecific effects of siRNA molecules, and the key design considerations for effective delivery systems has spurred progress toward developing clinically-successful siRNA therapies. A logical aim for initial siRNA translation is local therapies, as delivering siRNA directly to its site of action helps to ensure that a sufficient dose reaches the target tissue, lessens the potential for off-target side effects, and circumvents the substantial systemic delivery barriers. While topical siRNA delivery has progressed into numerous clinical trials, an enormous opportunity also exists to develop sustained-release, local delivery systems that enable both spatial and temporal control of gene silencing. This review focuses on material platforms that establish both localized and controlled gene silencing, with emphasis on the systems that show most promise for clinical translation. PMID:26476177

Release of Cyclic Phosphatidic Acid from Gelatin-based Hydrogels Inhibit Colon Cancer Cell Growth and Migration

PubMed Central

Tsukahara, Tamotsu; Murakami-Murofushi, Kimiko

2012-01-01

Microparticle and nanoparticle formulations are widely used to improve the bioavailability of low-solubility drugs and as vehicles for organ- and tissue-specific targeted drug delivery. We investigated the effect of a novel, controlled-release form of a bioactive lipid, cyclic phosphatidic acid (cPA), on human colon cancer cell line functions. We encapsulated cPA in gelatin-based hydrogels and examined its ability to inhibit the viability and migration of HT-29 and DLD-1 cells in vitro and the LPA-induced activity of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). The hydrogel delivery system prolonged cPA release into the culture medium. Accordingly, cPA-hydrogel microspheres substantially inhibited LPA-induced PPARγ activity and cell growth and migration compared with that of cells cultured with cPA alone. Thus, hydrogel microspheres are a potential system for stable and efficient delivery of bioactive lipids such as cPA and may offer a new strategy for targeted colon cancer treatment. PMID:23008752

Nanocomposite Hydrogels: 3D Polymer-Nanoparticle Synergies for On-Demand Drug Delivery.

PubMed

Merino, Sonia; Martín, Cristina; Kostarelos, Kostas; Prato, Maurizio; Vázquez, Ester

2015-05-26

Considerable progress in the synthesis and technology of hydrogels makes these materials attractive structures for designing controlled-release drug delivery systems. In particular, this review highlights the latest advances in nanocomposite hydrogels as drug delivery vehicles. The inclusion/incorporation of nanoparticles in three-dimensional polymeric structures is an innovative means for obtaining multicomponent systems with diverse functionality within a hybrid hydrogel network. Nanoparticle-hydrogel combinations add synergistic benefits to the new 3D structures. Nanogels as carriers for cancer therapy and injectable gels with improved self-healing properties have also been described as new nanocomposite systems.

Colon-specific delivery of 5-aminosalicylic acid from chitosan-Ca-alginate microparticles.

PubMed

Mladenovska, K; Raicki, R S; Janevik, E I; Ristoski, T; Pavlova, M J; Kavrakovski, Z; Dodov, M G; Goracinova, K

2007-09-05

Chitosan-Ca-alginate microparticles for colon-specific delivery and controlled release of 5-aminosalicylic acid after peroral administration were prepared using spray drying method followed by ionotropic gelation/polyelectrolyte complexation. Physicochemical characterization pointed to the negatively charged particles with spherical morphology having a mean diameter less than 9 microm. Chitosan was localized dominantly in the particle wall, while for alginate, a homogeneous distribution throughout the particles was observed. (1)H NMR, FTIR, X-ray and DSC studies indicated molecularly dispersed drug within the particles with preserved stability during microencapsulation and in simulated in vivo drug release conditions. In vitro drug release studies carried out in simulated in vivo conditions in respect to pH, enzymatic and salt content confirmed the potential of the particles to release the drug in a controlled manner. The diffusional exponents according to the general exponential release equation indicated anomalous (non-Fickian) transport in 5-ASA release controlled by a polymer relaxation, erosion and degradation. Biodistribution studies of [(131)I]-5-ASA loaded chitosan-Ca-alginate microparticles, carried out within 2 days after peroral administration to Wistar male rats in which TNBS colitis was induced, confirmed the dominant localization of 5-ASA in the colon with low systemic bioavailability.

pH-Responsive carriers for oral drug delivery: challenges and opportunities of current platforms.

PubMed

Liu, Lin; Yao, WenDong; Rao, YueFeng; Lu, XiaoYang; Gao, JianQing

2017-11-01

Oral administration is a desirable alternative of parenteral administration due to the convenience and increased compliance to patients, especially for chronic diseases that require frequent administration. The oral drug delivery is a dynamic research field despite the numerous challenges limiting their effective delivery, such as enzyme degradation, hydrolysis and low permeability of intestinal epithelium in the gastrointestinal (GI) tract. pH-Responsive carriers offer excellent potential as oral therapeutic systems due to enhancing the stability of drug delivery in stomach and achieving controlled release in intestines. This review provides a wide perspective on current status of pH-responsive oral drug delivery systems prepared mainly with organic polymers or inorganic materials, including the strategies used to overcome GI barriers, the challenges in their development and future prospects, with focus on technology trends to improve the bioavailability of orally delivered drugs, the mechanisms of drug release from pH-responsive oral formulations, and their application for drug delivery, such as protein and peptide therapeutics, vaccination, inflammatory bowel disease (IBD) and bacterial infections.

Recent Advances in Drug Eluting Stents

PubMed Central

Puranik, Amey S.; Dawson, Eileen R.; Peppas, Nicholas A.

2013-01-01

One of the most common medical interventions to reopen an occluded vessel is the implantation of a coronary stent. While this method of treatment is effective initially, restenosis, or the re-narrowing of the artery frequently occurs largely due to neointimal hyperplasia of smooth muscle cells. Drug eluting stents were developed in order to provide local, site-specific, controlled release of drugs that can inhibit neointima formation. By implementing a controlled release delivery system it may be possible to control the time release of the pharmacological factors and thus be able to bypass some of the critical events associated with stent hyperplasia and prevent the need for subsequent intervention. However, since the advent of first-generation drug eluting stents, long-term adverse effects have raised concerns regarding their safety. These limitations in safety and efficacy have triggered considerable research in developing biodegradable stents and more potent drug delivery systems. In this review, we shed light on the current state-of-the-art in drug eluting stents, problems related to them and highlight some of the ongoing research in this area. PMID:23117022

Long-Term Delivery of Protein Therapeutics

PubMed Central

Vaishya, Ravi; Khurana, Varun; Patel, Sulabh; Mitra, Ashim K

2015-01-01

Introduction Proteins are effective biotherapetics with applications in diverse ailments. Despite being specific and potent, their full clinical potential has not yet been realized. This can be attributed to short half-lives, complex structures, poor in vivo stability, low permeability frequent parenteral administrations and poor adherence to treatment in chronic diseases. A sustained release system, providing controlled release of proteins, may overcome many of these limitations. Areas covered This review focuses on recent development in approaches, especially polymer-based formulations, which can provide therapeutic levels of proteins over extended periods. Advances in particulate, gel based formulations and novel approaches for extended protein delivery are discussed. Emphasis is placed on dosage form, method of preparation, mechanism of release and stability of biotherapeutics. Expert opinion Substantial advancements have been made in the field of extended protein delivery via various polymer-based formulations over last decade despite the unique delivery-related challenges posed by protein biologics. A number of injectable sustained-release formulations have reached market. However, therapeutic application of proteins is still hampered by delivery related issues. A large number of protein molecules are under clinical trials and hence there is an urgent need to develop new methods to deliver these highly potent biologics. PMID:25251334

Long-term delivery of protein therapeutics.

PubMed

Vaishya, Ravi; Khurana, Varun; Patel, Sulabh; Mitra, Ashim K

2015-03-01

Proteins are effective biotherapeutics with applications in diverse ailments. Despite being specific and potent, their full clinical potential has not yet been realized. This can be attributed to short half-lives, complex structures, poor in vivo stability, low permeability, frequent parenteral administrations and poor adherence to treatment in chronic diseases. A sustained release system, providing controlled release of proteins, may overcome many of these limitations. This review focuses on recent development in approaches, especially polymer-based formulations, which can provide therapeutic levels of proteins over extended periods. Advances in particulate, gel-based formulations and novel approaches for extended protein delivery are discussed. Emphasis is placed on dosage form, method of preparation, mechanism of release and stability of biotherapeutics. Substantial advancements have been made in the field of extended protein delivery via various polymer-based formulations over last decade despite the unique delivery-related challenges posed by protein biologics. A number of injectable sustained-release formulations have reached market. However, therapeutic application of proteins is still hampered by delivery-related issues. A large number of protein molecules are under clinical trials, and hence, there is an urgent need to develop new methods to deliver these highly potent biologics.

Preparation and in vitro evaluation of guar gum based triple-layer matrix tablet of diclofenac sodium

PubMed Central

Chavda, H.V.; Patel, M.S.; Patel, C.N.

2012-01-01

The objective of the present study was to design an oral controlled drug delivery system for sparingly soluble diclofenac sodium (DCL) using guar gum as triple-layer matrix tablets. Matrix tablet granules containing 30% (D1), 40% (D2) or 50% (D3) of guar gum were prepared by the conventional wet granulation technique. Matrix tablets of diclofenac sodium were prepared by compressing three layers one by one. Centre layer of sandwich like structure was incorporated with matrix granules containing DCL which was covered on either side by guar gum granule layers containing either 70, 80 or 87% of guar gum as release retardant layers. The tablets were evaluated for hardness, thickness, drug content, and drug release studies. To ascertain the kinetics of drug release, the dissolution profiles were fitted to various mathematical models. The in vitro drug release from proposed system was best explained by the Hopfenberg model indicating that the release of drug from tablets displayed heterogeneous erosion. D3G3, containing 87% of guar gum in guar gum layers and 50% of guar gum in DCL matrix granule layer was found to provide the release rate for prolonged period of time. The results clearly indicate that guar gum could be a potential hydrophilic carrier in the development of oral controlled drug delivery systems. PMID:23181081

Extended ocular drug delivery systems for the anterior and posterior segments: biomaterial options and applications.

PubMed

Kang-Mieler, Jennifer J; Dosmar, Emily; Liu, Wenqiang; Mieler, William F

2017-05-01

The development of new therapies for treating various eye conditions has led to a demand for extended release delivery systems, which would lessen the need for frequent application while still achieving therapeutic drug levels in the target tissues. Areas covered: Following an overview of the different ocular drug delivery modalities, this article surveys the biomaterials used to develop sustained release drug delivery systems. Microspheres, nanospheres, liposomes, hydrogels, and composite systems are discussed in terms of their primary materials. The advantages and disadvantages of each drug delivery system are discussed for various applications. Recommendations for modifications and strategies for improvements to these basic systems are also discussed. Expert opinion: An ideal sustained release drug delivery system should be able to encapsulate and deliver the necessary drug to the target tissues at a therapeutic level without any detriment to the drug. Drug encapsulation should be as high as possible to minimize loss and unless it is specifically desired, the initial burst of drug release should be kept to a minimum. By modifying various biomaterials, it is possible to achieve sustained drug delivery to both the anterior and posterior segments of the eye.

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.

Recent Advances in Stimuli-Responsive Release Function Drug Delivery Systems for Tumor Treatment.

PubMed

Ding, Chendi; Tong, Ling; Feng, Jing; Fu, Jiajun

2016-12-20

Benefiting from the development of nanotechnology, drug delivery systems (DDSs) with stimuli-responsive controlled release function show great potential in clinical anti-tumor applications. By using a DDS, the harsh side effects of traditional anti-cancer drug treatments and damage to normal tissues and organs can be avoided to the greatest extent. An ideal DDS must firstly meet bio-safety standards and secondarily the efficiency-related demands of a large drug payload and controlled release function. This review highlights recent research progress on DDSs with stimuli-responsive characteristics. The first section briefly reviews the nanoscale scaffolds of DDSs, including mesoporous nanoparticles, polymers, metal-organic frameworks (MOFs), quantum dots (QDs) and carbon nanotubes (CNTs). The second section presents the main types of stimuli-responsive mechanisms and classifies these into two categories: intrinsic (pH, redox state, biomolecules) and extrinsic (temperature, light irradiation, magnetic field and ultrasound) ones. Clinical applications of DDS, future challenges and perspectives are also mentioned.

Interpenetrating Polymer Networks as Innovative Drug Delivery Systems

PubMed Central

Lohani, Alka; Singh, Garima; Bhattacharya, Shiv Sankar; Verma, Anurag

2014-01-01

Polymers have always been valuable excipients in conventional dosage forms, also have shown excellent performance into the parenteral arena, and are now capable of offering advanced and sophisticated functions such as controlled drug release and drug targeting. Advances in polymer science have led to the development of several novel drug delivery systems. Interpenetrating polymer networks (IPNs) have shown superior performances over the conventional individual polymers and, consequently, the ranges of applications have grown rapidly for such class of materials. The advanced properties of IPNs like swelling capacity, stability, biocompatibility, nontoxicity and biodegradability have attracted considerable attention in pharmaceutical field especially in delivering bioactive molecules to the target site. In the past few years various research reports on the IPN based delivery systems showed that these carriers have emerged as a novel carrier in controlled drug delivery. The present review encompasses IPNs, their types, method of synthesis, factors which affects the morphology of IPNs, extensively studied IPN based drug delivery systems, and some natural polymers widely used for IPNs. PMID:24949205

Light-Induced Acid Generation on a Gatekeeper for Smart Nitric Oxide Delivery.

PubMed

Choi, Hyung Woo; Kim, Jihoon; Kim, Jinhwan; Kim, Yonghwi; Song, Hyun Beom; Kim, Jeong Hun; Kim, Kimoon; Kim, Won Jong

2016-04-26

We report herein the design of a light-responsive gatekeeper for smart nitric oxide (NO) delivery. The gatekeeper is composed of a pH-jump reagent as an intermediary of stimulus and a calcium phosphate (CaP) coating as a shielding layer for NO release. The light irradiation and subsequent acid generation are used as triggers for uncapping the gatekeeper and releasing NO. The acids generated from a light-activated pH-jump agent loaded in the mesoporous nanoparticles accelerated the degradation of the CaP-coating layers on the nanoparticles, facilitating the light-responsive NO release from diazeniumdiolate by exposing a NO donor to physiological conditions. Using the combination of the pH-jump reagent and CaP coating, we successfully developed a light-responsive gatekeeper system for spatiotemporal-controlled NO delivery.

Antibacterial, anti-inflammatory, and bone-regenerative dual-drug-loaded calcium phosphate nanocarriers-in vitro and in vivo studies.

PubMed

Madhumathi, K; Rubaiya, Y; Doble, Mukesh; Venkateswari, R; Sampath Kumar, T S

2018-05-01

A dual local drug delivery system (DDS) composed of calcium phosphate bioceramic nanocarriers aimed at treating the antibacterial, anti-inflammatory, and bone-regenerative aspects of periodontitis has been developed. Calcium-deficient hydroxyapatite (CDHA, Ca/P = 1.61) and tricalcium phosphate (β-TCP) were prepared by microwave-accelerated wet chemical synthesis method. The phase purity of the nanocarriers was confirmed by x-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), while the transmission electron microscopy (TEM) confirmed their nanosized morphology. CDHA was selected as carrier for the antibiotic (tetracycline) while TCP was chosen as the anti-inflammatory drug (ibuprofen) carrier. Combined drug release profile was studied in vitro from CDHA/TCP (CTP) system and compared with a HA/TCP (BCP) biphasic system. The tetracycline and ibuprofen release rate was 71 and 23% from CTP system as compared to 63 and 20% from BCP system. CTP system also showed a more controlled drug release profile compared to BCP system. Modeling of drug release kinetics from CTP system indicated that the release follows Higuchi model with a non-typical Fickian diffusion profile. In vitro biological studies showed the CTP system to be biocompatible with significant antibacterial and anti-inflammatory activity. In vivo implantation studies on rat cranial defects showed greater bone healing and new bone formation in the drug-loaded CTP system compared to control (no carrier) at the end of 12 weeks. The in vitro and in vivo results suggest that the combined drug delivery platform can provide a comprehensive management for all bone infections requiring multi-drug therapy.

Use of fibrin sealants for the localized, controlled release of cefazolin

PubMed Central

Tredwell, Stephen; Jackson, John K.; Hamilton, Donald; Lee, Vivian; Burt, Helen M.

2006-01-01

Background Fibrin sealants are used increasingly in surgery to reduce bleeding and improve wound healing. They have great potential as biocompatible, biodegradable drug delivery systems, because the sealant may adhere to the target tissue and allow controlled release of the drug over an extended period. We investigated the encapsulation, stability and controlled release of erythromycin and cefazolin from Beriplast fibrin sealants (Aventis Behring Canada). Methods Drug-loaded clots were cast in glass vials and allowed to set. We observed the clots for drug precipitation and aggregation, and we assessed the effect of drug encapsulation on clot strength. Drug stability and release from the clots in phosphate buffered saline (PBS) was quantified by ultraviolet and visible violet absorbance spectroscopy and high-performance liquid chromatography. Results Erythromycin was found to release slowly from the fibrin clots over the first 2 hours but then degrade rapidly. Cefazolin was found to be very stable in clots in PBS (97% stable at 2 d and 93% stable at 5 d). The drug released in a controlled manner over 2 days, with most being released during the first day. The dose of drug released could be varied by changing the amount placed in the thrombin solution. Clot thickness had no effect on the rate of cefazolin release. Conclusion Overall, the 2-day release profile and the excellent stability of the drug suggest that cefazolin-loaded fibrin sealants may offer an effective route of postoperative antibiotic delivery. PMID:17152573

Synthesis and Characterisation of Photocrosslinked poly(ethylene glycol) diacrylate Implants for Sustained Ocular Drug Delivery.

PubMed

McAvoy, Kathryn; Jones, David; Thakur, Raghu Raj Singh

2018-01-16

To investigate the sustained ocular delivery of small and large drug molecules from photocrosslinked poly(ethylene glycol) diacrylate (PEGDA) implants with varying pore forming agents. Triamcinolone acetonide and ovalbumin loaded photocrosslinked PEGDA implants, with or without pore-forming agents, were fabricated and characterised for chemical, mechanical, swelling, network parameters, as well as drug release and biocompatibility. HPLC-based analytical methods were employed for analysis of two molecules; ELISA was used to demonstrate bioactivity of ovalbumin. Regardless of PEGDA molecular weight or pore former composition all implants loaded with triamcinolone acetonide released significantly faster than those loaded with ovalbumin. Higher molecular weight PEGDA systems (700 Da) resulted in faster drug release of triamcinolone acetonide than their 250 Da counterpart. All ovalbumin released over the 56-day time period was found to be bioactive. Increasing PEGDA molecular weight resulted in increased system swelling, decreased crosslink density (Ve), increased polymer-water interaction parameter (χ), increased average molecular weight between crosslinks (Mc) and increased mesh size (ε). SEM studies showed the porosity of implants increased with increasing PEGDA molecular weight. Biocompatibility showed both PEGDA molecular weight implants were non-toxic when exposed to retinal epithelial cells over a 7-day period. Photocrosslinked PEGDA implant based systems are capable of controlled drug release of both small and large drug molecules through adaptations in the polymer system network. We are currently continuing evaluation of these systems as potential sustained drug delivery devices.

Controlled release of metronidazole from composite poly-ε-caprolactone/alginate (PCL/alginate) rings for dental implants.

PubMed

Lan, Shih-Feng; Kehinde, Timilehin; Zhang, Xiangming; Khajotia, Sharukh; Schmidtke, David W; Starly, Binil

2013-06-01

Dental implants provide support for dental crowns and bridges by serving as abutments for the replacement of missing teeth. To prevent bacterial accumulation and growth at the site of implantation, solutions such as systemic antibiotics and localized delivery of bactericidal agents are often employed. The objective of this study was to demonstrate a novel method of controlled localized delivery of antibacterial agents to an implant site using a biodegradable custom fabricated ring. The study involved incorporating a model antibacterial agent (metronidazole) into custom designed poly-ε-caprolactone/alginate (PCL/alginate) composite rings to produce the intended controlled release profile. The rings can be designed to fit around the body of any root form dental implants of various diameters, shapes and sizes. In vitro release studies indicate that pure (100%) alginate rings exhibited an expected burst release of metronidazole in the first few hours, whereas Alginate/PCL composite rings produced a medium burst release followed by a sustained release for a period greater than 4 weeks. By varying the PCL/alginate weight ratios, we have shown that we can control the amount of antibacterial agents released to provide the minimal inhibitory concentration (MIC) needed for adequate protection. The fabricated composite rings have achieved a 50% antibacterial agent release profile over the first 48 h and the remaining amount slowly released over the remainder of the study period. The PCL/alginate agent release characteristic fits the Ritger-Peppas model indicating a diffusion-based mechanism during the 30-day study period. The developed system demonstrates a controllable drug release profile and the potential for the ring to inhibit bacterial biofilm growth for the prevention of diseases such as peri-implantitis resulting from bacterial infection at the implant site. Copyright © 2013 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Rumen-stable delivery systems.

PubMed

Papas; Wu

1997-12-08

Ruminants have a distinct digestive system which serves a unique symbiotic relationship between the host animal and predominantly anaerobic rumen bacteria and protozoa. Rumen fermentation can be both beneficial by enabling utilization of cellulose and non-protein nitrogen and detrimental by reducing the nutritive value of some carbohydrates, high biological value proteins and by hydrogenating unsaturated lipids. In addition it can also result in the modification and inactivation of many pharmacologically active ingredients administered to the host animal via the oral route. The advances in ruminant nutrition and health demand a rumen-stable delivery system which can deliver the active ingredient post-ruminally while simultaneously meet efficacy, safety and cost criteria. In contrast to drug delivery systems for humans, the demand for low-cost has hindered the development of effective rumen-stable delivery systems. Historically, heat and chemical treatment of feed components, low solubility analogues or lipid-based formulations have been used to achieve some degree of rumen-stability, and products have been developed accordingly. Recently, a polymeric pH-dependent rumen-stable delivery system has been developed and commercialized. The rationale of this delivery system is based on the pH difference between ruminal and abomasal fluids. The delivery system is composed of a basic polymer, a hydrophobic substance and a pigment material. It can be applied as a coating to solid particles via a common encapsulation method such as air-suspension coating. In the future, the delivery system could be used to deliver micronutrients and pharmaceuticals post-ruminally to ruminant animals. A further possible application of the delivery system is that it could also be combined with other controlled delivery devices/systems in order to enhance slow release or to achieve targeted delivery needs for ruminants. This paper discusses the rumen protection and the abomasal release mechanism of the polymeric coating. It also reviews other rumen stable delivery systems and methods for evaluating their in vitro and in vivo performance.

Novel sol-gel organic-inorganic hybrid materials for drug delivery.

PubMed

Catauro, Michelina; Verardi, Duilio; Melisi, Daniela; Belotti, Federico; Mustarelli, Piercarlo

2010-01-01

The aim of the present study was to synthetize and characterize novel sol-gel organic-inorganic hybrid materials to be used for controlled drug delivery application. Organic-inorganic hybrid class I materials based on poly(epsilon-caprolactone) (PCL 6, 12, 24 and 50 wt%) and zirconia-yttria (ZrO2-5%Y2O3) were synthesized by a sol-gel method, from a multicomponent solution containing zirconium propoxide [Zr(OC2H7)4], yttrium chloride (YCl3), PCL, water and chloroform (CHCl3). The structure of the hybrids was obtained by means of hydrogen bonds between the Zr-OH group (H-donor) in the sol-gel intermediate species and the carboxylic group (H-acceptor) in the repeating units of the polymer. The presence of hydrogen bonds between organic-inorganic components of the hybrid materials was suggested by Fourier transform infrared (FTIR) analysis, and strongly supported by solid-state NMR. A single-step, sol-gel process was then used to precipitate microspheres containing ketoprofen or indomethacin for controlled drug delivery applications. Release kinetics in a simulated body fluid (SBF) were subsequently investigated. The amount of drug released was detected by UV-VIS spectroscopy. Pure anti-inflammatory agents exhibited linear release with time, in contrast drugs entrapped in the organic-inorganic hybrids were released with a logarithmic time dependence, starting with an initial burst effect followed by a gradual decrease. The synthesis of amorphous materials containing drugs, obtained by sol-gel methods, helps to devise new strategies for controlled drug delivery system design.

Fabrication of core-shell nanofibers for controlled delivery of bromelain and salvianolic acid B for skin regeneration in wound therapeutics.

PubMed

Shoba, Ekambaram; Lakra, Rachita; Syamala Kiran, Manikantan; Korrapati, Purna Sai

2017-06-05

The physiological and pathological complexity of the wound healing process makes it more challenging to design an ideal tissue regeneration scaffold. Precise scaffolding with high drug loading efficiency, efficient intracellular efficacy for therapeutic delivery, minimal nonspecific cellular and blood protein binding, and maximum biocompatibility forms the basis for an ideal delivery system. This paper describes a combinational multiphasic delivery system, where biomolecules are delivered through the fabrication of coaxial electrospinning of different biocompatible polymers. The ratio and specificity of polymers for specific biofunction are optimized and the delivery system is completely characterized with reference to the mechanical property and structural integrity of bromelain (debridement enzyme) and salvianolic acid B (pro-angiogenesis and re-epithelialization). The in vitro release profile illustrated the sustained release of debriding protease and bioactive component in a timely fashion. The fabricated scaffold showed angiogenic potential through in vitro migration of endothelial cells and increased new capillaries from the existing blood vessel in response to an in ovo chicken chorioallantoic membrane assay. In addition, in vivo studies confirm the efficacy of the fabricated scaffold. Our results therefore open up a new avenue for designing a bioactive combinational multiphasic delivery system to enhance wound healing.

Sericin/Dextran Injectable Hydrogel as an Optically Trackable Drug Delivery System for Malignant Melanoma Treatment.

PubMed

Liu, Jia; Qi, Chao; Tao, Kaixiong; Zhang, Jinxiang; Zhang, Jian; Xu, Luming; Jiang, Xulin; Zhang, Yunti; Huang, Lei; Li, Qilin; Xie, Hongjian; Gao, Jinbo; Shuai, Xiaoming; Wang, Guobin; Wang, Zheng; Wang, Lin

2016-03-01

Severe side effects of cancer chemotherapy prompt developing better drug delivery systems. Injectable hydrogels are an effective site-target system. For most of injectable hydrogels, once delivered in vivo, some properties including drug release and degradation, which are critical to chemotherapeutic effects and safety, are challenging to monitor. Developing a drug delivery system for effective cancer therapy with in vivo real-time noninvasive trackability is highly desired. Although fluorescence dyes are used for imaging hydrogels, the cytotoxicity limits their applications. By using sericin, a natural photoluminescent protein from silk, we successfully synthesized a hydrazone cross-linked sericin/dextran injectable hydrogel. This hydrogel is biodegradable and biocompatible. It achieves efficient drug loading and controlled release of both macromolecular and small molecular drugs. Notably, sericin's photoluminescence from this hydrogel is directly and stably correlated with its degradation, enabling long-term in vivo imaging and real-time monitoring of the remaining drug. The hydrogel loaded with Doxorubicin significantly suppresses tumor growth. Together, the work demonstrates the efficacy of this drug delivery system, and the in vivo effectiveness of this sericin-based optical monitoring strategy, providing a potential approach for improving hydrogel design toward optimal efficiency and safety of chemotherapies, which may be widely applicable to other drug delivery systems.

Ion-Responsive Drug Delivery Systems.

PubMed

Yoshida, Takayuki; Shakushiro, Kohsuke; Sako, Kazuhiro

2018-02-08

Some kinds of cations and anions are contained in body fluids such as blood, interstitial fluid, gastrointestinal juice, and tears at relatively high concentration. Ionresponsive drug delivery is available to design the unique dosage formulations which provide optimized drug therapy with effective, safe and convenient dosing of drugs. The objective of the present review was to collect, summarize, and categorize recent research findings on ion-responsive drug delivery systems. Ions in body fluid/formulations caused structural changes of polymers/molecules contained in the formulations, allow formulations exhibit functions. The polymers/molecules responding to ions were ion-exchange resins/fibers, anionic or cationic polymers, polymers exhibiting transition at lower critical solution temperature, self-assemble supramolecular systems, peptides, and metalorganic frameworks. The functions of ion-responsive drug delivery systems were categorized to controlled drug release, site-specific drug release, in situ gelation, prolonged retention at the target sites, and enhancement of drug permeation. Administration of the formulations via oral, ophthalmic, transdermal, and nasal routes has showed significant advantages in the recent literatures. Many kinds of drug delivery systems responding to ions have been reported recently for several administration routes. Improvement and advancement of these systems can maximize drugs potential and contribute to patients in the world. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Formulation and evaluation of controlled release antibiotic biodegradable implants for post operative site delivery.

PubMed

Mathur, Vijay; Mudnaik, Rajesh; Barde, Laxmikant; Roy, Arghya; Shivhare, Umesh; Bhusari, Kishore

2010-03-01

Biodegradable implants of ciprofloxacin hydrochloride for post operative site delivery were prepared using glyceryl monostearate and different concentrations of polyethylene glycol (PEG 6000), glycerol and Tween 80 as erosion enhancers by compression and molding technique. Formulations were subjected to in vitro drug release by the USP dissolution method, while promising formulations were subjected to in vitro drug release by the agar gel method and also to stability studies. It was observed that glyceryl monostearate formed hydrophobic matrix and delayed the drug delivery. Antibiotic release profile was controlled by using different combinations of erosion enhancers. The formulation prepared by the compression method showed more delayed release compared to formulations prepared by the molding method.

Applications of Natural Polymeric Materials in Solid Oral Modified-Release Dosage Forms.

PubMed

Li, Liang; Zhang, Xin; Gu, Xiangqin; Mao, Shirui

2015-01-01

Solid oral modified-release dosage forms provide numerous advantages for drug delivery compared to dosage forms where the drugs are released and absorbed rapidly following ingestion. Natural polymers are of particular interest as drug carriers due to their good safety profile, biocompatibility, biodegradability, and rich sources. This review described the current applications of important natural polymers, such as chitosan, alginate, pectin, guar gum, and xanthan gum, in solid oral modified-release dosage forms. It was shown that natural polymers have been widely used to fabricate solid oral modified-release dosage forms such as matrix tablets, pellets and beads, and especially oral drug delivery systems such as gastroretentive and colon drug delivery systems. Moreover, chemical modifications could overcome the shortcomings associated with the use of natural polymers, and the combination of two or more polymers presented further advantages compared with that of single polymer. In conclusion, natural polymers and modified natural polymers have promising applications in solid oral modified-release dosage forms. However, commercial products based on them are still limited. To accelerate the application of natural polymers in commercial products, in vivo behavior of natural polymers-based solid oral modified-release dosage forms should be deeply investigated, and meanwhile quality of the natural polymers should be controlled strictly, and the influence of formulation and process parameters need to be understood intensively.

Iontophoresis: A Potential Emergence of a Transdermal Drug Delivery System

PubMed Central

Dhote, Vinod; Bhatnagar, Punit; Mishra, Pradyumna K.; Mahajan, Suresh C.; Mishra, Dinesh K.

2012-01-01

The delivery of drugs into systemic circulation via skin has generated much attention during the last decade. Transdermal therapeutic systems propound controlled release of active ingredients through the skin and into the systemic circulation in a predictive manner. Drugs administered through these systems escape first-pass metabolism and maintain a steady state scenario similar to a continuous intravenous infusion for up to several days. However, the excellent impervious nature of the skin offers the greatest challenge for successful delivery of drug molecules by utilizing the concepts of iontophoresis. The present review deals with the principles and the recent innovations in the field of iontophoretic drug delivery system together with factors affecting the system. This delivery system utilizes electric current as a driving force for permeation of ionic and non-ionic medications. The rationale behind using this technique is to reversibly alter the barrier properties of skin, which could possibly improve the penetration of drugs such as proteins, peptides and other macromolecules to increase the systemic delivery of high molecular weight compounds with controlled input kinetics and minimum inter-subject variability. Although iontophoresis seems to be an ideal candidate to overcome the limitations associated with the delivery of ionic drugs, further extrapolation of this technique is imperative for translational utility and mass human application. PMID:22396901

Human gene therapy: novel approaches to improve the current gene delivery systems.

PubMed

Cucchiarini, Magali

2016-06-01

Even though gene therapy made its way through the clinics to treat a number of human pathologies since the early years of experimental research and despite the recent approval of the first gene-based product (Glybera) in Europe, the safe and effective use of gene transfer vectors remains a challenge in human gene therapy due to the existence of barriers in the host organism. While work is under active investigation to improve the gene transfer systems themselves, the use of controlled release approaches may offer alternative, convenient tools of vector delivery to achieve a performant gene transfer in vivo while overcoming the various physiological barriers that preclude its wide use in patients. This article provides an overview of the most significant contributions showing how the principles of controlled release strategies may be adapted for human gene therapy.

Tailoring controlled-release oral dosage forms by combining inkjet and flexographic printing techniques.

PubMed

Genina, Natalja; Fors, Daniela; Vakili, Hossein; Ihalainen, Petri; Pohjala, Leena; Ehlers, Henrik; Kassamakov, Ivan; Haeggström, Edward; Vuorela, Pia; Peltonen, Jouko; Sandler, Niklas

2012-10-09

We combined conventional inkjet printing technology with flexographic printing to fabricate drug delivery systems with accurate doses and tailored drug release. Riboflavin sodium phosphate (RSP) and propranolol hydrochloride (PH) were used as water-soluble model drugs. Three different paper substrates: A (uncoated woodfree paper), B (triple-coated inkjet paper) and C (double-coated sheet fed offset paper) were used as porous model carriers for drug delivery. Active pharmaceutical ingredient (API) containing solutions were printed onto 1 cm × 1 cm substrate areas using an inkjet printer. The printed APIs were coated with water insoluble polymeric films of different thickness using flexographic printing. All substrates were characterized with respect to wettability, surface roughness, air permeability, and cell toxicity. In addition, content uniformity and release profiles of the produced solid dosage forms before and after coating were studied. The substrates were nontoxic for the human cell line assayed. Substrate B was smoothest and least porous. The properties of substrates B and C were similar, whereas those of substrate A differed significantly from those of B, C. The release kinetics of both printed APIs was slowest from substrate B before and after coating with the water insoluble polymer film, following by substrate C, whereas substrate A showed the fastest release. The release rate decreased with increasing polymer coating film thickness. The printed solid dosage forms showed excellent content uniformity. So, combining the two printing technologies allowed fabricating controlled-release oral dosage forms that are challenging to produce using a single technique. The approach opens up new perspectives in the manufacture of flexible doses and tailored drug-delivery systems. Copyright © 2012 Elsevier B.V. All rights reserved.

Current trend in drug delivery considerations for subcutaneous insulin depots to treat diabetes.

PubMed

P V, Jayakrishnapillai; Nair, Shantikumar V; Kamalasanan, Kaladhar

2017-05-01

Diabetes mellitus (DM) is a metabolic disorder due to irregularities in glucose metabolism, as a result of insulin disregulation. Chronic DM (Type 1) is treated by daily insulin injections by subcutaneous route. Daily injections cause serious patient non-compliance and medication non-adherence. Insulin Depots (ID) are parenteral formulations designed to release the insulin over a specified period of time, to control the plasma blood glucose level for intended duration. Physiologically, pancreas produces and secretes insulin in basal and pulsatile mode into the blood. Delivery systems mimicking basal release profiles are known as open-loop systems and current marketed products are open-loop systems. Future trend in open-loop systems is to reduce the number of injections per week by enhancing duration of action, by modifying the depot properties. The next generation technologies are closed-loop systems that mimic the pulsatile mode of delivery by pancreas. In closed-loop systems insulin will be released in response to plasma glucose. This review focuses on future trend in open-loop systems; by understanding (a) the secretion of insulin from pancreas, (b) the insulin regulation normal and in DM, (c) insulin depots and (d) the recent progress in open-loop depot technology particularly with respect to nanosystems. Copyright © 2017 Elsevier B.V. All rights reserved.

Advances in nanotechnology-based carrier systems for targeted delivery of bioactive drug molecules with special emphasis on immunotherapy in drug resistant tuberculosis - a critical review.

PubMed

Singh, Jagdeep; Garg, Tarun; Rath, Goutam; Goyal, Amit K

2016-06-01

From the early sixteenth and seventeenth centuries to the present day of life, tuberculosis (TB) still is a global health threat with some new emergence of resistance. This type of emergence poses a vital challenge to control TB cases across the world. Mortality and morbidity rates are high due to this new face of TB. The newer nanotechnology-based drug-delivery approaches involving micro-metric and nano-metric carriers are much needed at this stage. These delivery systems would provide more advantages over conventional systems of treatment by producing enhanced therapeutic efficacy, uniform distribution of drug molecule to the target site, sustained and controlled release of drug molecules and lesser side effects. The main aim to develop these novel drug-delivery systems is to improve the patient compliance and reduce therapy time. This article reviews and elaborates the new concepts and drug-delivery approaches for the treatment of TB involving solid-lipid particulate drug-delivery systems (solid-lipid micro- and nanoparticles, nanostructured lipid carriers), vesicular drug-delivery systems (liposomes, niosomes and liposphere), emulsion-based drug-delivery systems (micro and nanoemulsion) and some other novel drug-delivery systems for the effective treatment of tuberculosis and role of immunomodulators as an adjuvant therapy for management of MDR-TB and XDR-TB.

Advances in nanotechnology-based carrier systems for targeted delivery of bioactive drug molecules with special emphasis on immunotherapy in drug resistant tuberculosis - a critical review.

PubMed

Singh, Jagdeep; Garg, Tarun; Rath, Goutam; Goyal, Amit K

2015-08-11

From the early sixteenth and seventeenth centuries to the present day of life, tuberculosis (TB) still is a global health threat with some new emergence of resistance. This type of emergence poses a vital challenge to control TB cases across the world. Mortality and morbidity rates are high due to this new face of TB. The newer nanotechnology-based drug-delivery approaches involving micro-metric and nano-metric carriers are much needed at this stage. These delivery systems would provide more advantages over conventional systems of treatment by producing enhanced therapeutic efficacy, uniform distribution of drug molecule to the target site, sustained and controlled release of drug molecules and lesser side effects. The main aim to develop these novel drug-delivery systems is to improve the patient compliance and reduce therapy time. This article reviews and elaborates the new concepts and drug-delivery approaches for the treatment of TB involving solid-lipid particulate drug-delivery systems (solid-lipid micro- and nanoparticles, nanostructured lipid carriers), vesicular drug-delivery systems (liposomes, niosomes and liposphere), emulsion-based drug-delivery systems (micro and nanoemulsion) and some other novel drug-delivery systems for the effective treatment of tuberculosis and role of immunomodulators as an adjuvant therapy for management of MDR-TB and XDR-TB.

Enhanced colonic delivery of ciclosporin A self-emulsifying drug delivery system encapsulated in coated minispheres.

PubMed

Keohane, Kieran; Rosa, Mónica; Coulter, Ivan S; Griffin, Brendan T

2016-01-01

Investigate the potential of coated minispheres (SmPill®) to enhance localized Ciclosporin A (CsA) delivery to the colon. CsA self-emulsifying drug delivery systems (SEDDS) were encapsulated into SmPill® minispheres. Varying degrees of coating thickness (low, medium and high) were applied using ethylcellulose and pectin (E:P) polymers. In vitro CsA release was evaluated in simulated gastric and intestinal media. Bioavailability of CsA in vivo following oral administration to pigs of SmPill® minispheres was compared to Neoral® po and Sandimmun® iv in a pig model. CsA concentrations in blood and intestinal tissue were determined by HPLC-UV. In vitro CsA release from coated minispheres decreased with increasing coating thickness. A linear relationship was observed between in vitro CsA release and in vivo bioavailability (r(2) = 0.98). CsA concentrations in the proximal, transverse and distal colon were significantly higher following administration of SmPill®, compared to Neoral® po and Sandimmun® iv (p < 0.05). Analysis of transverse colon tissue subsections also revealed significantly higher CsA concentrations in the mucosa and submucosa using SmPill® minispheres (p < 0.05). Modulating E:P coating thickness controls release of CsA from SmPill® minispheres. Coated minispheres limited CsA release in the small intestine and enhanced delivery and uptake in the colon. These findings demonstrate clinical advantages of an oral coated minisphere-enabled CsA formulation in the treatment of inflammatory conditions of the large intestine.

Antibiotic-containing polymers for localized, sustained drug delivery

PubMed Central

Stebbins, Nicholas D.; Ouimet, Michelle A.; Uhrich, Kathryn E.

2014-01-01

Many currently used antibiotics suffer from issues such as systemic toxicity, short half-life, and increased susceptibility to bacterial resistance. Although most antibiotic classes are administered systemically through oral or intravenous routes, a more efficient delivery system is needed. This review discusses the chemical conjugation of antibiotics to polymers, achieved by forming covalent bonds between antibiotics and a pre-existing polymer or by developing novel antibiotic-containing polymers. Through conjugating antibiotics to polymers, unique polymer properties can be taken advantage of. These polymeric antibiotics display controlled, sustained drug release and vary in antibiotic class type, synthetic method, polymer composition, bond lability, and antibacterial activity. The polymer synthesis, characterization, drug release, and antibacterial activities, if applicable, will be presented to offer a detailed overview of each system. PMID:24751888

Preparation, characterization and in vivo evaluation of a combination delivery system based on hyaluronic acid/jeffamine hydrogel loaded with PHBV/PLGA blend nanoparticles for prolonged delivery of Teriparatide.

PubMed

Bahari Javan, Nika; Montazeri, Hamed; Rezaie Shirmard, Leila; Jafary Omid, Nersi; Barbari, Ghullam Reza; Amini, Mohsen; Ghahremani, Mohammad Hossein; Rafiee-Tehrani, Morteza; Abedin Dorkoosh, Farid

2017-04-01

In the current study, biodegradable PHBV/PLGA blend nanoparticles (NPs) containing Teriparatide were loaded in hyaluronic acid/jeffamine (HA-JEF ED-600) hydrogel to prepare a combination delivery system (CDS) for prolonged delivery of Teriparatide. The principal purpose of the present study was to formulate an effective and prolonged Teriparatide delivery system in order to reduce the frequency of injection and thus enhance patient's compliance. Morphological properties, swelling behaviour, crosslinking efficiency and rheological characterization of HA-JEF ED-600 hydrogel were evaluated. The CDS was acquired by adding PHBV/PLGA NPs to HA-JEF ED-600 hydrogel simultaneously with crosslinking reaction. The percentage of NPs incorporation within the hydrogel as well as the loading capacity and morphology of Teriparatide loaded CDS were examined. Intrinsic fluorescence and circular dichroism spectroscopy proved that Teriparatide remains stable after processing. The release profile represented 63% Teriparatide release from CDS within 50days with lower burst release compared to NPs and hydrogel. MTT assay was conducted by using NIH3T3 cell line and no sign of reduction in cell viability was observed. Based on Miller and Tainter method, LD 50 of Teriparatide loaded CDS was 131.8mg/kg. In vivo studies demonstrated that Teriparatide loaded CDS could effectively increase serum calcium level after subcutaneous injection in mice. Favourable results in the current study introduced CDS as a promising candidate for controlled delivery of Teriparatide and pave the way for future investigations in the field of designing prolonged delivery systems for other peptides and proteins. Copyright © 2017 Elsevier B.V. All rights reserved.

Noncovalent interaction-assisted drug delivery system with highly efficient uptake and release of paclitaxel for anticancer therapy.

PubMed

Wei, Yuping; Ma, Liang; Zhang, Liang; Xu, Xia

2017-01-01

An effective drug delivery system requires efficient drug uptake and release inside cancer cells. Here, we report a novel drug delivery system, in which paclitaxel (PTX) interacts with a novel cell penetrating peptide (CPP) through noncovalent interaction designed based on molecular simulations. This CPP/PTX complex confers high efficiency in delivering PTX into cancer cells not by endocytosis but by an energy-independent pathway. Once inside cells, the noncovalent interaction between PTX and the CPP may allow fast release of PTX within cells due to the direct translocation of CPP/PTX. This drug delivery system exhibits strong capacity for inhibition of tumor growth and offers a new avenue for the development of advanced drug delivery systems for anticancer therapy.

Electrospinning of PLGA/gum tragacanth nanofibers containing tetracycline hydrochloride for periodontal regeneration.

PubMed

Ranjbar-Mohammadi, Marziyeh; Zamani, M; Prabhakaran, M P; Bahrami, S Hajir; Ramakrishna, S

2016-01-01

Controlled drug release is a process in which a predetermined amount of drug is released for longer period of time, ranging from days to months, in a controlled manner. In this study, novel drug delivery devices were fabricated via blend electrospinning and coaxial electrospinning using poly lactic glycolic acid (PLGA), gum tragacanth (GT) and tetracycline hydrochloride (TCH) as a hydrophilic model drug in different compositions and their performance as a drug carrier scaffold was evaluated. Scanning electron microscopy (SEM) results showed that fabricated PLGA, blend PLGA/GT and core shell PLGA/GT nanofibers had a smooth and bead-less morphology with the diameter ranging from 180 to 460 nm. Drug release studies showed that both the fraction of GT within blend nanofibers and the core-shell structure can effectively control TCH release rate from the nanofibrous membranes. By incorporation of TCH into core-shell nanofibers, drug release was sustained for 75 days with only 19% of burst release within the first 2h. The prolonged drug release, together with proven biocompatibility, antibacterial and mechanical properties of drug loaded core shell nanofibers make them a promising candidate to be used as drug delivery system for periodontal diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

A smart pH-responsive nano-carrier as a drug delivery system for the targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways.

PubMed

Jiang, Kai; Chi, Ting; Li, Tao; Zheng, Guirong; Fan, Lulu; Liu, Yajun; Chen, Xiufen; Chen, Sijia; Jia, Lee; Shao, Jingwei

2017-07-13

Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted UA@M-CS-FA) was designed and successfully synthesized, and was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for the targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cell growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cell apoptosis and inhibited migration via cell cycle arrest in the G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that a CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chemopreventive agent.

Hydrogels containing redispersible spray-dried melatonin-loaded nanocapsules: a formulation for transdermal-controlled delivery

NASA Astrophysics Data System (ADS)

Hoffmeister, Cristiane RD; Durli, Taís L.; Schaffazick, Scheila R.; Raffin, Renata P.; Bender, Eduardo A.; Beck, Ruy CR; Pohlmann, Adriana R.; Guterres, Sílvia S.

2012-05-01

The aim of the present study was to develop a transdermal system for controlled delivery of melatonin combining three strategies: nanoencapsulation of melatonin, drying of melatonin-loaded nanocapsules, and incorporation of nanocapsules in a hydrophilic gel. Nanocapsules were prepared by interfacial deposition of the polymer and were spray-dried using water-soluble excipients. In vitro drug release profiles were evaluated by the dialysis bag method, and skin permeation studies were carried out using Franz cells with porcine skin as the membrane. The use of 10% ( w/ v) water-soluble excipients (lactose or maltodextrin) as spray-drying adjuvants furnished redispersible powders (redispersibility index approximately 1.0) suitable for incorporation into hydrogels. All formulations showed a better controlled in vitro release of melatonin compared with the melatonin solution. The best controlled release results were achieved with hydrogels prepared with dried nanocapsules (hydrogels > redispersed dried nanocapsules > nanocapsule suspension > melatonin solution). The skin permeation studies demonstrated a significant modulation of the transdermal melatonin permeation for hydrogels prepared with redispersible nanocapsules. In this way, the additive effect of the different approaches used in this study (nanoencapsulation, spray-drying, and preparation of semisolid dosage forms) allows not only the control of melatonin release, but also transdermal permeation.

Calcium silicate-based drug delivery systems.

PubMed

Zhu, Ying-Jie; Guo, Xiao-Xuan; Sham, Tsun-Kong

2017-02-01

Compared with other inorganic materials such as silica, metal oxides, noble metals and carbon, calcium silicate-based materials, especially nanostructured calcium silicate materials, have high biocompatibility, bioactivity and biodegradability, high specific surface area, nanoporous/hollow structure, high drug-loading capacity, pH-responsive drug release behavior and desirable drug release properties, and thus they are promising for the application in drug delivery. Calcium silicate-based drug delivery systems have a long drug-release time, which can significantly prolong the therapeutic effect of drugs. Another advantage of calcium silicate-based drug delivery systems is their pH-responsive drug release property, which can act as an ideal platform for targeted drug delivery. Areas covered: In recent years, studies have been carried out on calcium silicate-based drug delivery systems, and important results and insights have been documented. This article is not intended to offer a comprehensive review on the research on calcium silicate-based drug delivery systems, but presents some examples reported in the literature, and includes new insights obtained by tracking the interactions between drug molecules and calcium silicate carriers on the molecular level using the synchrotron-based X-ray spectroscopy. Expert opinion: Finally, our opinions on calcium silicate-based drug delivery systems are provided, and several research directions for the future studies are proposed.

Improving the Efficacy of Anticancer Drugs via Encapsulation and Acoustic Release.

PubMed

Ahmed, Salma E; Awad, Nahid; Paul, Vinod; Moussa, Hesham G; Husseini, Ghaleb A

2018-06-08

Conventional chemotherapeutics lack the specificity and controllability, thus may poison healthy cells while attempting to kill cancerous ones. Newly developed nano-drug delivery systems have shown promise in delivering anti-tumor agents with enhanced stability, durability and overall performance; especially when used along with targeting and triggering techniques. This work traces back the history of chemotherapy, addressing the main challenges that have encouraged the medical researchers to seek a sanctuary in nanotechnological-based drug delivery systems that are grafted with appropriate targeting techniques and drug release mechanisms. A special focus will be paid towards acoustically triggered liposomes encapsulating doxorubicin. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Controlled release of paclitaxel from a self-assembling peptide hydrogel formed in situ and antitumor study in vitro

PubMed Central

Liu, Jingping; Zhang, Lanlan; Yang, Zehong; Zhao, Xiaojun

2011-01-01

Background A nanoscale injectable in situ-forming hydrogel drug delivery system was developed in this study. The system was based on a self-assembling peptide RADA16 solution, which can spontaneously form a hydrogel rapidly under physiological conditions. We used the RADA16 hydrogel for the controlled release of paclitaxel (PTX), a hydrophobic antitumor drug. Methods The RADA16-PTX suspension was prepared simply by magnetic stirring, followed by atomic force microscopy, circular dichroism analysis, dynamic light scattering, rheological analysis, an in vitro release assay, and a cell viability test. Results The results indicated that RADA16 and PTX can interact with each other and that the amphiphilic peptide was able to stabilize hydrophobic drugs in aqueous solution. The particle size of PTX was markedly decreased in the RADA16 solution compared with its size in water. The RADA16-PTX suspension could form a hydrogel in culture medium, and the elasticity of the hydrogel showed a positive correlation with peptide concentration. In vitro release measurements indicated that hydrogels with a higher peptide concentration had a longer half-release time. The RADA16-PTX hydrogel could effectively inhibit the growth of the breast cancer cell line, MDA-MB-435S, in vitro, and hydrogels with higher peptide concentrations were more effective at inhibiting tumor cell proliferation. The RADA16-PTX hydrogel was effective at controlling the release of PTX and inhibiting tumor cell growth in vitro. Conclusion Self-assembling peptide hydrogels may work well as a system for drug delivery. PMID:22114478

Folate-containing reduction-sensitive lipid-polymer hybrid nanoparticles for targeted delivery of doxorubicin.

PubMed

Wu, Bo; Yu, Ping; Cui, Can; Wu, Ming; Zhang, Yang; Liu, Lei; Wang, Cai-Xia; Zhuo, Ren-Xi; Huang, Shi-Wen

2015-04-01

The development and evaluation of folate-targeted and reduction-triggered biodegradable nanoparticles are introduced to the research on targeted delivery of doxorubicin (DOX). This type of folate-targeted lipid-polymer hybrid nanoparticles (FLPNPs) is comprised of a poly(D,L-lactide-co-glycolide) (PLGA) core, a soybean lecithin monolayer, a monomethoxy-poly(ethylene glycol)-S-S-hexadecyl (mPEG-S-S-C16) reduction-sensitive shell, and a folic acid-targeted ligand. FLPNPs exhibited high size stability but fast disassembly in a simulated cancer cell reductive environment. The experiments on the release process in vitro revealed that as a reduction-sensitive drug delivery system, FLPNPs released DOX faster in the presence of 10 mM dithiothreitol (DTT). Results from flow cytometry, confocal image and in vitro cytotoxicity assays revealed that FLPNPs further enhanced cell uptake and generated higher cytotoxicity against human epidermoid carcinoma in the oral cavity than non-targeted redox-sensitive and targeted redox-insensitive controls. Furthermore, in vivo animal experiments demonstrated that systemic administration of DOX-loaded FLPNPs remarkably reduced tumor growth. Experiments on biodistribution of DOX-loaded FLPNPs showed that an increasing amount of DOX accumulated in the tumor. Therefore, FLPNPs formulations have proved to be a stable, controllable and targeted anticancer drug delivery system.

Magnetic nanoparticles for a new drug delivery system to control quercetin releasing for cancer chemotherapy

NASA Astrophysics Data System (ADS)

Barreto, A. C. H.; Santiago, V. R.; Mazzetto, S. E.; Denardin, J. C.; Lavín, R.; Mele, Giuseppe; Ribeiro, M. E. N. P.; Vieira, Icaro G. P.; Gonçalves, Tamara; Ricardo, N. M. P. S.; Fechine, P. B. A.

2011-12-01

Quercetin belongs to the chemical class of flavonoids and can be found in many common foods, such as apples, nuts, berries, etc. It has been demonstrated that quercetin has a wide array of biological effects that are considered beneficial to health treatment, mainly as anticancer. However, therapeutic applications of quercetin have been restricted to oral administration due to its sparing solubility in water and instability in physiological medium. A drug delivery methodology was proposed in this work to study a new quercetin release system in the form of magnetite-quercetin-copolymer (MQC). These materials were characterized through XRD, TEM, IR, and Thermal analysis. In addition, the magnetization curves and quercetin releasing experiments were performed. It was observed a nanoparticle average diameter of 11.5 and 32.5 nm at Fe3O4 and MQC, respectively. The presence of magnetic nanoparticles in this system offers the promise of targeting specific organs within the body. These results indicate the great potential for future applications of the MQC to be used as a new quercetin release system.

Nanoparticle-Enabled Transdermal Drug Delivery Systems for Enhanced Dose Control and Tissue Targeting.

PubMed

Palmer, Brian C; DeLouise, Lisa A

2016-12-15

Transdermal drug delivery systems have been around for decades, and current technologies (e.g., patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases.

Nanoparticle enabled transdermal drug delivery systems for enhanced dose control and tissue targeting

PubMed Central

Palmer, Brian C.; DeLouise, Lisa A.

2017-01-01

Transdermal drug delivery systems have been around for decades, and current technologies (e.g. patches, ointments, and creams) enhance the skin permeation of low molecular weight, lipophilic drugs that are efficacious at low doses. The objective of current transdermal drug delivery research is to discover ways to enhance skin penetration of larger, hydrophilic drugs and macromolecules for disease treatment and vaccination. Nanocarriers made of lipids, metals, or polymers have been successfully used to increase penetration of drugs or vaccines, control drug release, and target drugs to specific areas of skin in vivo. While more research is needed to identify the safety of nanocarriers, this technology has the potential to expand the use of transdermal routes of administration to a wide array of therapeutics. Here, we review the current state of nanoparticle skin delivery systems with special emphasis on targeting skin diseases. PMID:27983701

Novel approach for a PTX/VEGF dual drug delivery system in cardiovascular applications-an innovative bulk and surface drug immobilization.

PubMed

Wulf, Katharina; Teske, Michael; Matschegewski, Claudia; Arbeiter, Daniela; Bajer, Dalibor; Eickner, Thomas; Schmitz, Klaus-Peter; Grabow, Niels

2018-06-01

The successive incorporation of several drugs into the polymeric bulk of implants mostly results in loss of considerable quantity of one drug, and/or the loss in quality of the coating and also in changes of drug release time points. A dual drug delivery system (DDDS) based on poly-L-lactide (PLLA) copolymers combining the effective inhibition of smooth muscle cell proliferation while simultaneously promoting re-endothelialization was successfully developed. To overcome possible antagonistic drug interactions and the limitation of the polymeric bulk material as release system for dual drugs, a novel concept which combines the bulk and surface drug immobilization for a DDDS was investigated. The advantage of this DDDS is that the bulk incorporation of fluorescein diacetate (FDAc) (model drug for paclitaxel (PTX)) via spray coating enhanced the subsequent cleavable surface coupling of vascular endothelial growth factor (VEGF) via the crosslinker bissulfosuccinimidyl suberate (BS 3 ). In the presence of the embedded FDAc, the VEGF loading and release are about twice times higher than in absence. Furthermore, the DDDS combines the diffusion drug delivery (FDAc or PTX) and the chemical controlled drug release, VEGF via hydrolysable ester bonds, without loss in quantity and quality of the drug release curves. Additionally, the performed in vitro biocompatibility study showed the bimodal influences of PTX and VEGF on human endothelial EA.hy926 cells. In conclusion, it was possible to show the feasibility to develop a novel DDDS which has a high potential for the medical application due to the possible easy and short modification of a polymer-based PTX delivery system.

A surface-mediated siRNA delivery system developed with chitosan/hyaluronic acid-siRNA multilayer films through layer-by-layer self-assembly

NASA Astrophysics Data System (ADS)

Wu, Lijuan; Wu, Changlin; Liu, Guangwan; Liao, Nannan; Zhao, Fang; Yang, Xuxia; Qu, Hongyuan; Peng, Bo; Chen, Li; Yang, Guang

2016-12-01

siRNA delivery remains highly challenging because of its hydrophilic and anionic nature and its sensitivity to nuclease degradation. Effective siRNA loading and improved transfection efficiency into cells represents a key problem. In our study, we prepared Chitosan/Hyaluronic acid-siRNA multilayer films through layer-by-layer self-assembly, in which siRNAs can be effectively loaded and protected. The construction process was characterized by FTIR, 13C NMR (CP/MAS), UV-vis spectroscopy, and atomic force microscopy (AFM). We presented the controlled-release performance of the films during incubation in 1 M NaCl solution for several days through UV-vis spectroscopy and polyacrylamide gel electrophoresis (PAGE). Additionally, we verified the stability and integrity of the siRNA loaded on multilayer films. Finally, the biological efficacy of the siRNA delivery system was evaluated via cells adhesion and gene silencing analyses in eGFP-HEK 293T cells. This new type of surface-mediated non-viral multilayer films may have considerable potential in the localized and controlled-release delivery of siRNA in mucosal tissues, and tissue engineering application.

Sustained-releasing hollow microparticles with dual-anticancer drugs elicit greater shrinkage of tumor spheroids.

PubMed

Baek, Jong-Suep; Choo, Chee Chong; Tan, Nguan Soon; Loo, Say Chye Joachim

2017-10-06

Polymeric particulate delivery systems are vastly explored for the delivery of chemotherapeutic agents. However, the preparation of polymeric particulate systems with the capability of providing sustained release of two or more drugs is still a challenge. Herein, poly (D, L-lactic-co-glycolic acid, 50:50) hollow microparticles co-loaded with doxorubicin and paclitaxel were developed through double-emulsion solvent evaporation technique. Hollow microparticles were formed through the addition of an osmolyte into the fabrication process. The benefits of hollow over solid microparticles were found to be higher encapsulation efficiency and a more rapid drug release rate. Further modification of the hollow microparticles was accomplished through the introduction of methyl-β-cyclodextrin. With this, a higher encapsulation efficiency of both drugs and an enhanced cumulative release were achieved. Spheroid study further demonstrated that the controlled release of the drugs from the methyl-β-cyclodextrin -loaded hollow microparticles exhibited enhanced tumor regressions of MCF-7 tumor spheroids. Such hollow dual-drug-loaded hollow microparticles with sustained releasing capabilities may have a potential for future applications in cancer therapy.

Platinum covalent shell cross-linked micelles designed to deliver doxorubicin for synergistic combination cancer therapy

PubMed Central

Zhu, Caiying; Xiao, Jingjing; Tang, Ming; Feng, Hua; Chen, Wulian; Du, Ming

2017-01-01

The preparation of polymer therapeutics capable of controlled release of multiple chemotherapeutic drugs has remained a tough problem in synergistic combination cancer therapy. Herein, a novel dual-drug co-delivery system carrying doxorubicin (DOX) and platinum(IV) (Pt[IV]) was developed. An amphiphilic diblock copolymer, PCL-b-P(OEGMA-co-AzPMA), was synthesized and used as a nanoscale drug carrier in which DOX and Pt(IV) could be packaged together. The copolymers were shell cross-linked by Pt(IV) prodrug via a click reaction. Studies on the in vitro drug release and cellular uptake of the dual-drug co-delivery system showed that the micelles were effectively taken up by the cells and simultaneously released drugs in the cells. Futhermore, the co-delivery polymer nanoparticles caused much higher cell death in HeLa and A357 tumor cells than either the free drugs or single-drug-loaded micelles at the same dosage, exhibiting a synergistic combination of DOX and Pt(IV). The results obtained with the shell cross-linked micelles based on an anticancer drug used as a cross-linking linkage suggested a promising application of the micelles for multidrug delivery in combination cancer therapy. PMID:28553108

Electrospun nanofibers-mediated on-demand drug release.

PubMed

Chen, Menglin; Li, Yan-Fang; Besenbacher, Flemming

2014-11-01

A living system has a complex and accurate regulation system with intelligent sensor-processor-effector components to enable the release of vital bioactive substances on demand at a specific site and time. Stimuli-responsive polymers mimic biological systems in a crude way where an external stimulus results in a change in conformation, solubility, or alternation of the hydrophilic/hydrophobic balance, and consequently release of a bioactive substance. Electrospinning is a straightforward and robust method to produce nanofibers with the potential to incorporate drugs in a simple, rapid, and reproducible process. This feature article emphasizes an emerging area using an electrospinning technique to generate biomimetic nanofibers as drug delivery devices that are responsive to different stimuli, such as temperature, pH, light, and electric/magnetic field for controlled release of therapeutic substances. Although at its infancy, the mimicry of these stimuli-responsive nanofibers to the function of the living systems includes both the fibrous structural feature and bio-regulation function as an on demand drug release depot. The electrospun nanofibers with extracellular matrix morphology intrinsically guide cellular drug uptake, which will be highly desired to translate the promise of drug delivery for the clinical success. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Formulation and in-vitro evaluation of floating bilayer tablet of lisinopril maleate and metoprolol tartrate.

PubMed

Ijaz, Hira; Qureshi, Junaid; Danish, Zeeshan; Zaman, Muhammad; Abdel-Daim, Mohamed; Hanif, Muhammad; Waheed, Imran; Mohammad, Imran Shair

2015-11-01

The purpose of this study was to introduce the technology for the development of rate-controlled oral drug delivery system to overcome various physiological problems. Several approaches are being used for the purpose of increasing the gastric retentive time, including floating drug delivery system. Gastric floating lisinopril maleate and metoprolol tartrate bilayer tablets were formulated by direct compression method using the sodium starch glycolate, crosscarmellose sodium for IR layer. Eudragit L100, pectin, acacia as sustained release polymers in different ratios for SR metoprolol tartrate layer and sodium bicarbonate, citric acid as gas generating agents for the floating extended release layer. The floating bilayer tablets of lisinopril maleate and metoprolol tartrate were designed to overcome the various problems associated with conventional oral dosage form. Floating tablets were evaluated for floating lag time, drug contents and in-vitro dissolution profile and different kinetic release models were applied. It was clear that the different ratios of polymers affected the drug release and floating time. L2 and M4 showed good drug release profile and floating behavior. The linear regression and model fitting showed that all formulation followed Higuchi model of drug release model except M4 that followed zero order kinetic. From the study it is evident that a promising controlled release by floating bilyer tablets of lisinopril maleate and metoprolol tartrate can be developed successfully.

Light-controlled drug release from singlet-oxygen sensitive nanoscale coordination polymers enabling cancer combination therapy.

PubMed

Liu, Jingjing; Yang, Guangbao; Zhu, Wenwen; Dong, Ziliang; Yang, Yu; Chao, Yu; Liu, Zhuang

2017-11-01

The development of smart drug delivery systems to realize controlled drug release for highly specific cancer treatment has attracted tremendous attention. Herein, nanoscale coordination polymers (NCPs) constructed from hafnium ions and bis-(alkylthio) alkene (BATA), a singlet-oxygen responsive linker, are fabricated and applied as nanocarriers to realize light-controlled drug release under a rather low optical power density. In this system, NCPs synthesized through a solvothermal method are sequentially loaded with chlorin e6 (Ce6), a photosensitizer, and doxorubicin (DOX), a chemotherapeutic drug, and then coated with lipid bilayer to allow modification with polyethylene glycol (PEG) to acquire excellent colloidal stability. The singlet oxygen produced by such NCP-Ce6-DOX-PEG nanocomposite can be used not only for photodynamic therapy, but also to induce the break of BATA linker and thus the destruction of nanoparticle structures under light exposure, thereby triggering effective drug release. Notably, with efficient tumor accumulation after intravenous injection as revealed by CT imaging, those NCP-Ce6-DOX-PEG nanoparticles could be utilized for combined chemo-photodynamic therapy with great antitumor efficacy. Thus, this work presents a unique type of NCP-based drug delivery system with biodegradability, sensitive responses to light, as well as highly efficient tumor retention for effective cancer combinational treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Development of a calcium phosphate co-precipitate/poly(lactide-co-glycolide) DNA delivery system: release kinetics and cellular transfection studies.

PubMed

Kofron, Michelle D; Laurencin, Cato T

2004-06-01

One of the most common non-viral methods for the introduction of foreign deoxyribonucleic acid (DNA) into cultured cells is calcium phosphate co-precipitate transfection. This technique involves the encapsulation of DNA within a calcium phosphate co-precipitate, particulate addition to in vitro cell culture, endocytosis of the co-precipitate, and exogenous DNA expression by the transfected cell. In this study, we fabricated a novel non-viral gene transfer system by adsorbing DNA, encapsulated in calcium phosphate (DNA/Ca-P) co-precipitates, to biodegradable two- and three-dimensional poly(lactide-co-glycolide) matrices (2D-DNA/Ca-P/PLAGA, 3D-DNA/Ca-P/PLAGA). Co-precipitate release studies demonstrated an initial burst release over the first 48 h. By day 7, approximately 96% of the initially adsorbed DNA/Ca-P co-precipitate had been released. This was followed by low levels of co-precipitate release for 42 days. Polymerase chain reaction was used to demonstrate the ability of the released DNA containing co-precipitates to transfect SaOS-2 cells cultured in vitro on the 3D-DNA/Ca-P/PLAGA matrix and maintenance of the structural integrity of the exogenous DNA. In summary, a promising system for the incorporation and controlled delivery of exogenous genes encapsulated within a calcium phosphate co-precipitate from biodegradable polymeric matrices has been developed and may have applicability to the delivery of therapeutic genes and the transfection of other cell types.

Cellulose nanofiber aerogel as a promising biomaterial for customized oral drug delivery

PubMed Central

Bhandari, Jyoti; Mishra, Harshita; Mishra, Pawan Kumar; Wimmer, Rupert; Ahmad, Farhan J; Talegaonkar, Sushama

2017-01-01

Cellulose nanofiber (CNF) aerogels with favorable floatability and mucoadhesive properties prepared by the freeze-drying method have been introduced as new possible carriers for oral controlled drug delivery system. Bendamustine hydrochloride is considered as the model drug. Drug loading was carried out by the physical adsorption method, and optimization of drug-loaded formulation was done using central composite design. A very lightweight-aerogel-with-matrix system was produced with drug loading of 18.98%±1.57%. The produced aerogel was characterized for morphology, tensile strength, swelling tendency in media with different pH values, floating behavior, mucoadhesive detachment force and drug release profiles under different pH conditions. The results showed that the type of matrix was porous and woven with excellent mechanical properties. The drug release was assessed by dialysis, which was fitted with suitable mathematical models. Approximately 69.205%±2.5% of the drug was released in 24 hours in medium of pH 1.2, whereas ~78%±2.28% of drug was released in medium of pH 7.4, with floating behavior for ~7.5 hours. The results of in vivo study showed a 3.25-fold increase in bioavailability. Thus, we concluded that CNF aerogels offer a great possibility for a gastroretentive drug delivery system with improved bioavailability. PMID:28352172

Polymer-Based Nanofibers Impregnated with Drug Infused Plant Virus Particles as a Responsive Fabric for Therapeutic Delivery

NASA Astrophysics Data System (ADS)

Honarbakhsh, Sara

A biodegradable and controlled drug delivery system has been developed herein composed of electrospun polymeric nanofibers impregnated with cargo loaded Red clover necrotic mosaic virus (RCNMV)---a robust plant virus---as the drug carrier nanoparticle. In this system, controlled drug release is achieved by altering the porosity of the biodegradable matrix as well as controlling the position and distribution of the cargo loaded nanocarriers in the matrix. Solution electrospinning as well as dipping method are used to create and to impregnate the matrix (the fibers of which possess uniformly distributed nano-size surface pores) with cargo loaded nanocarriers. Prior to the impregnation stage of cargo loaded nanocarriers into the matrix, compatibility of a group of candidate cargos (Ampicillin, Novanthrone, Doxorubicin and Ethidium Bromide) and RCNMV functionality with potential electrospinning solvents were investigated and a solvent with the least degradative effect was selected. In order to achieve both sustained and immediate drug release profiles, cargo loaded nanocarriers were embedded into the matrix---through co-spinning process---as well as on the surface of matrix fibers---through dipping method. SEM, TEM and Fluorescent Light Microscopy images of the medicated structures suggested that the nanocarriers were incorporated into/on the matrix. In vitro release assays were also carried out the results of which confirmed having obtained sustained release in the co-spun medicated structures where as dipped samples showed an immediate release profile.

PLGA-lecithin-PEG core-shell nanoparticles for controlled drug delivery.

PubMed

Chan, Juliana M; Zhang, Liangfang; Yuet, Kai P; Liao, Grace; Rhee, June-Wha; Langer, Robert; Farokhzad, Omid C

2009-03-01

Current approaches to encapsulate and deliver therapeutic compounds have focused on developing liposomal and biodegradable polymeric nanoparticles (NPs), resulting in clinically approved therapeutics such as Doxil/Caelyx and Genexol-PM, respectively. Our group recently reported the development of biodegradable core-shell NP systems that combined the beneficial properties of liposomal and polymeric NPs for controlled drug delivery. Herein we report the parameters that alter the biological and physicochemical characteristics, stability, drug release properties and cytotoxicity of these core-shell NPs. We further define scalable processes for the formulation of these NPs in a reproducible manner. These core-shell NPs consist of (i) a poly(D,L-lactide-co-glycolide) hydrophobic core, (ii) a soybean lecithin monolayer, and (iii) a poly(ethylene glycol) shell, and were synthesized by a modified nanoprecipitation method combined with self-assembly. Preparation of the NPs showed that various formulation parameters such as the lipid/polymer mass ratio and lipid/lipid-PEG molar ratio controlled NP physical stability and size. We encapsulated a model chemotherapy drug, docetaxel, in the NPs and showed that the amount of lipid coverage affected its drug release kinetics. Next, we demonstrated a potentially scalable process for the formulation, purification, and storage of NPs. Finally, we tested the cytotoxicity using MTT assays on two model human cell lines, HeLa and HepG2, and demonstrated the biocompatibility of these particles in vitro. Our data suggest that the PLGA-lecithin-PEG core-shell NPs may be a useful new controlled release drug delivery system.

Protein instability and immunogenicity: roadblocks to clinical application of injectable protein delivery systems for sustained release.

PubMed

Jiskoot, Wim; Randolph, Theodore W; Volkin, David B; Middaugh, C Russell; Schöneich, Christian; Winter, Gerhard; Friess, Wolfgang; Crommelin, Daan J A; Carpenter, John F

2012-03-01

Protein instability and immunogenicity are two main roadblocks to the clinical success of novel protein drug delivery systems. In this commentary, we discuss the need for more extensive analytical characterization in relation to concerns about protein instability in injectable drug delivery systems for sustained release. We then will briefly address immunogenicity concerns and outline current best practices for using state-of-the-art analytical assays to monitor protein stability for both conventional and novel therapeutic protein dosage forms. Next, we provide a summary of the stresses on proteins arising during preparation of drug delivery systems and subsequent in vivo release. We note the challenges and difficulties in achieving the absolute requirement of quantitatively assessing the degradation of protein molecules in a drug delivery system. We describe the potential roles for academic research in further improving protein stability and developing new analytical technologies to detect protein degradation byproducts in novel drug delivery systems. Finally, we provide recommendations for the appropriate approaches to formulation design and assay development to ensure that stable, minimally immunogenic formulations of therapeutic proteins are created. These approaches should help to increase the probability that novel drug delivery systems for sustained protein release will become more readily available as effective therapeutic agents to treat and benefit patients. Copyright © 2011 Wiley Periodicals, Inc.

Sequential delivery of BMP-2 and IGF-1 using a chitosan gel with gelatin microspheres enhances early osteoblastic differentiation

PubMed Central

Kim, Sungwoo; Kang, Yunqing; Krueger, Chad A.; Sen, Milan; Holcomb, John B.; Chen, Di; Wenke, Joseph C.; Yang, Yunzhi

2012-01-01

The purpose of this study was to develop and characterize a chitosan gel/gelatin microspheres (MSs) dual delivery system for sequential release of bone morphogenetic protein-2 (BMP-2) and insulin-like growth factor-1 (IGF-1) to enhance osteoblast differentiation in vitro. We made and characterized the delivery system based on its degree of cross-linking, degradation, and release kinetics. We also evaluated the cytotoxicity of the delivery system and the effect of growth factors on cell response using pre-osteoblast W-20-17 mouse bone marrow stromal cells. IGF-1 was first loaded into MSs, and then the IGF-1 containing MSs were encapsulated into the chitosan gel which contained BMP-2. Cross-linking of gelatin with glyoxal via Schiff bases significantly increased thermal stability and decreased the solubility of the MSs, leading to a significant decrease in the initial release of IGF-1. Encapsulation of the MSs into the chitosan gel generated polyelectrolyte complexes by intermolecular interactions, which further affected the release kinetics of IGF-1. This combinational delivery system provided an initial release of BMP-2 followed by a slow and sustained release of IGF-1. Significantly greater alkaline phosphatase activity was found in W-20-17 cells treated with the sequential delivery system than other treatments (p<0.05) after a week of culture. PMID:22293583

PLGA-Mesoporous Silicon Microspheres for the in Vivo Controlled Temporospatial Delivery of Proteins.

PubMed

Minardi, Silvia; Pandolfi, Laura; Taraballi, Francesca; De Rosa, Enrica; Yazdi, Iman K; Liu, Xeuwu; Ferrari, Mauro; Tasciotti, Ennio

2015-08-05

In regenerative medicine, the temporospatially controlled delivery of growth factors (GFs) is crucial to trigger the desired healing mechanisms in the target tissues. The uncontrolled release of GFs has been demonstrated to cause severe side effects in the surrounding tissues. The aim of this study was to optimize a translational approach for the fine temporal and spatial control over the release of proteins, in vivo. Hence, we proposed a newly developed multiscale composite microsphere based on a core consisting of the nanostructured silicon multistage vector (MSV) and a poly(dl-lactide-co-glycolide) acid (PLGA) outer shell. Both of the two components of the resulting composite microspheres (PLGA-MSV) can be independently tailored to achieve multiple release kinetics contributing to the control of the release profile of a reporter protein in vitro. The influence of MSV shape (hemispherical or discoidal) and size (1, 3, or 7 μm) on PLGA-MSV's morphology and size distribution was investigated. Second, the copolymer ratio of the PLGA used to fabricate the outer shell of PLGA-MSV was varied. The composites were fully characterized by optical microscopy, scanning electron microscopy, ζ potential, Fourier transform infrared spectroscopy, and thermogravimetric analysis-differential scanning calorimetry, and their release kinetics over 30 days. PLGA-MSV's biocompatibility was assessed in vitro with J774 macrophages. Finally, the formulation of PLGA-MSV was selected, which concurrently provided the most consistent microsphere size and allowed for a zero-order release kinetic. The selected PLGA-MSVs were injected in a subcutaneous model in mice, and the in vivo release of the reporter protein was followed over 2 weeks by intravital microscopy, to assess if the zero-order release was preserved. PLGA-MSV was able to retain the payload over 2 weeks, avoiding the initial burst release typical of most drug delivery systems. Finally, histological evaluation assessed the biocompatibility of the platform in vivo.

Cytarabine-AOT catanionic vesicle-loaded biodegradable thermosensitive hydrogel as an efficient cytarabine delivery system.

PubMed

Liu, Jing; Jiang, Yue; Cui, Yuting; Xu, Chuanshan; Ji, Xiaoqing; Luan, Yuxia

2014-10-01

Carrier with high drug loading content is one of the most important issues in drug delivery system. In the present work, an ion-pair amphiphilic molecule composed of anticancer drug cation and surfactant anion is used for straightforward fabricating vesicles for cancer therapy. Anticancer drug (cytarabine hydrochloride) and anionic surfactant (AOT) are selected for the fabrication of ion-pair amphiphilic molecule. One amphiphilic molecule contains one drug cation, thus the drug loading content is 50% (mol/mol) in theory. The in vitro drug release study shows that the release time of cytarabine is about 3 times of the pure cytarabine solution and the permeability of cytarabine has been improved about 160 times tested by parallel artificial membrane permeability assay model. However, the hemolytic toxicity is largely decreased in the studied concentration range. The in vitro cytotoxicity results show that cytarabine-AOT amphiphiles have a much lower IC50 (drug concentration resulting in 50% cell death) value and a higher cell inhibition rate comparing with their respective components, indicating its effective therapy for leukemic cells. To obtain a longer and a convenient drug release system, the prepared vesicles are further incorporated into the thermosensitive PLGA-PEG-PLGA hydrogel to prepare a subcutaneous administration. The in vivo drug release results indicate that cytarabine-AOT vesicle-loaded hydrogel is a good injectable delivery system for controlled release of cytarabine for cancer therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Controlling Release Kinetics of PLG Microspheres Using a Manufacturing Technique

NASA Astrophysics Data System (ADS)

Berchane, Nader

2005-11-01

Controlled drug delivery offers numerous advantages compared with conventional free dosage forms, in particular: improved efficacy and patient compliance. Emulsification is a widely used technique to entrap drugs in biodegradable microspheres for controlled drug delivery. The size of the formed microspheres has a significant influence on drug release kinetics. Despite the advantages of controlled drug delivery, previous attempts to achieve predetermined release rates have seen limited success. This study develops a tool to tailor desired release kinetics by combining microsphere batches of specified mean diameter and size distribution. A fluid mechanics based correlation that predicts the average size of Poly(Lactide-co-Glycolide) [PLG] microspheres from the manufacturing technique, is constructed and validated by comparison with experimental results. The microspheres produced are accurately represented by the Rosin-Rammler mathematical distribution function. A mathematical model is formulated that incorporates the microsphere distribution function to predict the release kinetics from mono-dispersed and poly-dispersed populations. Through this mathematical model, different release kinetics can be achieved by combining different sized populations in different ratios. The resulting design tool should prove useful for the pharmaceutical industry to achieve designer release kinetics.

Process evaluation and in vitro selectivity analysis of aptamer-drug polymeric formulation for targeted pharmaceutical delivery.

PubMed

Tan, Kei X; Lau, Sie Yon; Danquah, Michael K

2018-05-01

Targeted drug delivery is a promising strategy to promote effective delivery of conventional and emerging pharmaceuticals. The emergence of aptamers as superior targeting ligands to direct active drug molecules specifically to desired malignant cells has created new opportunities to enhance disease therapies. The application of biodegradable polymers as delivery carriers to develop aptamer-navigated drug delivery system is a promising approach to effectively deliver desired drug dosages to target cells. This study reports the development of a layer-by-layer aptamer-mediated drug delivery system (DPAP) via a w/o/w double emulsion technique homogenized by ultrasonication or magnetic stirring. Experimental results showed no significant differences in the biophysical characteristics of DPAP nanoparticles generated using the two homogenization techniques. The DPAP formulation demonstrated a strong targeting performance and selectivity towards its target receptor molecules in the presence of non-targets. The DPAP formulation demonstrated a controlled and sustained drug release profile under the conditions of pH 7 and temperature 37 °C. Also, the drug release rate of DPAP formulation was successfully accelerated under an endosomal acidic condition of ∼pH 5.5, indicating the potential to enhance drug delivery within the endosomal micro-environment. The findings from this work are useful to understanding polymer-aptamer-drug relationship and their impact on developing effective targeted delivery systems. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Electrosynthesis of magnetoresponsive microrobot for targeted drug delivery using calcium alginate.

PubMed

Chengzhi Hu; Riederer, Katharina; Klemmer, Michael; Pane, Salvador; Nelson, Bradley J

2016-08-01

Targeted drug delivery systems deliver drugs precisely to a specific targeted site inside the body, and can also release the drugs with controlled kinetics to prolong the efficacy of single dose administration. The advantageous properties of hydrogels make them attractive for use in the area of drug delivery. Calcium alginate is a pH sensitive hydrogel stable in acidic media and soluble in basic media. This enables the hydrogel to absorb and release aqueous solutions at certain ranges of pH values. By absorbing an aqueous solution containing a drug, an active drug release can be triggered at a specified range of pH value. In this paper, we combined calcium alginate with cobalt nickel (CoNi) in a cylindrical hybrid micro robot by electrodeposition. The designed microrobot can be wirelessly actuated with an external magnetic manipulation system and, hence, targeted to a specific location in the human body. At this specific location, characterized by its pH range, the absorbed drug will be released. Here, the fabrication steps of the specified microrobot are characterized, namely the production of a template on a silicon chip and the subsequent template-assisted electrodeposition of CoNi and alginate. Additionally, the dynamics of drug release of calcium alginate is studied.

Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson's Disease.

PubMed

Baek, Jong-Suep; Tee, Jie Kai; Pang, Yi Yun; Tan, Ern Yu; Lim, Kah Leong; Ho, Han Kiat; Loo, Say Chye Joachim

2018-06-01

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.

Polyanionic carbohydrate doxorubicin–dextran nanocomplex as a delivery system for anticancer drugs: in vitro analysis and evaluations

PubMed Central

Yousefpour, Parisa; Atyabi, Fatemeh; Farahani, Ebrahim Vashegani; Sakhtianchi, Ramin; Dinarvand, Rassoul

2011-01-01

This study deals with the preparation and investigation of a nanoscale delivery system for the anticancer drug doxorubicin (DOX) using its complexation with polyanionic carbohydrate dextran sulfate (DS). Dynamic light scattering, SEM, and zeta potential determination were used to characterize nanocomplexes. DOX-DS complexation was studied in the presence of ethanol as a hydrogen-bond disrupting agent, NaCl as an electrostatic shielding agent, and chitosan as a positively charged polymer. Thermodynamics of DOX-DS interaction was studied using isothermal titration calorimetry (ITC). A dialysis method was applied to investigate the release profile of DOX from DOX-DS nanocomplexes. Spherical and smooth-surfaced DOX-DS nanocomplexes (250–500 nm) with negative zeta potential were formed at a DS/DOX (w/w) ratio of 0.4–0.6, with over 90% drug encapsulation efficiency. DOX when complexed with DS showed lower fluorescence emission and 480 nm absorbance plus a 15 nm bathometric shift in its visible absorbance spectrum. Electrostatic hydrogen bonding and π-π stacking interactions are the main contributing interactions in DOX-DS complexation. Thermal analysis of DOX-DS complexation by ITC revealed that each DOX molecule binds with 3 DS glycosyl monomers. Drug release profile of nanocomplexes showed a fast DOX release followed by a slow sustained release, leading to release of 32% of entrapped DOX within 15 days. DOX-DS nanocomplexes may serve as a drug delivery system with efficient drug encapsulation and also may be taken into consideration in designing DOX controlled-release systems. PMID:21796249

A novel automated alternating current biosusceptometry method to characterization of controlled-release magnetic floating tablets of metronidazole.

PubMed

Ferrari, Priscileila Colerato; dos Santos Grossklauss, Dany Bruno Borella; Alvarez, Matheus; Paixão, Fabiano Carlos; Andreis, Uilian; Crispim, Alexandre Giordano; de Castro, Ana Dóris; Evangelista, Raul Cesar; de Arruda Miranda, José Ricardo

2014-08-01

Alternating Current Biosusceptometry is a magnetically method used to characterize drug delivery systems. This work presents a system composed by an automated ACB sensor to acquire magnetic images of floating tablets. The purpose of this study was to use an automated Alternating Current Biosusceptometry (ACB) to characterize magnetic floating tablets for controlled drug delivery. Floating tablets were prepared with hydroxypropyl methylcellulose (HPMC) as hydrophilic gel material, sodium bicarbonate as gas-generating agent and ferrite as magnetic marker. ACB was used to characterize the floating lag time and the tablet hydration rate, by quantification of the magnetic images to magnetic area. Besides the buoyancy, the floating tablets were evaluated for weight uniformity, hardness, swelling and in vitro drug release. The optimized tablets were prepared with equal amounts of HPMC and ferrite, and began to float within 4 min, maintaining the flotation during more than 24 h. The data of all physical parameters lied within the pharmacopeial limits. Drug release at 24 h was about 40%. The ACB results showed that this study provided a new approach for in vitro investigation of controlled-release dosage forms. Moreover, using automated ACB will also be possible to test these parameters in humans allowing to establish an in vitro.in vivo correlation (IVIVC).

Novel Pentablock Copolymers as Thermosensitive Self-Assembling Micelles for Ocular Drug Delivery

PubMed Central

Alami-Milani, Mitra; Zakeri-Milani, Parvin; Valizadeh, Hadi; Salehi, Roya; Salatin, Sara; Naderinia, Ali; Jelvehgari, Mitra

2017-01-01

Many studies have focused on how drugs are formulated in the sol state at room temperature leading to the formation of in situ gel at eye temperature to provide a controlled drug release. Stimuli-responsive block copolymer hydrogels possess several advantages including uncomplicated drug formulation and ease of application, no organic solvent, protective environment for drugs, site-specificity, prolonged and localized drug delivery, lower systemic toxicity, and capability to deliver both hydrophobic and hydrophilic drugs. Self-assembling block copolymers (such as diblock, triblock, and pentablock copolymers) with large solubility variation between hydrophilic and hydrophobic segments are capable of making temperature-dependent micellar assembles, and with further increase in the temperature, of jellifying due to micellar aggregation. In general, molecular weight, hydrophobicity, and block arrangement have a significant effect on polymer crystallinity, micelle size, and in vitro drug release profile. The limitations of creature triblock copolymers as initial burst release can be largely avoided using micelles made of pentablock copolymers. Moreover, formulations based on pentablock copolymers can sustain drug release for a longer time. The present study aims to provide a concise overview of the initial and recent progresses in the design of hydrogel-based ocular drug delivery systems. PMID:28507933

Controlled release of metformin from chitosan-based nanocomposite films containing mesoporous MCM-41 nanoparticles as novel drug delivery systems.

PubMed

Shariatinia, Zahra; Zahraee, Zahra

2017-09-01

Biocompatible nanocomposite films based on blended chitosan and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (BP) polymers containing metformin (MET) drug and MCM-41 or MCM-41-APS (APS=aminopropylsilane) nanoparticles (NPs) were designed and fabricated in order to prepare novel drug delivery systems which are useful for controlled drug release purposes. The total pore volume and mesopore volume of MCM-41 were measured equal to 1.08 and 1.05 cm 3 /g but those of MCM-41-APS were 0.54 and 0.26 cm 3 /g indicating smaller values for the APS functionalized material. The film thickness was the highest for CS-BP-G-10%MET (70μm) but it was the smallest for the CS-BP-G-4%MCM-41 (49μm). For all of the films, the swelling percent was the highest in acidic medium but it was decreased in PBS and the least water uptake occurred in the alkaline environment. The lowest and the highest water uptake was observed for the films incorporated with 4%MCM-41NPs and 4%MCM-41-APS-10%MET, respectively. The SEM micrographs of the films after three days water uptake in pH=4 medium exhibited that all of the films were stable against cracking and/or tearing. It was found that increasing the MCM-41 or MCM-41-APS amount within the films decreased the elongation at break but enhanced the tensile stress. The release of the MET was sharply increased within ∼22-24h (burst release) but after that the drug release was slowly enhanced during 15days (sustained release). Finally, it was concluded that the film 4% MCM-41-APS-10%MET NPs was the most promising drug delivery system because it had improved hydrophilicity, hydrolytic stability, biocompatibility, mechanical and drug release properties. Copyright © 2017 Elsevier Inc. All rights reserved.

pH-driven colloidal transformations based on the vasoactive drug nicergoline.

PubMed

Salentinig, Stefan; Tangso, Kristian J; Hawley, Adrian; Boyd, Ben J

2014-12-16

The structure of colloidal self-assembled drug delivery systems can be influenced by intermolecular interactions between drug and amphiphilic molecules, and is important to understand in the context of designing improved delivery systems. Controlling these structures can enable controlled or targeted release systems for poorly water-soluble drugs. Here we present the interaction of the hydrophobic vasoactive drug nicergoline with the internal structure of nanostructured emulsion particles based on the monoglyceride-water system. Addition of this drug leads to modification of the internal bicontinuous cubic structure to generate highly pH-responsive systems. The colloidal structures were characterized with small-angle X-ray scattering and visualized using cryogenic transmission electron microscopy. Reversible transformations to inverse micelles at high pH, vesicles at low pH, and the modification of the spacing of the bicontinuous cubic structure at intermediate pH were observed, and enabled the in situ determination of an apparent pKa for the drug in this system--a difficult task using solution-based approaches. The characterization of this phase behavior is also highly interesting for the design of pH-responsive controlled release systems for poorly water-soluble drug molecules.

Fibrin matrices: The versatile therapeutic delivery systems.

PubMed

Ahmad, Ejaj; Fatima, Munazza Tamkeen; Hoque, Mehboob; Owais, Mohammad; Saleemuddin, Mohammed

2015-11-01

Fibrin sealants, that have been employed for over a century by surgeons to stop post surgery bleeding, are finding novel applications in the controlled delivery of antibiotics and several other therapeutics. Fibrinogen can be easily purified from blood plasma and converted by thrombolysis to fibrin that undergoes spontaneous aggregation to form insoluble clot. During the gelling, fibrin can be formulated into films, clots, threads, microbeads, nanoconstructs and nanoparticles. Whole plasma clots in the form of beads and microparticles can also be prepared by activating endogenous thrombin, for possible drug delivery. Fibrin formulations offer remarkable scope for controlling the porosity as well as in vivo degradability and hence the release of the associated therapeutics. Binding/covalent-linking of therapeutics to the fibrin matrix, crosslinking of the matrix with bifunctional reagents and coentrapment of protease inhibitors have been successful in regulating both in vitro and in vivo release of the therapeutics. The release rates can also be remarkably lowered by preentrapment of therapeutics in insoluble particles like liposomes or by anchoring them to the matrix via molecules that bind them as well as fibrin. Copyright © 2015 Elsevier B.V. All rights reserved.

An emerging platform for drug delivery: aerogel based systems.

PubMed

Ulker, Zeynep; Erkey, Can

2014-03-10

Over the past few decades, advances in "aerogel science" have provoked an increasing interest for these materials in pharmaceutical sciences for drug delivery applications. Because of their high surface areas, high porosities and open pore structures which can be tuned and controlled by manipulation of synthesis conditions, nanostructured aerogels represent a promising class of materials for delivery of various drugs as well as enzymes and proteins. Along with biocompatible inorganic aerogels and biodegradable organic aerogels, more complex systems such as surface functionalized aerogels, composite aerogels and layered aerogels have also been under development and possess huge potential. Emphasis is given to the details of the aerogel synthesis and drug loading methods as well as the influence of synthesis parameters and loading methods on the adsorption and release of the drugs. Owing to their ability to increase the bioavailability of low solubility drugs, to improve both their stability and their release kinetics, there are an increasing number of research articles concerning aerogels in different drug delivery applications. This review presents an up to date overview of the advances in all kinds of aerogel based drug delivery systems which are currently under investigation. Copyright © 2014 Elsevier B.V. All rights reserved.

Porous silicon-cyclodextrin based polymer composites for drug delivery applications.

PubMed

Hernandez-Montelongo, J; Naveas, N; Degoutin, S; Tabary, N; Chai, F; Spampinato, V; Ceccone, G; Rossi, F; Torres-Costa, V; Manso-Silvan, M; Martel, B

2014-09-22

One of the main applications of porous silicon (PSi) in biomedicine is drug release, either as a single material or as a part of a composite. PSi composites are attractive candidates for drug delivery systems because they can display new chemical and physical characteristics, which are not exhibited by the individual constituents alone. Since cyclodextrin-based polymers have been proven efficient materials for drug delivery, in this work β-cyclodextrin-citric acid in-situ polymerization was used to functionalize two kinds of PSi (nanoporous and macroporous). The synthesized composites were characterized by microscopy techniques (SEM and AFM), physicochemical methods (ATR-FTIR, XPS, water contact angle, TGA and TBO titration) and a preliminary biological assay was performed. Both systems were tested as drug delivery platforms with two different model drugs, namely, ciprofloxacin (an antibiotic) and prednisolone (an anti-inflammatory), in two different media: pure water and PBS solution. Results show that both kinds of PSi/β-cyclodextrin-citric acid polymer composites, nano- and macro-, provide enhanced release control for drug delivery applications than non-functionalized PSi samples. Copyright © 2014 Elsevier Ltd. All rights reserved.

An implantable thermoresponsive drug delivery system based on Peltier device.

PubMed

Yang, Rongbing; Gorelov, Alexander V; Aldabbagh, Fawaz; Carroll, William M; Rochev, Yury

2013-04-15

Locally dropping the temperature in vivo is the main obstacle to the clinical use of a thermoresponsive drug delivery system. In this paper, a Peltier electronic element is incorporated with a thermoresponsive thin film based drug delivery system to form a new drug delivery device which can regulate the release of rhodamine B in a water environment at 37 °C. Various current signals are used to control the temperature of the cold side of the Peltier device and the volume of water on top of the Peltier device affects the change in temperature. The pulsatile on-demand release profile of the model drug is obtained by turning the current signal on and off. The work has shown that the 2600 mAh power source is enough to power this device for 1.3 h. Furthermore, the excessive heat will not cause thermal damage in the body as it will be dissipated by the thermoregulation of the human body. Therefore, this simple novel device can be implanted and should work well in vivo. Copyright © 2013 Elsevier B.V. All rights reserved.

Trojan particles: Large porous carriers of nanoparticles for drug delivery

PubMed Central

Tsapis, N.; Bennett, D.; Jackson, B.; Weitz, D. A.; Edwards, D. A.

2002-01-01

We have combined the drug release and delivery potential of nanoparticle (NP) systems with the ease of flow, processing, and aerosolization potential of large porous particle (LPP) systems by spray drying solutions of polymeric and nonpolymeric NPs into extremely thin-walled macroscale structures. These hybrid LPPs exhibit much better flow and aerosolization properties than the NPs; yet, unlike the LPPs, which dissolve in physiological conditions to produce molecular constituents, the hybrid LPPs dissolve to produce NPs, with the drug release and delivery advantages associated with NP delivery systems. Formation of the large porous NP (LPNP) aggregates occurs via a spray-drying process that ensures the drying time of the sprayed droplet is sufficiently shorter than the characteristic time for redistribution of NPs by diffusion within the drying droplet, implying a local Peclet number much greater than unity. Additional control over LPNPs physical characteristics is achieved by adding other components to the spray-dried solutions, including sugars, lipids, polymers, and proteins. The ability to produce LPNPs appears to be largely independent of molecular component type as well as the size or chemical nature of the NPs. PMID:12200546

Enzymatic- and temperature-sensitive controlled release of ultrasmall superparamagnetic iron oxides (USPIOs)

PubMed Central

2011-01-01

Background Drug and contrast agent delivery systems that achieve controlled release in the presence of enzymatic activity are becoming increasingly important, as enzymatic activity is a hallmark of a wide array of diseases, including cancer and atherosclerosis. Here, we have synthesized clusters of ultrasmall superparamagnetic iron oxides (USPIOs) that sense enzymatic activity for applications in magnetic resonance imaging (MRI). To achieve this goal, we utilize amphiphilic poly(propylene sulfide)-bl-poly(ethylene glycol) (PPS-b-PEG) copolymers, which are known to have excellent properties for smart delivery of drug and siRNA. Results Monodisperse PPS polymers were synthesized by anionic ring opening polymerization of propylene sulfide, and were sequentially reacted with commercially available heterobifunctional PEG reagents and then ssDNA sequences to fashion biofunctional PPS-bl-PEG copolymers. They were then combined with hydrophobic 12 nm USPIO cores in the thin-film hydration method to produce ssDNA-displaying USPIO micelles. Micelle populations displaying complementary ssDNA sequences were mixed to induce crosslinking of the USPIO micelles. By design, these crosslinking sequences contained an EcoRV cleavage site. Treatment of the clusters with EcoRV results in a loss of R2 negative contrast in the system. Further, the USPIO clusters demonstrate temperature sensitivity as evidenced by their reversible dispersion at ~75°C and re-clustering following return to room temperature. Conclusions This work demonstrates proof of concept of an enzymatically-actuatable and thermoresponsive system for dynamic biosensing applications. The platform exhibits controlled release of nanoparticles leading to changes in magnetic relaxation, enabling detection of enzymatic activity. Further, the presented functionalization scheme extends the scope of potential applications for PPS-b-PEG. Combined with previous findings using this polymer platform that demonstrate controlled drug release in oxidative environments, smart theranostic applications combining drug delivery with imaging of platform localization are within reach. The modular design of these USPIO nanoclusters enables future development of platforms for imaging and drug delivery targeted towards proteolytic activity in tumors and in advanced atherosclerotic plaques. PMID:21352596

Smart Nanostructures for Cargo Delivery: Uncaging and Activating by Light.

PubMed

Karimi, Mahdi; Sahandi Zangabad, Parham; Baghaee-Ravari, Soodeh; Ghazadeh, Mehdi; Mirshekari, Hamid; Hamblin, Michael R

2017-04-05

Nanotechnology has begun to play a remarkable role in various fields of science and technology. In biomedical applications, nanoparticles have opened new horizons, especially for biosensing, targeted delivery of therapeutics, and so forth. Among drug delivery systems (DDSs), smart nanocarriers that respond to specific stimuli in their environment represent a growing field. Nanoplatforms that can be activated by an external application of light can be used for a wide variety of photoactivated therapies, especially light-triggered DDSs, relying on photoisomerization, photo-cross-linking/un-cross-linking, photoreduction, and so forth. In addition, light activation has potential in photodynamic therapy, photothermal therapy, radiotherapy, protected delivery of bioactive moieties, anticancer drug delivery systems, and theranostics (i.e., real-time monitoring and tracking combined with a therapeutic action to different diseases sites and organs). Combinations of these approaches can lead to enhanced and synergistic therapies, employing light as a trigger or for activation. Nonlinear light absorption mechanisms such as two-photon absorption and photon upconversion have been employed in the design of light-responsive DDSs. The integration of a light stimulus into dual/multiresponsive nanocarriers can provide spatiotemporal controlled delivery and release of therapeutic agents, targeted and controlled nanosystems, combined delivery of two or more agents, their on-demand release under specific conditions, and so forth. Overall, light-activated nanomedicines and DDSs are expected to provide more effective therapies against serious diseases such as cancers, inflammation, infections, and cardiovascular disease with reduced side effects and will open new doors toward the treatment of patients worldwide.

Near-IR-induced dissociation of thermally-sensitive star polymers.

PubMed

Dai, Yuqiong; Sun, Hao; Pal, Sunirmal; Zhang, Yunlu; Park, Sangwoo; Kabb, Christopher P; Wei, Wei David; Sumerlin, Brent S

2017-03-01

Responsive systems sensitive to near-infrared (NIR) light are promising for triggered release due to efficient deep tissue penetration of NIR irradiation relative to higher energy sources ( e.g. , UV), allowing for spatiotemporal control over triggering events with minimal potential for tissue damage. Herein, we report star polymers containing thermally-labile azo linkages that dissociate during conventional heating or during localized heating via the photothermal effect upon NIR irradiation. Controlled release during conventional heating was investigated for the star polymers loaded with a model dye, with negligible release being observed at 25 °C and >80% release at 90 °C. Star polymers co-loaded with NIR-responsive indocyanine green showed rapid dye release upon NIR irradiation ( λ ≥ 715 nm) due to the photothermally-induced degradation of azo linkages within the cores of the star polymers. This approach provides access to a new class of delivery and release systems that can be triggered by noninvasive external stimulation.

Ionic Driven Embedment of Hyaluronic Acid Coated Liposomes in Polyelectrolyte Multilayer Films for Local Therapeutic Delivery

NASA Astrophysics Data System (ADS)

Hayward, Stephen L.; Francis, David M.; Sis, Matthew J.; Kidambi, Srivatsan

2015-10-01

The ability to control the spatial distribution and temporal release of a therapeutic remains a central challenge for biomedical research. Here, we report the development and optimization of a novel substrate mediated therapeutic delivery system comprising of hyaluronic acid covalently functionalized liposomes (HALNPs) embedded into polyelectrolyte multilayer (PEM) platform via ionic stabilization. The PEM platform was constructed from sequential deposition of Poly-L-Lysine (PLL) and Poly(Sodium styrene sulfonate) (SPS) “(PLL/SPS)4.5” followed by adsorption of anionic HALNPs. An adsorption affinity assay and saturation curve illustrated the preferential HALNP deposition density for precise therapeutic loading. (PLL/SPS)2.5 capping layer on top of the deposited HALNP monolayer further facilitated complete nanoparticle immobilization, cell adhesion, and provided nanoparticle confinement for controlled linear release profiles of the nanocarrier and encapsulated cargo. To our knowledge, this is the first study to demonstrate the successful embedment of a translatable lipid based nanocarrier into a substrate that allows for temporal and spatial release of both hydrophobic and hydrophilic drugs. Specifically, we have utilized our platform to deliver chemotherapeutic drug Doxorubicin from PEM confined HALNPs. Overall, we believe the development of our HALNP embedded PEM system is significant and will catalyze the usage of substrate mediated delivery platforms in biomedical applications.

Light induced cytosolic drug delivery from liposomes with gold nanoparticles.

PubMed

Lajunen, Tatu; Viitala, Lauri; Kontturi, Leena-Stiina; Laaksonen, Timo; Liang, Huamin; Vuorimaa-Laukkanen, Elina; Viitala, Tapani; Le Guével, Xavier; Yliperttula, Marjo; Murtomäki, Lasse; Urtti, Arto

2015-04-10

Externally triggered drug release at defined targets allows site- and time-controlled drug treatment regimens. We have developed liposomal drug carriers with encapsulated gold nanoparticles for triggered drug release. Light energy is converted to heat in the gold nanoparticles and released to the lipid bilayers. Localized temperature increase renders liposomal bilayers to be leaky and triggers drug release. The aim of this study was to develop a drug releasing system capable of releasing its cargo to cell cytosol upon triggering with visible and near infrared light signals. The liposomes were formulated using either heat-sensitive or heat- and pH-sensitive lipid compositions with star or rod shaped gold nanoparticles. Encapsulated fluorescent probe, calcein, was released from the liposomes after exposure to the light. In addition, the pH-sensitive formulations showed a faster drug release in acidic conditions than in neutral conditions. The liposomes were internalized into human retinal pigment epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) and did not show any cellular toxicity. The light induced cytosolic delivery of calcein from the gold nanoparticle containing liposomes was shown, whereas no cytosolic release was seen without light induction or without gold nanoparticles in the liposomes. The light activated liposome formulations showed a controlled content release to the cellular cytosol at a specific location and time. Triggering with visual and near infrared light allows good tissue penetration and safety, and the pH-sensitive liposomes may enable selective drug release in the intracellular acidic compartments (endosomes, lysosomes). Thus, light activated liposomes with gold nanoparticles are an attractive option for time- and site-specific drug delivery into the target cells. Copyright © 2015 Elsevier B.V. All rights reserved.

In situ forming implants for the delivery of metronidazole to periodontal pockets: formulation and drug release studies.

PubMed

Kilicarslan, Muge; Koerber, Martin; Bodmeier, Roland

2014-05-01

This study was performed to obtain prolonged drug release with biodegradable in situ forming implants for the local delivery of metronidazole to periodontal pockets. The effect of polymer type (capped and uncapped PLGA), solvent type (water-miscible and water-immiscible) and the polymer/drug ratio on in vitro drug release studies were investigated. In situ implants with sustained metronidazole release and low initial burst consisted of capped PLGA and N-methyl-2-pyrolidone as solvent. Mucoadhesive polymers were incorporated into the in situ implants in order to modify the properties of the delivery systems towards longer residence times in vivo. Addition of the polymers changed the adhesiveness and increased the viscosity and drug release of the formulations. However, sustained drug release over 10 days was achievable. Biodegradable in situ forming implants are therefore an attractive delivery system to achieve prolonged release of metronidazole at periodontal therapy.

Controlled Release Strategies for Bone, Cartilage, and Osteochondral Engineering—Part II: Challenges on the Evolution from Single to Multiple Bioactive Factor Delivery

PubMed Central

Santo, Vítor E.; Mano, João F.; Reis, Rui L.

2013-01-01

The development of controlled release systems for the regeneration of bone, cartilage, and osteochondral interface is one of the hot topics in the field of tissue engineering and regenerative medicine. However, the majority of the developed systems consider only the release of a single growth factor, which is a limiting step for the success of the therapy. More recent studies have been focused on the design and tailoring of appropriate combinations of bioactive factors to match the desired goals regarding tissue regeneration. In fact, considering the complexity of extracellular matrix and the diversity of growth factors and cytokines involved in each biological response, it is expected that an appropriate combination of bioactive factors could lead to more successful outcomes in tissue regeneration. In this review, the evolution on the development of dual and multiple bioactive factor release systems for bone, cartilage, and osteochondral interface is overviewed, specifically the relevance of parameters such as dosage and spatiotemporal distribution of bioactive factors. A comprehensive collection of studies focused on the delivery of bioactive factors is also presented while highlighting the increasing impact of platelet-rich plasma as an autologous source of multiple growth factors. PMID:23249320

Drug Release and Skin Permeation from Lipid Liquid Crystalline Phases

NASA Astrophysics Data System (ADS)

Costa-Balogh, F. O.; Sparr, E.; Sousa, J. J. S.; Pais, A. A. C. C.

We have studied drug release and skin permeation from several different liquid crystalline lipid formulations that may be used to control the respective release rates. We have studied the release and permeation through human skin of a water-soluble and amphiphilic drug, propranolol hydrochloride, from several formulations prepared with monoolein and phytantriol as permeation enhancers and controlled release excipients. Diolein and cineol were added to selected formulations. We observed that viscosity decreases with drug load, wich is compatible with the occurrence of phase changes. Diolein stabilizes the bicontinuous cubic phases leading to an increase in viscosity and sustained release of the drug. The slowest release was found for the cubic phases with higher viscosity. Studies on skin permeation showed that these latter formulations also presented lower permeability than the less viscous monoolein lamellar phases. Formulations containing cineol originated higher permeability with higher enhancement ratios. Thus, the various formulations are adapted to different circumstances and delivery routes. While a slow release is usually desired for drug sustained delivery, the transdermal route may require a faster release. Lamellar phases, which are less viscous, are more adapted to transdermal applications. Thus, systems involving lamellar phases of monoolein and cineol are good candidates to be used as skin permeation enhancers for propranolol hydrochloride.

Strategies for Controlled Delivery of Growth Factors and Cells for Bone Regeneration

PubMed Central

Vo, Tiffany N.; Kasper, F. Kurtis; Mikos, Antonios G.

2012-01-01

The controlled delivery of growth factors and cells within biomaterial carriers can enhance and accelerate functional bone formation. The carrier system can be designed with preprogrammed release kinetics to deliver bioactive molecules in a localized, spatiotemporal manner most similar to the natural wound healing process. The carrier can also act as an extracellular matrix-mimicking substrate for promoting osteoprogenitor cellular infiltration and proliferation for integrative tissue repair. This review discusses the role of various regenerative factors involved in bone healing and their appropriate combinations with different delivery systems for augmenting bone regeneration. The general requirements of protein, cell and gene therapy are described, with elaboration on how the selection of materials, configurations and processing affects growth factor and cell delivery and regenerative efficacy in both in vitro and in vivo applications for bone tissue engineering. PMID:22342771

Smart drug release systems based on stimuli-responsive polymers.

PubMed

Qing, Guangyan; Li, Minmin; Deng, Lijing; Lv, Ziyu; Ding, Peng; Sun, Taolei

2013-07-01

Stimuli-responsive polymers could respond to external stimuli, such as temperature, pH, photo-irradiation, electric field, biomolecules in solution, etc., which further induce reversible transformations in the structures and conformations of polymers, providing an excellent platform for controllable drug release, while the accuracy of drug delivery could obtain obvious improvement in this system. In this review, recent progresses in the drug release systems based on stimuli-responsive polymers are summarized, in which drugs can be released in an intelligent mode with high accuracy and efficiency, while potential damages to normal cells and tissues can also be effectively prevented owing to the unique characteristics of materials. Moreover, we introduce some smart nanoparticles-polymers conjugates and drug release devices, which are especially suitable for the long-term sustained drug release.

Biodegradable Hybrid Stomatocyte Nanomotors for Drug Delivery

PubMed Central

2017-01-01

We report the self-assembly of a biodegradable platinum nanoparticle-loaded stomatocyte nanomotor containing both PEG-b-PCL and PEG-b-PS as a potential candidate for anticancer drug delivery. Well-defined stomatocyte structures could be formed even after incorporation of 50% PEG-b-PCL polymer. Demixing of the two polymers was expected at high percentage of semicrystalline poly(ε-caprolactone) (PCL), resulting in PCL domain formation onto the membrane due to different properties of two polymers. The biodegradable motor system was further shown to move directionally with speeds up to 39 μm/s by converting chemical fuel, hydrogen peroxide, into mechanical motion as well as rapidly delivering the drug to the targeted cancer cell. Uptake by cancer cells and fast doxorubicin drug release was demonstrated during the degradation of the motor system. Such biodegradable nanomotors provide a convenient and efficient platform for the delivery and controlled release of therapeutic drugs. PMID:28187254

Magnetic high throughput screening system for the development of nano-sized molecularly imprinted polymers for controlled delivery of curcumin.

PubMed

Piletska, Elena V; Abd, Bashar H; Krakowiak, Agata S; Parmar, Anitha; Pink, Demi L; Wall, Katie S; Wharton, Luke; Moczko, Ewa; Whitcombe, Michael J; Karim, Kal; Piletsky, Sergey A

2015-05-07

Curcumin is a versatile anti-inflammatory and anti-cancer agent known for its low bioavailability, which could be improved by developing materials capable of binding and releasing drug in a controlled fashion. The present study describes the preparation of magnetic nano-sized Molecularly Imprinted Polymers (nanoMIPs) for the controlled delivery of curcumin and their high throughput characterisation using microtitre plates modified with magnetic inserts. NanoMIPs were synthesised using functional monomers chosen with the aid of molecular modelling. The rate of release of curcumin from five polymers was studied under aqueous conditions and was found to correlate well with the binding energies obtained computationally. The presence of specific monomers was shown to be significant in ensuring effective binding of curcumin and to the rate of release obtained. Characterisation of the polymer particles was carried out using dynamic light scattering (DLS) technique and scanning electron microscopy (SEM) in order to establish the relationship between irradiation time and particle size. The protocols optimised during this study could be used as a blueprint for the development of nanoMIPs capable of the controlled release of potentially any compound of interest.

Floating matrix tablets based on low density foam powder: effects of formulation and processing parameters on drug release.

PubMed

Streubel, A; Siepmann, J; Bodmeier, R

2003-01-01

The aim of this study was to develop and physicochemically characterize single unit, floating controlled drug delivery systems consisting of (i). polypropylene foam powder, (ii). matrix-forming polymer(s), (iii). drug, and (iv). filler (optional). The highly porous foam powder provided low density and, thus, excellent in vitro floating behavior of the tablets. All foam powder-containing tablets remained floating for at least 8 h in 0.1 N HCl at 37 degrees C. Different types of matrix-forming polymers were studied: hydroxypropyl methylcellulose (HPMC), polyacrylates, sodium alginate, corn starch, carrageenan, gum guar and gum arabic. The tablets eroded upon contact with the release medium, and the relative importance of drug diffusion, polymer swelling and tablet erosion for the resulting release patterns varied significantly with the type of matrix former. The release rate could effectively be modified by varying the "matrix-forming polymer/foam powder" ratio, the initial drug loading, the tablet geometry (radius and height), the type of matrix-forming polymer, the use of polymer blends and the addition of water-soluble or water-insoluble fillers (such as lactose or microcrystalline cellulose). The floating behavior of the low density drug delivery systems could successfully be combined with accurate control of the drug release patterns.

Retention and release of oil-in-water emulsions from filled hydrogel beads composed of calcium alginate: impact of emulsifier type and pH.

PubMed

Zeeb, Benjamin; Saberi, Amir Hossein; Weiss, Jochen; McClements, David Julian

2015-03-21

Delivery systems based on filled hydrogel particles (microgels) can be fabricated from natural food-grade lipids and biopolymers. The potential for controlling release characteristics by modulating the electrostatic interactions between emulsifier-coated lipid droplets and the biopolymer matrix within hydrogel particles was investigated. A multistage procedure was used to fabricate calcium alginate beads filled with lipid droplets stabilized by non-ionic, cationic, anionic, or zwitterionic emulsifiers. Oil-in-water emulsions stabilized by Tween 60, DTAB, SDS, or whey protein were prepared by microfluidization, mixed with various alginate solutions, and then microgels were formed by simple extrusion into calcium solutions. The microgels were placed into a series of buffer solutions with different pH values (2 to 11). Lipid droplets remained encapsulated under acidic and neutral conditions, but were released under highly basic conditions (pH 11) due to hydrogel swelling when the alginate concentration was sufficiently high. Lipid droplet release increased with decreasing alginate concentration, which could be attributed to an increase in the pore size of the hydrogel matrix. These results have important implications for the design of delivery systems to entrap and control the release of lipophilic bioactive components within filled hydrogel particles.

Sequential Delivery of Cyclopeptide RA-V and Doxorubicin for Combination Therapy on Resistant Tumor and In Situ Monitoring of Cytochrome c Release

PubMed Central

Chen, Huachao; Wang, Yurong; Yao, Yongrong; Qiao, Shenglin; Wang, Hao; Tan, Ninghua

2017-01-01

A programmed drug delivery system that can achieve sequential release of multiple therapeutics under different stimulus holds great promise to enhance the treatment efficacy and overcome multi-drug resistance (MDR) in tumor. Herein, multi-organelle-targeted and pH/ cytochrome c (Cyt c) dual-responsive nanoparticles were designed for combination therapy on resistant tumor. In this system (designated DGLipo NPs), doxorubicin (Dox) was intercalated into the DNA duplex containing a Cyt c aptamer, which subsequently loaded in the dendrigraftpoly-L-lysines (DGL) cores of DGLipo NPs, while cyclopeptide RA-V was doped into the pH-sensitive liposomal shells. After dual modification with c(RGDfK) and mitochondria-penetrating peptide (MPP), DGLipo NPs could successively deliver the two drugs into lysosome and mitochondria of cancer cells, and achieve sequential drug release in virtue of the unique characteristic of these two organelles. The organelle-specific and spatiotemporally controlled release of Dox and RA-V led to enhanced therapeutic outcomes in MDR tumor. More significantly, the DGLipo NPs were successfully applied to monitor Cyt c release during mitochondria-mediated apoptotic process. This work represents a versatile strategy for precise combination therapy against resistant tumor with spatiotemporal control, and provides a potential tool for Cyt c-related apoptotic studies. PMID:29109776

The evaluation of doxycycline controlled release gel versus doxycycline controlled release implant in the management of periodontitis

PubMed Central

Chadha, Vandana Srikrishna; Bhat, Khandige Mahalinga

2012-01-01

Background: Investigators have sought different methods to deliver antimicrobials to periodontal pockets. This study was designed to assess the efficacy of locally made doxycycline gel versus locally made doxycycline implant as biodegradable controlled local delivery systems, by evaluating the pharmacological drug release and improvement in gingival status, gain in attachment, and reduction in pocket depth. Materials and Methods: Thirty patients with localized periodontal pockets ≥5 mm were randomly divided into three groups. The first group received the doxycycline gel, the second the doxycycline implant, and the third received only scaling and root planing (the control group). The patients in the first two groups were selected for the drug release. Clinical parameters such as gingival index, plaque index, probing depth, and attachment levels were recorded at baseline and the 90th day. Gingival crevicular fluid (GCF) and saliva samples were collected 1 hour following gel and implant placement and then on the 10th, 30th, and 60th days. Results: There was a statistically significant difference in the release of doxycycline from the gel when compared with the implant in the GCF and saliva on the 10th and 30th days. All the three groups showed improvement in clinical parameters. The improvements in both gel and implant groups were greater when compared with the control group with no statistically significant difference between the implant and gel systems. Conclusion: The use of local delivery of doxycycline through gel and Implant media further enhances the positive changes obtained following scaling and root planing. The release of doxycycline from the implant and the gel was comparable. PMID:23055585

Drug Delivery of the Future: Chasing the Invisible Gorilla

PubMed Central

Park, Kinam

2015-01-01

For more than 60 years drug delivery systems have produced numerous controlled release formulations helping patients improve compliance and maximize the drug efficacy. Development of new controlled drug delivery systems was very productive during the period 1950-1980. The productivity, as measured by the number of clinically used formulations, dropped significantly during 1980-2010. This reduced productivity needs to be understood so that the future development of drug delivery systems can be accelerated and prolific again. This requires critical evaluation of the current drug delivery field, so that the factors inhibiting rapid progress can be identified and resolved. The current drug delivery field is faced with an invisible gorilla syndrome, i.e., seeing a gorilla when it is not present and missing a gorilla when it actually exists. Overcoming this syndrome requires a new way of thinking, questioning the status quo. Advances in drug delivery technologies occur by an evolutionary process, and thus, the more trials and errors lead to faster advances. The drug delivery area needs to nurture the environment where vastly different ideas can be tested, and all data, positive or negative, need to be exchanged freely as they have equal importance. PMID:26519857

Long-term Controlled Drug Release from bi-component Electrospun Fibers

NASA Astrophysics Data System (ADS)

Xu, Shanshan; Zhang, Zixin; Xia, Qinghua; Han, Charles

Multi-drug delivery systems with timed programmed release are hard to be produced due to the complex drug release kinetics which mainly refers to the diffusion of drug molecules from the fiber and the degradation of the carrier. This study focused on the whole life-time story of the long-term drug releasing fibrous systems. Electrospun membrane utilizing FDA approved polymers and broad-spectrum antibiotics showed specific drug release profiles which could be divided into three stages based on the profile slope. With throughout morphology observation, cumulative release amount and releasing duration, releasing kinetics and critical factors were fully discussed during three stages. Through changing the second component, approximately linear drug release profile and a drug release duration about 13 days was prepared, which is perfect for preventing post-operative infection. The addition of this semi-crystalline polymer in turn influenced the fiber swelling and created drug diffusion channels. In conclusion, through adjusting and optimization of the blending component, initial burst release, delayed release for certain duration, and especially the sustained release profile could all be controlled, as well as specific anti-bacterial behavior could be obtained.

pH-controlled drug loading and release from biodegradable microcapsules.

PubMed

Zhao, Qinghe; Li, Bingyun

2008-12-01

Microcapsules made of biopolymers are of both scientific and technological interest and have many potential applications in medicine, including their use as controlled drug delivery devices. The present study makes use of the electrostatic interaction between polycations and polyanions to form a multilayered microcapsule shell and also to control the loading and release of charged drug molecules inside the microcapsule. Micron-sized calcium carbonate (CaCO3) particles were synthesized and integrated with chondroitin sulfate (CS) through a reaction between sodium carbonate and calcium nitrate tetrahydrate solutions suspended with CS macromolecules. Oppositely charged biopolymers were alternately deposited onto the synthesized particles using electrostatic layer-by-layer self-assembly, and glutaraldehyde was introduced to cross-link the multilayered shell structure. Microcapsules integrated with CS inside the multilayered shells were obtained after decomposition of the CaCO3 templates. The integration of a matrix (i.e., CS) permitted the subsequent selective control of drug loading and release. The CS-integrated microcapsules were loaded with a model drug, bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA), and it was shown that pH was an effective means of controlling the loading and release of FITC-BSA. Such CS-integrated microcapsules may be used for controlled localized drug delivery as biodegradable devices, which have advantages in reducing systemic side effects and increasing drug efficacy.

Stabilization challenges and formulation strategies associated with oral biologic drug delivery systems.

PubMed

Truong-Le, Vu; Lovalenti, Phillip M; Abdul-Fattah, Ahmad M

2015-10-01

Delivery of proteins to mucosal tissues of GI tract typically utilize formulations which protect against proteolysis and target the mucosal tissues. Using case studies from literature and the authors' own work, the in-process stability and solid state storage stability of biopharmaceuticals formulated in delivery systems designed for oral delivery to the GI tract will be reviewed. Among the range of delivery systems, biodegradable polymer systems for protection and controlled release of proteins have been the most studied; hence these systems will be covered in greater depth. These delivery systems include polymeric biodegradable microspheres or nanospheres that contain proteins or vaccines, which are designed to reduce the number of administrations/inoculations and the total protein dose required to achieve the desired biological effect. Specifically, this review will include a landscape survey of the systems that have been studied, the manufacturing processes involved, stability through the manufacturing process, key pharmaceutical formulation parameters that impact stability of the encased proteins, and storage stability of the encapsulated proteins in these delivery systems. Copyright © 2015 Elsevier B.V. All rights reserved.

Effect of co-administration of probiotics with polysaccharide based colon targeted delivery systems to optimize site specific drug release.

PubMed

Prudhviraj, G; Vaidya, Yogyata; Singh, Sachin Kumar; Yadav, Ankit Kumar; Kaur, Puneet; Gulati, Monica; Gowthamarajan, K

2015-11-01

Significant clinical success of colon targeted dosage forms has been limited by their inappropriate release profile at the target site. Their failure to release the drug completely in the colon may be attributed to changes in the colonic milieu because of pathological state, drug effect and psychological stress accompanying the diseased state or, a combination of these. Alteration in normal colonic pH and bacterial picture leads to incomplete release of drug from the designed delivery system. We report the effectiveness of a targeted delivery system wherein the constant replenishment of the colonic microbiota is achieved by concomitant administration of probiotics along with the polysaccharide based drug delivery system. Guar gum coated spheroids of sulfasalazine were prepared. In the dissolution studies, these spheroids showed markedly higher release in the simulated colonic fluid. In vivo experiments conducted in rats clearly demonstrated the therapeutic advantage of co-administration of probiotics with guar gum coated spheroids. Our results suggest that concomitant use of probiotics along with the polysaccharide based delivery systems can be a simple strategy to achieve satisfactory colon targeting of drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

Modulation of release kinetics by plasma polymerization of ampicillin-loaded β-TCP ceramics

NASA Astrophysics Data System (ADS)

Labay, C.; Buxadera-Palomero, J.; Avilés, M.; Canal, C.; Ginebra, M. P.

2016-08-01

Beta-tricalcium phosphate (β-TCP) bioceramics are employed in bone repair surgery. Their local implantation in bone defects puts them in the limelight as potential materials for local drug delivery. However, obtaining suitable release patterns fitting the required therapeutics is a challenge. Here, plasma polymerization of ampicillin-loaded β-TCP is studied for the design of a novel antibiotic delivery system. Polyethylene glycol-like (PEG-like) coating of β-TCP by low pressure plasma polymerization was performed using diglyme as precursor, and nanometric PEG-like layers were obtained by simple and double plasma polymerization processes. A significant increase in hydrophobicity, and the presence of plasma polymer was visible on the surface by SEM and quantified by XPS. As a main consequence of the plasma polymerisation, the release kinetics were successfully modified, avoiding burst release, and slowing down the initial rate of release leading to a 4.5 h delay in reaching the same antibiotic release percentage, whilst conservation of the activity of the antibiotic was simultaneously maintained. Thus, plasma polymerisation on the surface of bioceramics may be a good strategy to design controlled drug delivery matrices for local bone therapies.

Development of a drug delivery system for the treatment of periodontal disease based on bioerodible poly(ortho esters).

PubMed

Roskos, K V; Fritzinger, B K; Rao, S S; Armitage, G C; Heller, J

1995-03-01

Poly(ortho esters) prepared by the condensation of 1,2,6-hexanetriol and an alkyl orthoacetate are viscous, semisolid materials at room temperature that can be injected using a blunt needle. When tetracycline was incorporated into these materials, complete release occurred within about 24 hours, but when small amounts of Mg(OH)2 were incorporated into the polymer release could be extended to many weeks, and a loading of 0.5 wt% resulted in sustained release of about 10 days. When adhesion was tested using bovine teeth, cohesive failure of the pure polymer occurred at a force of about 392 mN cm-2 and cohesive failure of a polymer incorporating 10 wt% tetracycline and 1 wt% (Mg(OH)2 occurred at about 118 mN cm-2. The combination of injectability, dentoadhesiveness and ability to control accurately the release of incorporated antibiotics makes these materials promising candidates for bioerodible delivery systems useful in the treatment of periodontitis. Toxicological studies are currently in progress.

Application of ion exchange resin in floating drug delivery system.

PubMed

Upadhye, Abhijeet A; Ambike, Anshuman A; Mahadik, Kakasaheb R; Paradkar, Anant

2008-10-01

The purpose of this study was to explore the application of low-density ion exchange resin (IER) Tulsion(R) 344, for floating drug delivery system (FDDS), and study the effect of its particle size on rate of complexation, water uptake, drug release, and in situ complex formation. Batch method was used for the preparation of complexes, which were characterized by physical methods. Tablet containing resin with high degree of crosslinking showed buoyancy lag time (BLT) of 5-8 min. Decreasing the particle size of resin showed decrease in water uptake and drug release, with no significant effect on the rate of complexation and in situ complex formation for both preformed complexes (PCs) and physical mixtures (PMs). Thus, low-density and high degree of crosslinking of resin and water uptake may be the governing factor for controlling the initial release of tablet containing PMs but not in situ complex formation. However, further sustained release may be due to in situ complex formation.

Stimuli-sensitive hydrogels: ideal carriers for chronobiology and chronotherapy.

PubMed

Peppas, Nicholas A; Leobandung, William

2004-01-01

The development of solid-phase peptide synthesis in the early 1960s and recombinant DNA technology in the early 1970s boosted the scientific interest of utilizing proteins and peptides as potential therapeutic agents to battle poorly controlled diseases. While there has been rapid progress in the development and synthesis of new proteins and peptides as potential therapeutic agents, the formulation and development of the associated delivery systems is lacking. The development of delivery systems is equally important due to the problems of stability, low bioavailability and short half-life of proteins and peptides. The main problem in this field is that low stability leads to low bioavailability. In this review we draw attention to chrono-pharmacological drug-delivery systems, which can be used to match the delivery of therapeutic agents with the biological rhythm. They are very important especially in endocrinology and in vaccine therapy. We show that the treatment of hypopituitary dwarfism by administration of human growth-hormone-releasing hormone (GHRH) is more effective when GHRH is administered in a pulsatile manner that exhibits a period characteristic of the patient's circadian rhythm. Here we examine how to design novel chrono-pharmacological drug-delivery systems that should be able to release the therapeutic agents at predetermined intervals.

Gelatin Methacrylate Microspheres for Growth Factor Controlled Release

PubMed Central

Nguyen, Anh H.; McKinney, Jay; Miller, Tobias; Bongiorno, Tom; McDevitt, Todd C.

2014-01-01

Gelatin has been commonly used as a delivery vehicle for various biomolecules for tissue engineering and regenerative medicine applications due to its simple fabrication methods, inherent electrostatic binding properties, and proteolytic degradability. Compared to traditional chemical cross-linking methods, such as the use of glutaraldehyde (GA), methacrylate modification of gelatin offers an alternative method to better control the extent of hydrogel cross-linking. Here we examined the physical properties and growth factor delivery of gelatin methacrylate (GMA) microparticles formulated with a wide range of different cross-linking densities (15–90%). Less methacrylated MPs had decreased elastic moduli and larger mesh sizes compared to GA MPs, with increasing methacrylation correlating to greater moduli and smaller mesh sizes. As expected, an inverse correlation between microparticle cross-linking density and degradation was observed, with the lowest cross-linked GMA MPs degrading at the fastest rate, comparable to GA MPs. Interestingly, GMA MPs at lower cross-linking densities could be loaded with up to a 10-fold higher relative amount of growth factor over conventional GA cross-linked MPs, despite an order of magnitude greater gelatin content of GA MPs. Moreover, a reduced GMA cross-linking density resulted in more complete release of bone morphogenic protein 4 (BMP4) and basic fibroblast growth factor (bFGF) and accelerated release rate with collagenase treatment. These studies demonstrate that GMA MPs provide a more flexible platform for growth factor delivery by enhancing the relative binding capacity and permitting proteolytic degradation tunability, thereby offering a more potent controlled release system for growth factor delivery. PMID:25463489

Development of a novel drug delivery system, time-controlled explosion system (TES). IV. In vivo drug release behavior.

PubMed

Ueda, S; Ibuki, R; Kawamura, A; Murata, S; Takahashi, T; Kimura, S; Hata, T

1994-01-01

Time-Controlled Explosion System (TES) has the time-controlled drug release property with a pre-designed lag time. The drug release from the system is initiated by destruction of the membrane. In this study, metoprolol tartrate was used as a model drug. After five types of TES with different in vitro lag times were orally administrated to dogs, plasma metoprolol concentration was monitored. There existed a good correlation between in vitro and in vivo lag time, while the extent of absorbed metoprolol decreased with prolongation of lag time. Next, the in vivo drug release behavior was directly investigated using five different colored TES with a lag time of two hours. Each TES was consecutively administrated to the fasted dogs at predetermined intervals. The amount of metoprolol released was monitored by recovering the administered TES from the gastrointestinal trace. The in vivo release profile corresponded with the in vitro one. It is demonstrated that TES can release the drug in in vivo conditions similarly to in vitro. Based on these results, the decrease of the absorption is suggested to be caused by increased hepatic first-pass metabolism of the drug due to the retarded release rate with longer lag time.

Laser-triggered release of encapsulated molecules from polylactic-co-glycolic acid microcapsules

NASA Astrophysics Data System (ADS)

Ariyasu, Kazumasa; Ishii, Atsuhiro; Umemoto, Taiga; Terakawa, Mitsuhiro

2016-08-01

The controlled release of encapsulated molecules from a microcapsule is a promising method of targeted drug delivery. Laser-triggered methods for the release of encapsulated molecules have the advantage of spatial and temporal controllability. In this study, we demonstrated the release of encapsulated molecules from biodegradable polymer-based microcapsules using near-infrared femtosecond laser pulses. The polylactic-co-glycolic acid microcapsules encapsulating fluorescein isothiocyanate-dextran molecules were fabricated using a dual-coaxial nozzle system. Irradiation of femtosecond laser pulses enhanced the release of the molecules from the microcapsules, which was accompanied by a decrease in the residual ratio of the microcapsules. The laser-induced modification of the surface of the shell of the microcapsules indicated the potential for sustained release as well as burst release.

A review on oral liquid as an emerging technology in controlled drug delivery system.

PubMed

Torne, Sangmesh Raosaheb; Sheela, Angappan; Sarada, N C

2017-12-03

The oral liquid drug delivery system (OLDDS) remains as the primary choice of dosage form, though challenging, for the pharmaceutical scientists. In the last two decades, Oral Liquid Controlled Release (OLCR) formulation has gained a lot of attention because of its advantages over the conventional dosage forms. The world of nanotechnology has paved multiple ways to administer the drug through oral cavity in liquid dosage form with an additional advantage of control over the release. In the current study, the various approaches towards the same have been discussed comprehensively to understand the different mechanisms of OLCR. This review also emphasizes on the existing techniques and the developments that have been made to improve on its efficacy including various formulation related factors. It also provides valuable insights into the role of polymers in the development of OLCR formulation that can be used in the management of Gastroesophageal reflux disease (GERD). Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Dual stimuli-responsive nano-vehicles for controlled drug delivery: mesoporous silica nanoparticles end-capped with natural chitosan.

PubMed

Hakeem, Abdul; Duan, Ruixue; Zahid, Fouzia; Dong, Chao; Wang, Boya; Hong, Fan; Ou, Xiaowen; Jia, Yongmei; Lou, Xiaoding; Xia, Fan

2014-11-11

Herein, we report natural chitosan end-capped MCM-41 type MSNPs as novel, dual stimuli, responsive nano-vehicles for controlled anticancer drug delivery. The chitosan nanovalves tightly close the pores of the MSNPs to control premature cargo release under physiological conditions but respond to lysozyme and acidic media to release the trapped cargo.

Glucose-responsive microgels integrated with enzyme nanocapsules for closed-loop insulin delivery.

PubMed

Gu, Zhen; Dang, Tram T; Ma, Minglin; Tang, Benjamin C; Cheng, Hao; Jiang, Shan; Dong, Yizhou; Zhang, Yunlong; Anderson, Daniel G

2013-08-27

A glucose-responsive closed-loop insulin delivery system represents the ideal treatment of type 1 diabetes mellitus. In this study, we develop uniform injectable microgels for controlled glucose-responsive release of insulin. Monodisperse microgels (256 ± 18 μm), consisting of a pH-responsive chitosan matrix, enzyme nanocapsules, and recombinant human insulin, were fabricated through a one-step electrospray procedure. Glucose-specific enzymes were covalently encapsulated into the nanocapsules to improve enzymatic stability by protecting from denaturation and immunogenicity as well as to minimize loss due to diffusion from the matrix. The microgel system swelled when subjected to hyperglycemic conditions, as a result of the enzymatic conversion of glucose into gluconic acid and protonation of the chitosan network. Acting as a self-regulating valve system, microgels were adjusted to release insulin at basal release rates under normoglycemic conditions and at higher rates under hyperglycemic conditions. Finally, we demonstrated that these microgels with enzyme nanocapsules facilitate insulin release and result in a reduction of blood glucose levels in a mouse model of type 1 diabetes.

Bubble-generating nano-lipid carriers for ultrasound/CT imaging-guided efficient tumor therapy.

PubMed

Zhang, Nan; Li, Jia; Hou, Ruirui; Zhang, Jiangnan; Wang, Pei; Liu, Xinyang; Zhang, Zhenzhong

2017-12-20

Ideal therapeutic effectiveness of chemotherapy is obtained only when tumor cells are exposed to a maximal drug concentration, which is often hindered by dose-limiting toxicity. We designed a bubble-generating liposomal delivery system by introducing ammonium bicarbonate and gold nanorods into folic acid-conjugated liposomes to allow both multimodal imaging and the local release of drug (doxorubicin) with hyperthermia. The key component, ammonium bicarbonate, allows a controlled, rapid release of doxorubicin to provide an effective drug concentration in the tumor microenvironment. An in vitro temperature-triggered drug release study showed that cumulative release improved more than two-fold. In addition, in vitro and in vivo studies indicated that local heat treatment or ultrasonic cavitation enhanced the therapeutic efficiency greatly. The delivery system could also serve as an excellent contrast agent to allow ultrasonic imaging and computerized tomography imaging simultaneously to further achieve the aim of accurate diagnostics. Results of this study showed that this versatile bubble-generating liposome is a promising system to provide optimal therapeutic effects that are guided by multimodal imaging. Copyright © 2017 Elsevier B.V. All rights reserved.

S-protected thiolated chitosan: Synthesis and in vitro characterization

PubMed Central

Dünnhaupt, Sarah; Barthelmes, Jan; Thurner, Clemens C.; Waldner, Claudia; Sakloetsakun, Duangkamon; Bernkop-Schnürch, Andreas

2012-01-01

Purpose of the present study was the generation and evaluation of novel thiolated chitosans, so-named S-protected thiolated chitosans as mucosal drug delivery systems. Stability of all conjugates concerning swelling and disintegration behavior as well as drug release was examined. Mucoadhesive properties were evaluated in vitro on intestinal mucosa. Different thiolated chitosans were generated displaying increasing amounts of attached free thiol groups on the polymer, whereby more than 50% of these thiol groups were linked with 6-mercaptonicotinamide. Based on the implementation of this hydrophobic residue, the swelling behavior was 2-fold decreased, whereas stability was essentially improved. Their mucoadhesive properties were 2- and 14-fold increased compared to corresponding thiolated and unmodified chitosans, respectively. Release studies out of matrix tablets comprising the novel conjugates revealed a controlled release of a model peptide. Accordingly, S-protected thiomers represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems. PMID:22839999

Inhaled nano- and microparticles for drug delivery

PubMed Central

El-Sherbiny, Ibrahim M.; El-Baz, Nancy M.; Yacoub, Magdi H.

2015-01-01

The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems. PMID:26779496

Controlled release of glaucocalyxin - a self-nanoemulsifying system from osmotic pump tablets with enhanced bioavailability.

PubMed

Yanfei, Miao; Guoguang, Chen; Lili, Ren; Pingkai, Ouyang

2017-03-01

The purpose of this study was to develop a new formulation to enhance the bioavailability simultaneously with controlled release of glaucocalyxin A (GLA). In this study, controlled release of GLA was achieved by the osmotic release strategy taking advantage of the bioavailability enhancing capacity of self-nanoemulsifying drug delivery systems (SNEDDS). The formulation of GLA-SNEDDS was selected by the solubility and pseudoternary-phase diagrams studies. The prepared GLA-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis and zeta potential. The optimized GLA-SNEDDS were used to prepare GLA-SNEDDS osmotic pump tablet via direct powder compression method. The effect of formulation variables on the release characteristic was investigated. GLA-SNEDDS osmotic pump tablets were administered to beagle dogs and their pharmacokinetics were compared to GLA and GLA-SNEDDS as a control. In vitro drug release studies indicated that the GLA-SNEDDS osmotic pump tablet showed sustained release profiles with 90% released within 12 h. Pharmacokinetic study showed steady blood GLA with prolonged T max and mean residence time (MRT), and enhanced bioavailability for GLA-SNEDDS osmotic pump tablet. It was concluded that simultaneous controlling on GLA release and enhanced bioavailability had been achieved by a combination of osmotic pump tablet and SNEDDS.

Sustained delivery of bioactive neurotrophin-3 to the injured spinal cord.

PubMed

Elliott Donaghue, Irja; Tator, Charles H; Shoichet, Molly S

2015-01-01

Spinal cord injury is a debilitating condition that currently lacks effective clinical treatment. Neurotrophin-3 (NT-3) has been demonstrated in experimental animal models to induce axonal regeneration and functional improvements, yet its local delivery remains challenging. For ultimate clinical translation, a drug delivery system is required for localized, sustained, and minimally invasive release. Here, an injectable composite drug delivery system (DDS) composed of biodegradable polymeric nanoparticles dispersed in a hyaluronan/methyl cellulose hydrogel was injected into the intrathecal space to achieve acute local delivery to the spinal cord after a thoracic clip compression injury. NT-3 was encapsulated in the DDS and released in vitro for up to 50 d. With a single injection of the DDS into the intrathecal space of the injured spinal cord, NT-3 diffused ventrally through the cord and was detectable in the spinal cord for at least 28 d therein. Delivery of NT-3 resulted in significant axon growth with no effect on the astroglial response to injury in comparison with vehicle and injury controls. NT-3 treatment promoted functional improvements at 21 d according to the Basso Beattie Bresnahan locomotor scale in comparison with the DDS alone. The sustained delivery of bioactive NT-3 to the injured spinal cord achieved in this study demonstrates the promise of this DDS for central nervous system repair.

Poly (DL-lactide-co-glycolide) (PLGA) nanoparticles with entrapped trans-cinnamaldehyde and eugenol for antimicrobial delivery applications.

PubMed

Gomes, Carmen; Moreira, Rosana G; Castell-Perez, Elena

2011-03-01

Eugenol and trans-cinnamaldehyde are natural compounds known to be highly effective antimicrobials; however, both are hydrophobic molecules, a limitation to their use within the food industry. The goal of this study was to synthesize spherical poly (DL-lactide-co-glycolide) (PLGA) nanoparticles with entrapped eugenol and trans-cinnamaldehyde for future antimicrobial delivery applications. The emulsion evaporation method was used to form the nanoparticles in the presence of poly (vinyl alcohol) (PVA) as a surfactant. The inclusion of antimicrobial compounds into the PLGA nanoparticles was accomplished in the organic phase. Synthesis was followed by ultrafiltration (performed to eliminate the excess of PVA and antimicrobial compound) and freeze-drying. The nanoparticles were characterized by their shape, size, entrapment efficiency, and antimicrobial efficiency. The entrapment efficiency for eugenol and trans-cinnamaldehyde was approximately 98% and 92%, respectively. Controlled release experiments conducted in vitro at 37 °C and 100 rpm for 72 h showed an initial burst followed by a slower rate of release of the antimicrobial entrapped inside the PLGA matrix. All loaded nanoparticles formulations proved to be efficient in inhibiting growth of Salmonella spp. (Gram-negative bacterium) and Listeria spp. (Gram-positive bacterium) with concentrations ranging from 20 to 10 mg/mL. Results suggest that the application of these antimicrobial nanoparticles in food systems may be effective at inhibiting specific pathogens. Nanoencapsulation of lipophilic antimicrobial compounds has great potential for improving the effectiveness and efficiency of delivery in food systems. This study consisted of synthesizing PLGA nanoparticles with entrapped eugenol and trans-cinnamaldehyde. By characterizing these new delivery systems, one can understand the controlled-release mechanism and antimicrobial efficiency that provides a foundation that will enable food manufacturers to design smart food systems for future delivery applications, including packaging and processing, capable of ensuring food safety to consumers.

Effect of Nisin's Controlled Release on Microbial Growth as Modeled for Micrococcus luteus.

PubMed

Balasubramanian, Aishwarya; Lee, Dong Sun; Chikindas, Michael L; Yam, Kit L

2011-06-01

The need for safe food products has motivated food scientists and industry to find novel technologies for antimicrobial delivery for improving food safety and quality. Controlled release packaging is a novel technology that uses the package to deliver antimicrobials in a controlled manner and sustain antimicrobial stress on the targeted microorganism over the required shelf life. This work studied the effect of controlled release of nisin to inhibit growth of Micrococcus luteus (a model microorganism) using a computerized syringe pump system to mimic the release of nisin from packaging films which was characterized by an initially fast rate and a slower rate as time progressed. The results show that controlled release of nisin was strikingly more effective than instantly added ("formulated") nisin. While instant addition experiments achieved microbial inhibition only at the beginning, controlled release experiments achieved complete microbial inhibition for a longer time, even when as little as 15% of the amount of nisin was used as compared to instant addition.

Tough Composite Hydrogels with High Loading and Local Release of Biological Drugs.

PubMed

Li, Jianyu; Weber, Eckhard; Guth-Gundel, Sabine; Schuleit, Michael; Kuttler, Andreas; Halleux, Christine; Accart, Nathalie; Doelemeyer, Arno; Basler, Anne; Tigani, Bruno; Wuersch, Kuno; Fornaro, Mara; Kneissel, Michaela; Stafford, Alexander; Freedman, Benjamin R; Mooney, David J

2018-05-01

Hydrogels are under active development for controlled drug delivery, but their clinical translation is limited by low drug loading capacity, deficiencies in mechanical toughness and storage stability, and poor control over the drug release that often results in burst release and short release duration. This work reports a design of composite clay hydrogels, which simultaneously achieve a spectrum of mechanical, storage, and drug loading/releasing properties to address the critical needs from translational perspectives. The clay nanoparticles provide large surface areas to adsorb biological drugs, and assemble into microparticles that are physically trapped within and toughen hydrogel networks. The composite hydrogels demonstrate feasibility of storage, and extended release of large quantities of an insulin-like growth factor-1 mimetic protein (8 mg mL -1 ) over four weeks. The release rate is primarily governed by ionic exchange and can be upregulated by low pH, which is typical for injured tissues. A rodent model of Achilles tendon injury is used to demonstrate that the composite hydrogels allow for highly extended and localized release of biological drugs in vivo, while demonstrating biodegradation and biocompatibility. These attributes make the composite hydrogel a promising system for drug delivery and regenerative medicine. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

pH- and ion-sensitive polymers for drug delivery

PubMed Central

Yoshida, Takayuki; Lai, Tsz Chung; Kwon, Glen S; Sako, Kazuhiro

2013-01-01

Introduction Drug delivery systems (DDSs) are important for effective, safe, and convenient administration of drugs. pH- and ion-responsive polymers have been widely employed in DDS for site-specific drug release due to their abilities to exploit specific pH- or ion-gradients in the human body. Areas covered Having pH-sensitivity, cationic polymers can mask the taste of drugs and release drugs in the stomach by responding to gastric low pH. Anionic polymers responsive to intestinal high pH are used for preventing gastric degradation of drug, colon drug delivery and achieving high bioavailability of weak basic drugs. Tumor-targeted DDSs have been developed based on polymers with imidazole groups or poly(β-amino ester) responsive to tumoral low pH. Polymers with pH-sensitive chemical linkages, such as hydrazone, acetal, ortho ester and vinyl ester, pH-sensitive cell-penetrating peptides and cationic polymers undergoing pH-dependent protonation have been studied to utilize the pH gradient along the endocytic pathway for intracellular drug delivery. As ion-sensitive polymers, ion-exchange resins are frequently used for taste-masking, counterion-responsive drug release and sustained drug release. Polymers responding to ions in the saliva and gastrointestinal fluids are also used for controlled drug release in oral drug formulations. Expert opinion Stimuli-responsive DDSs are important for achieving site-specific and controlled drug release; however, intraindividual, interindividual and intercellular variations of pH should be considered when designing DDSs or drug products. Combination of polymers and other components, and deeper understanding of human physiology are important for development of pH- and ion-sensitive polymeric DDS products for patients. PMID:23930949

Characterization of Nano Bamboo Charcoal Drug Delivery System for Eucommia ulmoides Extract and Its Anticancer Effect In vitro.

PubMed

Zeng, Zhaoyan; Li, Xiangzhou; Zhang, Sheng; Huang, Dan

2017-01-01

Nano bamboo charcoal is being widely used as sustained release carrier for chemicals for its high specific surface area, sound biocompatibility, and nontoxicity; however, there have been no reports on nano bamboo charcoal as sustained release carrier for traditional Chinese medicine (TCM). To study the effect of nano bamboo charcoal in absorbing and sustained releasing Eucommia ulmoides extract (EUE) and to verify the in vitro anticancer effect of the sustained release liquid, so as to provide a theoretical basis for the development and utilization of nano bamboo charcoal as TCM sustained-release preparation. The adsorption capacity for the nano bamboo charcoal on EUE was measured by Langmuir model, and the release experiment was carried out under intestinal fluid condition. Characteristic changes for the nano bamboo charcoal nano-drug delivery system with and without adsorption of E. ulmoides were evaluated by scanning electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, and specific surface area. In addition, the anticancer effect from this novel bamboo charcoal E. ulmoides delivery system was evaluated against a human colon cancer cell line (HCT116). It was found that nano bamboo charcoal exhibits good adsorption capacity (up to 462.96 mg/g at 37°C). The cumulative release rate for EUE from this nano bamboo charcoal delivery system was 70.67%, and specific surface area for the nano bamboo charcoal decreased from 820.32 m 2 /g to 443.80 m 2 /g after EUE was loaded. An in vitro anticancer study showed that the inhibition rate for E. ulmoides against HCT116 cancer cells was 23.07%, for this novel bamboo charcoal nano-drug delivery system. This study provides a novel strategy for the delivery of traditional Chinese medicine using bamboo charcoal nano-drug delivery system. The adsorption equilibrium was reached after 30 min of ultrasonic treatmentThe saturated adsorption capacity of Eucommia ulmoides extract by nano bamboo charcoal under ultrosonic condition was 462. 96 mg/gThe cumulative release rate of E. ulmoides extract from the nano bamboo charcoal delivery system in artificial intestinal juice was 70.67%The inhibition ratio of HCT116 cancer cells by sustained release liquid was 23.07%. Abbreviation used: EUE: Eucommia ulmoides extract.

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

PubMed

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

2017-01-01

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

Walnut kernel-like mesoporous silica nanoparticles as effective drug carrier for cancer therapy in vitro

NASA Astrophysics Data System (ADS)

Ge, Kun; Ren, Huihui; Sun, Wentong; Zhao, Qi; Jia, Guang; Zang, Aimin; Zhang, Cuimiao; Zhang, Jinchao

2016-03-01

In drug delivery systems, nanocarriers could reduce the degradation and renal clearance of drugs, increase the half-life in the bloodstream and payload of drugs, control the release patterns, and improve the solubility of some insoluble drugs. In particular, mesoporous silica nanoparticles (MSNs) are considered to be attractive nanocarriers for application of delivery systems because of their large surface areas, large pore volume, tunable pore sizes, good biocompatibility, and the ease of surface functionalization. However, the large-scale synthesis of monodisperse MSNs that are smaller than 200 nm remains a challenge. In this study, monodisperse walnut kernel-like MSNs with diameters of approximately 100 nm were synthesized by a sol-gel route on a large scale. The morphology and structure of MSNs were characterized by scanning electron microscope, and transmission electron microscopy, N2 adsorption-desorption isotherms, Zeta potentials, and dynamic light scattering. Drug loading and release profile, cellular uptake, subcellular localization, and anticancer effect in vitro were further investigated. The results indicated that the loading efficiency of doxorubicinhydrochloride (DOX) into the MSNs was 57 %. The MSNs-DOX delivery system exhibited a drug-pronounced initial burst release within 12 h, followed by the slow sustained release of DOX molecules; moreover, MSNs could improve DOX release efficiency in acidic medium. Most free DOX was localized in the cytoplasm, whereas the MSNs-DOX was primarily distributed in lysosome. MSNs-DOX exhibited a potential anticancer effect against MCF-7, HeLa, and A549 cells in dose- and time-dependent manners. In summary, the as-synthesized MSNs may have well function as a promising drug carrier in drug delivery fields.

Indocyanine Green-Loaded Liposomes for Light-Triggered Drug Release.

PubMed

Lajunen, Tatu; Kontturi, Leena-Stiina; Viitala, Lauri; Manna, Moutusi; Cramariuc, Oana; Róg, Tomasz; Bunker, Alex; Laaksonen, Timo; Viitala, Tapani; Murtomäki, Lasse; Urtti, Arto

2016-06-06

Light-triggered drug delivery systems enable site-specific and time-controlled drug release. In previous work, we have achieved this with liposomes containing gold nanoparticles in the aqueous core. Gold nanoparticles absorb near-infrared light and release the energy as heat that increases the permeability of the liposomal bilayer, thus releasing the contents of the liposome. In this work, we replaced the gold nanoparticles with the clinically approved imaging agent indocyanine green (ICG). The ICG liposomes were stable at storage conditions (4-22 °C) and at body temperature, and fast near-infrared (IR) light-triggered drug release was achieved with optimized phospholipid composition and a 1:50 ICG-to-lipid molar ratio. Encapsulated small molecular calcein and FITC-dextran (up to 20 kDa) were completely released from the liposomes after light exposure for 15 s. Location of ICG in the PEG layer of the liposomes was simulated with molecular dynamics. ICG has important benefits as a light-triggering agent in liposomes: fast content release, improved stability, improved possibility of liposomal size control, regulatory approval to use in humans, and the possibility of imaging the in vivo location of the liposomes based on the fluorescence of ICG. Near-infrared light used as a triggering mechanism has good tissue penetration and safety. Thus, ICG liposomes are an attractive option for light-controlled and efficient delivery of small and large drug molecules.

Bioactive Molecule Delivery Systems for Dentin-pulp Tissue Engineering.

PubMed

Shrestha, Suja; Kishen, Anil

2017-05-01

Regenerative endodontic procedures use bioactive molecules (BMs), which are active signaling molecules that initiate and maintain cell responses and interactions. When applied in a bolus form, they may undergo rapid diffusion and denaturation resulting in failure to induce the desired effects on target cells. The controlled release of BMs from a biomaterial carrier is expected to enhance and accelerate functional tissue engineering during regenerative endodontic procedures. This narrative review presents a comprehensive review of different polymeric BM release strategies with relevance to dentin-pulp engineering. Carrier systems designed to allow the preprogrammed release of BMs in a spatial- and temporal-controlled manner would aid in mimicking the natural wound healing process while overcoming some of the challenges faced in clinical translation of regenerative endodontic procedures. Spatial- and temporal-controlled BM release systems have become an exciting option in dentin-pulp tissue engineering; nonetheless, further validation of this concept and knowledge is required for their potential clinical translation. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Drug Delivery Research: The Invention Cycle.

PubMed

Park, Kinam

2016-07-05

Controlled drug delivery systems have been successful in introducing improved formulations for better use of existing drugs and novel delivery of biologicals. The initial success of producing many oral products and some injectable depot formulations, however, reached a plateau, and the progress over the past three decades has been slow. This is likely due to the difficulties of formulating hydrophilic, high molecular weight drugs, such as proteins and nucleic acids, for targeting specific cells, month-long sustained delivery, and pulsatile release. Since the approaches that have served well for delivery of small molecules are not applicable to large molecules, it is time to develop new methods for biologicals. The process of developing future drug delivery systems, termed as the invention cycle, is proposed, and it starts with clearly defining the problems for developing certain formulations. Once the problems are well-defined, creative imagination examines all potential options and selects the best answer and alternatives. Then, innovation takes over to generate unique solutions for developing new formulations that resolve the previously identified problems. Ultimately, the new delivery systems will have to go through a translational process to produce the final formulations for clinical use. The invention cycle also emphasizes examining the reasons for success of certain formulations, not just the reasons for failure of many systems. Implementation of the new invention cycle requires new mechanisms of funding the younger generation of scientists and a new way of identifying their achievements, thereby releasing them from the burden of short-termism.

Three-dimensional printing in pharmaceutics: promises and problems.

PubMed

Yu, Deng Guang; Zhu, Li-Min; Branford-White, Christopher J; Yang, Xiang Liang

2008-09-01

Three-dimensional printing (3DP) is a rapid prototyping (RP) technology. Prototyping involves constructing specific layers that uses powder processing and liquid binding materials. Reports in the literature have highlighted the many advantages of the 3DP system over other processes in enhancing pharmaceutical applications, these include new methods in design, development, manufacture, and commercialization of various types of solid dosage forms. For example, 3DP technology is flexible in that it can be used in applications linked to linear drug delivery systems (DDS), colon-targeted DDS, oral fast disintegrating DDS, floating DDS, time controlled, and pulse release DDS as well as dosage form with multiphase release properties and implantable DDS. In addition 3DP can also provide solutions for resolving difficulties relating to the delivery of poorly water-soluble drugs, peptides and proteins, preparation of DDS for high toxic and potent drugs and controlled-release of multidrugs in a single dosage forms. Due to its flexible and highly reproducible manufacturing process, 3DP has some advantages over conventional compressing and other RP technologies in fabricating solid DDS. This enables 3DP to be further developed for use in pharmaceutics applications. However, there are some problems that limit the further applications of the system, such as the selections of suitable excipients and the pharmacotechnical properties of 3DP products. Further developments are therefore needed to overcome these issues where 3DP systems can be successfully combined with conventional pharmaceutics. Here we present an overview and the potential 3DP in the development of new drug delivery systems.

PELA microspheres with encapsulated arginine-chitosan/pBMP-2 nanoparticles induce pBMP-2 controlled-release, transfected osteoblastic progenitor cells, and promoted osteogenic differentiation.

PubMed

Xu, Xiaolong; Qiu, Sujun; Zhang, Yuxian; Yin, Jie; Min, Shaoxiong

2017-03-01

Repair of the bone injury remains a challenge in clinical practices. Recent progress in tissue engineering and therapeutic gene delivery systems have led to promising new strategies for successful acceleration of bone repair process. The aim of this study was to create a controlled-release system to slowly release the arginine-chitosan/plasmid DNA nanoparticles encoding BMP-2 gene (Arg-CS/pBMP-2 NPs), efficiently transfect osteoblastic progenitor cells, secrete functional BMP-2 protein, and promote osteogenic differentiation. In this study, chitosan was conjugated with arginine to generate arginine-chitosan polymer (Arg-CS) for gene delivery. Mix the Arg-CS with pBMP-2 to condense pBMP-2 into nano-sized particles. In vitro transfection assays demonstrated that the transfection efficiency of Arg-CS/pBMP-2 nanoparticles and the expression level of BMP-2 was obviously exceed control groups. Further, PELA microspheres as the controlled-release carrier for the nanoparticles were used to encapsulate Arg-CS/pBMP-2 NPs. We demonstrated that the Arg-CS/pBMP-2 NPs could slowly release from the PELA microspheres at least for 42 d. During the co-culture with the PELA microspheres, the content of BMP-2 protein secreted by MC3T3-E1 reached the peak at 7 d. After 21d, the secretion of BMP-2 protein still maintain a higher level. The alkaline phosphatase activity, alizarin red staining, and osteogenesis-related gene expression by real-time quantitative PCR analysis all showed the PELA microspheres entrapping with Arg-CS/pBMP-2 NPs can obviously induce the osteogenic differentiation. The results indicated that the Arg-CS is a suitable gene vector which can promote the gene transfection. And the novel PELA microspheres-nanoparticle controlled-release system has potential clinical application in the future after further research.

Structural and biological properties of thermosensitive chitosan-graphene hybrid hydrogels for sustained drug delivery applications.

PubMed

Saeednia, Leyla; Yao, Li; Berndt, Marcus; Cluff, Kim; Asmatulu, Ramazan

2017-09-01

Chitosan has the ability to make injectable thermosensitive hydrogels which has been highly investigated for drug delivery applications. The addition of nanoparticles is one way to increase the mechanical strength of thermosensitive chitosan hydrogel and subsequently and control the burst release of drug. Graphene nanoparticles have shown unique mechanical, optical and electrical properties which can be exploited for biomedical applications, especially in drug delivery. This study, have focused on the mechanical properties of a thermosensitive and injectable hybrid chitosan hydrogel incorporated with graphene nanoparticles. Scanning electron microscope (SEM), Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and X-ray diffraction (XRD) have been used for morphological and chemical characterization of graphene infused chitosan hydrogels. The cell viability and cytotoxicity of graphene-contained hydrogels were analyzed using the alamarBlue ® technique. In-vitro methotrexate (MTX) release was investigated from MTX-loaded hybrid hydrogels as well. As a last step, to evaluate their efficiency as a cancer treatment delivery system, an in vitro anti-tumor test was also carried out using MCF-7 breast cancer cell lines. Results confirmed that a thermosensitive chitosan-graphene hybrid hydrogel can be used as a potential breast cancer therapy system for controlled delivery of methotrexate. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2381-2390, 2017. © 2017 Wiley Periodicals, Inc.

Decades of research in drug targeting to the upper gastrointestinal tract using gastroretention technologies: where do we stand?

PubMed

Awasthi, Rajendra; Kulkarni, Giriraj T

2016-01-01

A major constraint in oral controlled release drug delivery is that not all the drug candidates are absorbed uniformly throughout the gastrointestinal tract (GIT). Drugs having "absorption window" are absorbed in a particular portion of GIT only or are absorbed to a different extent in various segments of the GIT. Thus, only the drug released in the region preceding and in close vicinity to the absorption window is available for absorption. The drug must be released from the dosage form in solution form; otherwise, it is generally not absorbed. Hence, much research has been dedicated to the development of gastroretentive drug delivery systems that may optimize the bioavailability and subsequent therapeutic efficacy of such drugs, as these systems have unique properties to bypass the gastric emptying process. These systems show excellent in vitro results but fail to give desirable in vivo performance. During the last 2-3 decades, researchers from the academia and industries are giving considerable importance in this field. Unfortunately, till date, few so-called gastroretentive dosage forms have been brought to the market in spite of numerous academic publications. The manuscript considers strategies that are commonly used in the development of gastroretentive drug delivery systems with a special attention on various parameters, which needs to be monitored during formulation development.

Kinetics and mechanism of release from glyceryl monostearate-based implants: evaluation of release in a gel simulating in vivo implantation.

PubMed

Allababidi, S; Shah, J C

1998-06-01

The overall objective of the study was to design an implantable delivery system based on glyceryl monostearate (GMS) for the site-specific delivery of antibiotics for the prevention of surgical wound infection. To design the implant, a release method had to be developed that simulate the in vivo implantation conditions to be able to predict the release characteristics from the implants when they are actually used in vivo. Also, identifying the release kinetics and mechanism and evaluating the factors that influence the release of drugs from the GMS-based matrix were necessary to allow further design of implants that could yield a desired release rate. The release of cefazolin was monitored from GMS matrixes implanted into agar gel, simulating subcutaneous tissues with respect to viscosity and water content. The gel method resulted in observation of spatial and temporal concentration profiles in the immediate vicinity of the implants, indicating the benefits of local drug delivery; however, there was no significant difference between the cumulative release profiles by the gel method or the vial release method. The release of cefazolin from the GMS-based matrix with the vial method followed Higuchi's square root of time kinetics. The release rate was found to be directly proportional to cefazolin load (A) and the surface area (SA) of the matrix as expressed by the following equation: = 0.24ASA. On the basis of this equation, one can design a variety of GMS matrixes that would result in a desired release rate or release duration. This also indicated that cefazolin release followed the release kinetics of a freely soluble drug from an insoluble matrix and hence it is a diffusion-controlled process. The effect of drug solubility on the release kinetics was determined by comparing the release kinetics of the poorly water soluble ciprofloxacin (0.16 mg/mL) to that of the highly water soluble cefazolin (325 mg/mL). The release duration of ciprofloxacin (80 h) was longer than that of cefazolin (25 h) from identical GMS matrixes. Although ciprofloxacin release was initially controlled by the matrix, agitation accelerated disintegration of the matrix and release due to its poor solubility, and ciprofloxacin release appeared to be a dissolution-controlled process following zero-order release kinetics.

In situ gelling polymers in ocular drug delivery systems: a review.

PubMed

Mundada, Atish S; Avari, Jasmine G

2009-01-01

The review article aims to highlight the recent developments in various in situ gel-forming polymeric systems that are used to achieve prolonged contact time of drugs with the cornea and increase their ocular bioavailability. These phase-change polymers, which trigger the drug release in response to external stimuli, are the most investigated in controlled drug delivery. The present review summarizes in detail these various polymers, which undergo sol-gel transition due to physical (temperature) or chemical (pH, ions) stimuli when instilled in the eye. As a whole, this article provides valuable insight into current trends in the field of in situ gel-forming ocular drug delivery systems.

Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses.

PubMed

Morris, Aaron H; Mahal, Rajwant S; Udell, Jillian; Wu, Michelle; Kyriakides, Themis R

2017-10-01

Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core-shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-κB (NF-κB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-β (TGF-β)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Using Gamma-Radiation for Drug Releasing from MWNT Vehicle

NASA Astrophysics Data System (ADS)

Li, Jun; Sun, Hao; Dai, Yao-Dong

2010-03-01

A drug delivery system via multi-walled carbon nanotube (MWNT) vehicle was synthesized in aqueous solution. MWNTs were first noncovalently functionalized with chitosan oligomers (CS) with a molecule weight of 4000-6000, making MWNTs water-soluble, and then a cancer ancillary drug tea polyphenols (TP) was conjugated mainly via the hydrogen bond between CS and TP molecules, making MWNTs efficient vehicle for drug delivering. The release of drug molecules can be realized by pH variation and γ-radiation, leading to new methods for controlling drug release from carbon nanotubes carrier. Due to the high penetrability of γ-rays, γ-radiation shows up new opportunities in controlled drug release, possibly facilitating the future cancer treatment in vivo.

Cyclodextrin based nanosponges for pharmaceutical use: a review.

PubMed

Tejashri, Gursalkar; Amrita, Bajaj; Darshana, Jain

2013-09-01

Nanosponges are a novel class of hyper-crosslinked polymer based colloidal structures consisting of solid nanoparticles with colloidal sizes and nanosized cavities. These nano-sized colloidal carriers have been recently developed and proposed for drug delivery, since their use can solubilize poorly water-soluble drugs and provide prolonged release as well as improve a drug's bioavailability by modifying the pharmacokinetic parameters of actives. Development of nanosponges as drug delivery systems, with special reference to cyclodextrin based nanosponges, is presented in this article. In the current review, attempts have been made to illustrate the features of cyclodextrin based nanosponges and their applications in pharmaceutical formulations. Special emphasis has been placed on discussing the methods of preparation, characterization techniques and applications of these novel drug delivery carriers for therapeutic purposes. Nanosponges can be referred to as solid porous particles having a capacity to load drugs and other actives into their nanocavity; they can be formulated as oral, parenteral, topical or inhalation dosage forms. Nanosponges offer high drug loading compared to other nanocarriers and are thus suitable for solving issues related to stability, solubility and delayed release of actives. Controlled release of the loaded actives and solubility enhancement of poorly water-soluble drugs are major advantages of nanosponge drug delivery systems.

Ultrasound enhanced release of therapeutics from drug-releasing implants based on titania nanotube arrays.

PubMed

Aw, Moom Sinn; Losic, Dusan

2013-02-25

A non-invasive and external stimulus-driven local drug delivery system (DDS) based on titania nanotube (TNT) arrays loaded with drug encapsulated polymeric micelles as drug carriers and ultrasound generator is described. Ultrasound waves (USW) generated by a pulsating sonication probe (Sonotrode) in phosphate buffered saline (PBS) at pH 7.2 as the medium for transmitting pressure waves, were used to release drug-loaded nano-carriers from the TNT arrays. It was demonstrated that a very rapid release in pulsatile mode can be achieved, controlled by several parameters on the ultrasonic generator. This includes pulse length, time, amplitude and power intensity. By optimization of these parameters, an immediate drug-micelles release of 100% that spans a desirable time of 5-50 min was achieved. It was shown that stimulated release can be generated and reproduced at any time throughout the TNT-Ti implant life, suggesting considerable potential of this approach as a feasible and tunable ultrasound-mediated drug delivery system in situ via drug-releasing implants. It is expected that this concept can be translated from an in vitro to in vivo regime for therapeutic applications using drug-releasing implants in orthopedic and coronary stents. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Synthesis and characterization of mesoporous and hollow-mesoporous MxFe3-xO4 (M=Mg, Mn, Fe, Co, Ni, Cu, Zn) microspheres for microwave-triggered controllable drug delivery

NASA Astrophysics Data System (ADS)

Chen, Ping; Cui, Bin; Bu, Yumei; Yang, Zhenfeng; Wang, Yaoyu

2017-12-01

Spinel ferrites can be used in magnetic targeting and microwave heating and can therefore be used for targeted and controllable drug delivery. We used the cetyltrimethylammonium bromide-assisted solvothermal method to synthesize a series of spinel ferrites (MxFe3-xO4, M=Mg, Mn, Fe, Co, Ni, Cu, Zn) with a mesoporous or hollow-mesoporous structure suitable for direct drug loading and the particle diameters ranging from 200 to 350 nm. We investigated the effects of M2+ cation on the morphology and properties of these products by analyzing their transmission electron microscopy images, mesoporous properties, magnetic properties, and microwave responses. We chose hollow-mesoporous MxFe3-xO4 (M=Fe, Co, Zn) nanoparticles, which had better overall properties, for the drug VP16 (etoposide) loading and microwave-controlled release. The CoxFe3-xO4 and Fe3O4 particles trapped 61.5 and 64.8%, respectively, of the VP16, which were higher than that (60.4%) of ZnxFe3-xO4. Controllable drug release by these simple magnetic nanocarriers can be achieved by microwave irradiation, and VP16-loaded CoxFe3-xO4 released the most VP16 molecules (more than 50% after 1 h and 69.1% after 6 h) under microwave irradiation. Our results confirm the favorable drug loading and microwave-controlled delivery by these ferrites, and lay a theoretical foundation to promote clinical application of the targeted controllable drug delivery system. [Figure not available: see fulltext.

Peptide/protein vaccine delivery system based on PLGA particles.

PubMed

Allahyari, Mojgan; Mohit, Elham

2016-03-03

Due to the excellent safety profile of poly (D,L-lactide-co-glycolide) (PLGA) particles in human, and their biodegradability, many studies have focused on the application of PLGA particles as a controlled-release vaccine delivery system. Antigenic proteins/peptides can be encapsulated into or adsorbed to the surface of PLGA particles. The gradual release of loaded antigens from PLGA particles is necessary for the induction of efficient immunity. Various factors can influence protein release rates from PLGA particles, which can be defined intrinsic features of the polymer, particle characteristics as well as protein and environmental related factors. The use of PLGA particles encapsulating antigens of different diseases such as hepatitis B, tuberculosis, chlamydia, malaria, leishmania, toxoplasma and allergy antigens will be described herein. The co-delivery of antigens and immunostimulants (IS) with PLGA particles can prevent the systemic adverse effects of immunopotentiators and activate both dendritic cells (DCs) and natural killer (NKs) cells, consequently enhancing the therapeutic efficacy of antigen-loaded PLGA particles. We will review co-delivery of different TLR ligands with antigens in various models, highlighting the specific strengths and weaknesses of the system. Strategies to enhance the immunotherapeutic effect of DC-based vaccine using PLGA particles can be designed to target DCs by functionalized PLGA particle encapsulating siRNAs of suppressive gene, and disease specific antigens. Finally, specific examples of cellular targeting where decorating the surface of PLGA particles target orally administrated vaccine to M-cells will be highlighted.

Peptide/protein vaccine delivery system based on PLGA particles

PubMed Central

Allahyari, Mojgan; Mohit, Elham

2016-01-01

abstract Due to the excellent safety profile of poly (D,L-lactide-co-glycolide) (PLGA) particles in human, and their biodegradability, many studies have focused on the application of PLGA particles as a controlled-release vaccine delivery system. Antigenic proteins/peptides can be encapsulated into or adsorbed to the surface of PLGA particles. The gradual release of loaded antigens from PLGA particles is necessary for the induction of efficient immunity. Various factors can influence protein release rates from PLGA particles, which can be defined intrinsic features of the polymer, particle characteristics as well as protein and environmental related factors. The use of PLGA particles encapsulating antigens of different diseases such as hepatitis B, tuberculosis, chlamydia, malaria, leishmania, toxoplasma and allergy antigens will be described herein. The co-delivery of antigens and immunostimulants (IS) with PLGA particles can prevent the systemic adverse effects of immunopotentiators and activate both dendritic cells (DCs) and natural killer (NKs) cells, consequently enhancing the therapeutic efficacy of antigen-loaded PLGA particles. We will review co-delivery of different TLR ligands with antigens in various models, highlighting the specific strengths and weaknesses of the system. Strategies to enhance the immunotherapeutic effect of DC-based vaccine using PLGA particles can be designed to target DCs by functionalized PLGA particle encapsulating siRNAs of suppressive gene, and disease specific antigens. Finally, specific examples of cellular targeting where decorating the surface of PLGA particles target orally administrated vaccine to M-cells will be highlighted. PMID:26513024

Effect of electron beam irradiation on bacterial cellulose membranes used as transdermal drug delivery systems

NASA Astrophysics Data System (ADS)

Stoica-Guzun, Anicuta; Stroescu, Marta; Tache, Florin; Zaharescu, Traian; Grosu, Elena

2007-12-01

Ionizing radiation is an effective energetic source for polymer surfaces modification in order to obtain transdermal systems with different controlled release properties. In this work, gamma rays have been applied to induce changes in bacterial cellulose membranes. Permeation of drug (tetracycline) was theoretically and experimentally investigated starting from the effect of γ-irradiation on membranes permeability. Release and permeation of drug from irradiated and non-irradiated membranes have been performed using a diffusion cell.

Smart Nanostructures for Cargo Delivery: Uncaging and Activating by Light

PubMed Central

Karimi, Mahdi; Zangabad, Parham Sahandi; Baghaee-Ravari, Soodeh; Ghazadeh, Mehdi; Mirshekari, Hamid; Hamblin, Michael R.

2017-01-01

Nanotechnology has begun to play a remarkable role in various fields of science and technology. In biomedical applications, nanoparticles have opened new horizons, especially for biosensing, targeted delivery of therapeutics, and so forth. Among drug delivery systems (DDSs), smart nanocarriers that respond to specific stimuli in their environment represent a growing field. Nanoplatforms that can be activated by an external application of light can be used for a wide variety of photoactivated therapies, especially light-triggered DDSs, relying on photoisomerization, photo-cross-linking/un-cross-linking, photoreduction, and so forth. In addition, light activation has potential in photodynamic therapy, photothermal therapy, radiotherapy, protected delivery of bioactive moieties, anticancer drug delivery systems, and theranostics (i.e., real-time monitoring and tracking combined with a therapeutic action to different diseases sites and organs). Combinations of these approaches can lead to enhanced and synergistic therapies, employing light as a trigger or for activation. Nonlinear light absorption mechanisms such as two-photon absorption and photon upconversion have been employed in the design of light-responsive DDSs. The integration of a light stimulus into dual/multiresponsive nanocarriers can provide spatiotemporal controlled delivery and release of therapeutic agents, targeted and controlled nanosystems, combined delivery of two or more agents, their on-demand release under specific conditions, and so forth. Overall, light-activated nanomedicines and DDSs are expected to provide more effective therapies against serious diseases such as cancers, inflammation, infections, and cardiovascular disease with reduced side effects and will open new doors toward the treatment of patients worldwide. PMID:28192672

Design and in vivo evaluation of a patch delivery system for insulin based on thiolated polymers.

PubMed

Grabovac, Vjera; Föger, Florian; Bernkop-Schnürch, Andreas

2008-02-04

The aim of this study was to develop and evaluate a novel three-layered oral delivery system for insulin in vivo. The patch system consisted of a mucoadhesive layer, a water insoluble backing layer made of ethylcellulose and an enteric coating made of Eudragit. Drug release studies were performed in media mimicking stomach and intestinal fluids. For in vivo studies patch systems were administered orally to conscious non-diabetic rats. Orally administered insulin in aqueous solution was used as control. After the oral administration of the patch systems a decrease of glucose and increase of insulin blood levels were measured. The mucoadhesive layer, exhibiting a diameter of 2.5mm and a weight of 5mg, comprised polycarbophil-cysteine conjugate (49%), bovine insulin (26%), gluthatione (5%) and mannitol (20%). 74.8+/-4.8% of insulin was released from the delivery system over 6h. Six hours after administration of the patch system mean maximum decrease of blood glucose level of 31.6% of the initial value could be observed. Maximum insulin concentration in blood was 11.3+/-6.2ng/ml and was reached 6h after administration. The relative bioavailability of orally administered patch system versus subcutaneous injection was 2.2%. The results indicate that the patch system provides enhancement of intestinal absorption and thereby offers a promising strategy for peroral peptide delivery.

Pharmacosomes: An Emerging Novel Vesicular Drug Delivery System for Poorly Soluble Synthetic and Herbal Drugs

PubMed Central

2013-01-01

In the arena of solubility enhancement, several problems are encountered. A novel approach based on lipid drug delivery system has evolved, pharmacosomes. Pharmacosomes are colloidal, nanometric size micelles, vesicles or may be in the form of hexagonal assembly of colloidal drug dispersions attached covalently to the phospholipid. They act as befitting carrier for delivery of drugs quite precisely owing to their unique properties like small size, amphiphilicity, active drug loading, high entrapment efficiency, and stability. They help in controlled release of drug at the site of action as well as in reduction in cost of therapy, drug leakage and toxicity, increased bioavailability of poorly soluble drugs, and restorative effects. There has been advancement in the scope of this delivery system for a number of drugs used for inflammation, heart diseases, cancer, and protein delivery along with a large number of herbal drugs. Hence, pharmacosomes open new challenges and opportunities for improved novel vesicular drug delivery system. PMID:24106615

Synthesis, characterization and in vitro cytotoxicity analysis of a novel cellulose based drug carrier for the controlled delivery of 5-fluorouracil, an anticancer drug

NASA Astrophysics Data System (ADS)

Anirudhan, Thayyath S.; Nima, Jayachandran; Divya, Peethambaran L.

2015-11-01

The present investigation concerns the development and evaluation of a novel drug delivery system, aminated-glycidylmethacrylate grafted cellulose-grafted polymethacrylic acid-succinyl cyclodextrin (Cell-g-(GMA/en)-PMA-SCD) for the controlled release of 5-Fluorouracil, an anticancer drug. The prepared drug carrier was characterized by FT-IR, XRD and SEM techniques. Binding kinetics and isotherm studies of 5-FU onto Cell-g-(GMA/en)-PMA-SCD were found to follow pseudo-second-order and Langmuir model respectively. Maximum binding capacity of drug carrier was found to be 149.09 mg g-1 at 37 °C. Swelling studies, in vitro release kinetics, drug loading efficiency and encapsulation efficiency of Cell-g-(GMA/en)-PMA-SCD were studied. The release kinetics was analyzed using Ritger-Peppas equation at pH 7.4. Cytotoxicity analysis on MCF-7 (human breast carcinoma) cells indicated that the drug carrier shows sustained and controlled release of drug to the target site. Hence, it is evident from this investigation that Cell-g-(GMA/en)-PMA-SCD could be a promising carrier for 5-FU.

Surface functionalized mesoporous silica nanoparticles for intracellular drug delivery

NASA Astrophysics Data System (ADS)

Vivero-Escoto, Juan Luis

Mesoporous silica nanoparticles (MSNs) are a highly promising platform for intracellular controlled release of drugs and biomolecules. Despite that the application of MSNs in the field of intracellular drug delivery is still at its infancy very exciting breakthroughs have been achieved in the last years. A general review of the most recent progress in this area of research is presented, including a description of the latest findings on the pathways of entry into live mammalian cells together with the intracellular trafficking, a summary on the contribution of MSNs to the development of site-specific drug delivery systems, a report on the biocompatibility of this material in vitro andin vivo, and a discussion on the most recent breakthroughs in the synthesis and application of stimuli-responsive mesoporous silica-based delivery vehicles. A gold nanoparticles (AuNPs)-capped MSNs-based intracellular photoinduced drug delivery system (PR-AuNPs-MSNs) for the controlled release of anticancer drug inside of human fibroblast and liver cells was synthesized and characterized. We found that the mesoporous channels of MSNs could be efficiently capped by the photoresponsive AuNPs without leaking the toxic drug, paclitaxel, inside of human cells. Furthermore, we demonstrated that the cargo-release property of this PR-AuNPs-MSNs system could be easily photo-controlled under mild and biocompatible conditions in vitro. In collaboration with Renato Mortera (a visiting student from Italy), a MSNs based intracellular delivery system for controlled release of cell membrane impermeable cysteine was developed. A large amount of cysteine molecules were covalently attached to the silica surface of MSNs through cleavable disulfide linkers. These cysteine-containing nanoparticles were efficiently endocytosed by human cervical cancer cells HeLa. These materials exhibit 450 times higher cell growth inhibition capability than that of the conventional N-acetylcysteine prodrug. The ability to functionalize the surface of the MSNs with organic groups was used as a way to incorporate functional molecules that can interact with intracellular structures. A series of oligonucleotides intercalating (propidium) derivative functionalized MSNs (PAP-LP-MSNs and AP-PAP-MSNs) materials were synthesized. We selectively decorated the exterior particle surface of PAP-LP-MSN and the interior pore surface of AP-PAP-MSN with the oligonucleotide intercalating functionality. We observed that these materials are internalized by HeLa cells despite that the propidium group is known by its cell membrane impermeable properties. By confocal microscopy and flow cytometry, we demonstrated that indeed PAP-LP-MSNs were able to bind to cytoplasmic oligonucleotides; such as messenger RNA, resulting in severe cell growth inhibition. In contrast, the cytotoxicity of AP-PAP-MSN, where the same oligonucleotide intercalating molecules were anchored inside the pores, was significantly lowered upon the endocytosis by HeLa cells. The results obtained prove that the biocompatibility and cell membrane trafficking properties of MSNs could be modified by selective functionalization of the two different surfaces (exterior particle and interior pore surfaces) and morphology control of MSNs.

Programmed near-infrared light-responsive drug delivery system for combined magnetic tumor-targeting magnetic resonance imaging and chemo-phototherapy.

PubMed

Feng, Qianhua; Zhang, Yuanyuan; Zhang, Wanxia; Hao, Yongwei; Wang, Yongchao; Zhang, Hongling; Hou, Lin; Zhang, Zhenzhong

2017-02-01

In this study, an intelligent drug delivery system was developed by capping doxorubicin (DOX)-loaded hollow mesoporous CuS nanoparticles (HMCuS NPs) with superparamagnetic iron oxide nanoparticles (IONPs). Under near infrared (NIR) light irradiation, the versatile HMCuS NPs could exploit the merits of both photothermal therapy (PTT) and photodynamic therapy (PDT) simultaneously. Herein, the multifunctional IONPs as gatekeeper with the enhanced capping efficiency were supposed to realize "zero premature release" and minimize the adverse side effects during the drug delivery in vivo. More importantly, the hybrid metal nanoplatform (HMCuS/DOX@IONP-PEG) allowed several emerging exceptional characteristics. Our studies have substantiated the hybrid nanoparticles possessed an enhanced PTT effect due to coupled plasmonic resonances with an elevated heat-generating capacity. Notably, an effective removal of IONP-caps occurred after NIR-induced photo-hyperthermia via weakening of the coordination interactions between HMCuS-NH 2 and IONPs, which suggested the feasibility of sophisticated controlled on-demand drug release upon exposing to NIR stimulus with spatial/temporal resolution. Benefiting from the favorable magnetic tumor targeting efficacy, the in vitro and in vivo experiments indicated a remarkable anti-tumor therapeutic efficacy under NIR irradiation, resulting from the synergistic combination of chemo-phototherapy. In addition, T 2 -weighted magnetic resonance imaging (MRI) contrast performance of IONPs provided the identification of cancerous lesions. Based on these findings, the well-designed drug delivery system via integration of programmed functions will provide knowledge for advancing multimodality theranostic strategy. As we all know, a series of shortcomings of conventional chemotherapy such as limited stability, rapid clearing and non-specific tumor targeting ability remain a significant challenge to achieve successful clinical therapeutic efficiency in cancer treatments. Fortunately, developing drug delivery system under the assistance of multifunctional nanocarries might be a great idea. For the first time, we proposed an intelligent drug delivery system by capping DOX-loaded hollow mesoporous CuS nanoparticles (HMCuS NPs) with multifunctional IONPs to integrate programmed functions including enhanced PTT effect, sophisticated controlled drug release, magnetic targeting property and MR imaging. The results showed HMCuS/DOX@IONP-PEG could significantly enhance anti-tumor therapeutic efficacy due to the synergistic combination of chemo-phototherapy. By this delicate design, we believe such smart and extreme versatile all-in-one drug delivery platform could arouse broad interests in the fields of biomaterials, nanotechnology, and drug delivery system. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Exploiting for medical and biological applications

NASA Astrophysics Data System (ADS)

Giano, Michael C.

Biotherapeutics are an emerging class of drug composed of molecules ranging in sizes from peptides to large proteins. Due to their poor stability and mucosal membrane permeability, biotherapeutics are administered by a parenteral method (i.e., syringe, intravenous or intramuscular). Therapeutics delivered systemically often experience short half-lives. While, local administration may involve invasive surgical procedures and suffer from poor retention at the site of application. To compensate, the patient receives frequent doses of highly concentrated therapeutic. Unfortunately, the off-target side effects and discomfort associated with multiple injections results in poor patient compliance. Therefore, new delivery methods which can improve therapeutic retention, reduce the frequency of administration and may aid in decreasing the off-target side effects is a necessity. Hydrogels are a class of biomaterials that are gaining interests for tissue engineering and drug delivery applications. Hydrogel materials are defined as porous, 3-dimensional networks that are primarily composed of water. Generally, they are mechanically rigid, cytocompatible and easily chemically functionalized. Collectively, these properties make hydrogels fantastic candidates to perform as drug delivery depots. Current hydrogel delivery systems physically entrap the target therapeutic which is then subsequently released over time at the site of administration. The swelling and degradation of the material effect the diffusion of the therapy from the hydrogel, and therefore should be controlled. Although these strategies provide some regulation over therapeutic release, full control of the delivery is not achieved. Newer approaches are focused on designing hydrogels that exploit known interactions, covalently attach the therapy or respond to an external stimulus in an effort to gain improved control over the therapy's release. Unfortunately, the biotherapeutic is typically required to be chemically functionalized which can lead to loss in function. Additionally, cytotoxic crosslinkers are employed to formulate hydrogels, providing another obstacle for their application. Therefore, newer materials that can provide various delivery profiles, remain cytocompatible with little or no loss in therapeutic activity are required. This thesis is focused on controlling material degradation and protein loading to modulate the release and activity of therapeutic proteins. In the first part of this thesis a series of five hydrogels prepared from self-assembling beta-hairpin peptides were designed to be enzymatically degraded by matrix metalloproteinase-13 (MMP-13) at controllable rates with the potential to effect on demand release of biotherapies. Hydrogel degradation products were characterized by high performance liquid chromatography and identified by mass spectrometry. Oscillatory rheology showed that various degradation profiles can be achieved by changing the primary amino acid sequence. An in vitro migration study showed that a model cell line was capable of degrading, invading and migrating through select hydrogels is possible. For applications that require steady delivery of a therapeutic, an alternative approach to controlling hydrogel degradation is to design a material whose degradation is dictated by hydrolysis. In the second part of the dissertation, the design and study of a novel bioadhesive hydrogel formed by mixing solutions of dextran-aldehyde and target protein(s) was studied for its potential use as a localized steady delivery system. The effect of changing the dextran chain length, dextran percent oxidiation, dextran concentration and crosslinking protein concentration on the mechanical and bioadhesive properties was explored with dynamic oscillatory rheology and lap-shear uniaxial tension measurements, respectively. Model degradation and release studies were performed in vitro and in vivo with a model fluorescent protein (eGFP). In addition, a therapeutically relevant recombinant interleukin-2 (rIL-2) was co-crosslinked with BSA and biologic function was assessed upon its release from the hydrogel network to gain insight into the hydrogels ability to delivery biotherapeutics. Lastly, the utility of the dextran-aldehyde crosslinked with polyethylenimine (PEI) bioadhesive hydrogel to prevent surgical site infections was explored. Surgical site infections that occur during the implantation of wound fillers can delay wound healing, resulting in increased antibiotic administration, longer hospital stays and, in the most severe cases, sepsis. To prevent bacterial infection during wound filling a new injectable bioadhesive antibacterial hydrogel was designed exploiting dextran-aldehyde crosslinked networks. Mechanical analysis, mammalian cytocompatibility and antibacterial properties of the material will be discussed.

Photo-triggered release of 5-fluorouracil from a MOF drug delivery vehicle.

PubMed

Roth Stefaniak, Kristina; Epley, Charity C; Novak, Joshua J; McAndrew, Margaret L; Cornell, Hannah D; Zhu, Jie; McDaniel, Dylan K; Davis, Jennifer L; Allen, Irving C; Morris, Amanda J; Grove, Tijana Z

2018-06-21

A nano metal-organic-framework (nanoMOF) was employed as a first-of-its kind drug delivery vehicle (DDV) for the photo-controlled release of therapeutics with simultaneous breakdown of the carrier into small molecules.

A sight on protein-based nanoparticles as drug/gene delivery systems.

PubMed

Salatin, Sara; Jelvehgari, Mitra; Maleki-Dizaj, Solmaz; Adibkia, Khosro

2015-01-01

Polymeric nanomaterials have extensively been applied for the preparation of targeted and controlled release drug/gene delivery systems. However, problems involved in the formulation of synthetic polymers such as using of the toxic solvents and surfactants have limited their desirable applications. In this regard, natural biomolecules including proteins and polysaccharide are suitable alternatives due to their safety. According to literature, protein-based nanoparticles possess many advantages for drug and gene delivery such as biocompatibility, biodegradability and ability to functionalize with targeting ligands. This review provides a general sight on the application of biodegradable protein-based nanoparticles in drug/gene delivery based on their origins. Their unique physicochemical properties that help them to be formulated as pharmaceutical carriers are also discussed.

Effect of a controlled-release drug delivery system made of oleanolic acid formulated into multivesicular liposomes on hepatocellular carcinoma in vitro and in vivo

PubMed Central

Luo, Yuling; Liu, Zhongbing; Zhang, Xiaoqin; Huang, Juan; Yu, Xin; Li, Jinwei; Xiong, Dan; Sun, Xiaoduan; Zhong, Zhirong

2016-01-01

The aim of the present study was to develop a novel dosage form of multivesicular liposomes for oleanolic acid (OA) to overcome its poor solubility, prolong therapeutic drug levels in the blood, and enhance the antitumor effect on hepatocellular carcinoma. OA-encapsulated multivesicular liposomes (OA-MVLs) were prepared by a double-emulsion method, and the formulation was optimized by the central composite design. The morphology, particle size, and drug-loading efficiency of OA-MVLs were investigated. Furthermore, OA-MVLs were also characterized both in vitro and in vivo. The results showed that OA-MVLs were spherical particles with an average particle size of 11.57 μm and an encapsulation efficiency of 82.3%±0.61%. OA-MVLs exhibited a sustained-release pattern in vitro, which was fitted to Ritger–Peppas equation. OA-MVLs inhibited the growth of human HepG2 cells which was confirmed by the MTT assay and fluorescence microscopy detection. The in vivo release of OA from OA-MVLs exhibited a sustained manner, indicating a longer circulation time compared to OA solution. The in vivo toxicity study indicated that medium-dose OA-MVLs exerted no toxic effect on the hosts. Importantly, OA-MVLs suppressed the growth of murine H22 hepatoma and prolonged the survival of tumor-bearing mice. In conclusion, the poorly soluble OA could be encapsulated into MVLs to form a novel controlled-release drug delivery system. The present study may hold promise for OA-MVLs as a new dosage form for sustained-release drug delivery in cancer therapy. PMID:27471381

A Review of the Structure, Preparation, and Application of NLCs, PNPs, and PLNs.

PubMed

Li, Qianwen; Cai, Tiange; Huang, Yinghong; Xia, Xi; Cole, Susan P C; Cai, Yu

2017-05-27

Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the characteristics of the SLN, improve drug stability and loading capacity, and prevent drug leakage. Polymer nanoparticles (PNPs) are an important component of drug delivery. These nanoparticles can effectively direct drug delivery to specific targets and improve drug stability and controlled drug release. Lipid-polymer nanoparticles (PLNs), a new type of carrier that combines liposomes and polymers, have been employed in recent years. These nanoparticles possess the complementary advantages of PNPs and liposomes. A PLN is composed of a core-shell structure; the polymer core provides a stable structure, and the phospholipid shell offers good biocompatibility. As such, the two components increase the drug encapsulation efficiency rate, facilitate surface modification, and prevent leakage of water-soluble drugs. Hence, we have reviewed the current state of development for the NLCs', PNPs', and PLNs' structures, preparation, and applications over the past five years, to provide the basis for further study on a controlled release drug delivery system.

A Review of the Structure, Preparation, and Application of NLCs, PNPs, and PLNs

PubMed Central

Li, Qianwen; Cai, Tiange; Huang, Yinghong; Xia, Xi; Cole, Susan P. C.; Cai, Yu

2017-01-01

Nanostructured lipid carriers (NLCs) are modified solid lipid nanoparticles (SLNs) that retain the characteristics of the SLN, improve drug stability and loading capacity, and prevent drug leakage. Polymer nanoparticles (PNPs) are an important component of drug delivery. These nanoparticles can effectively direct drug delivery to specific targets and improve drug stability and controlled drug release. Lipid–polymer nanoparticles (PLNs), a new type of carrier that combines liposomes and polymers, have been employed in recent years. These nanoparticles possess the complementary advantages of PNPs and liposomes. A PLN is composed of a core–shell structure; the polymer core provides a stable structure, and the phospholipid shell offers good biocompatibility. As such, the two components increase the drug encapsulation efficiency rate, facilitate surface modification, and prevent leakage of water-soluble drugs. Hence, we have reviewed the current state of development for the NLCs’, PNPs’, and PLNs’ structures, preparation, and applications over the past five years, to provide the basis for further study on a controlled release drug delivery system. PMID:28554993

Nanostructured Mineral Coatings Stabilize Proteins for Therapeutic Delivery.

PubMed

Yu, Xiaohua; Biedrzycki, Adam H; Khalil, Andrew S; Hess, Dalton; Umhoefer, Jennifer M; Markel, Mark D; Murphy, William L

2017-09-01

Proteins tend to lose their biological activity due to their fragile structural conformation during formulation, storage, and delivery. Thus, the inability to stabilize proteins in controlled-release systems represents a major obstacle in drug delivery. Here, a bone mineral inspired protein stabilization strategy is presented, which uses nanostructured mineral coatings on medical devices. Proteins bound within the nanostructured coatings demonstrate enhanced stability against extreme external stressors, including organic solvents, proteases, and ethylene oxide gas sterilization. The protein stabilization effect is attributed to the maintenance of protein conformational structure, which is closely related to the nanoscale feature sizes of the mineral coatings. Basic fibroblast growth factor (bFGF) released from a nanostructured mineral coating maintains its biological activity for weeks during release, while it maintains activity for less than 7 d during release from commonly used polymeric microspheres. Delivery of the growth factors bFGF and vascular endothelial growth factor using a mineral coated surgical suture significantly improves functional Achilles tendon healing in a rabbit model, resulting in increased vascularization, more mature collagen fiber organization, and a two fold improvement in mechanical properties. The findings of this study demonstrate that biomimetic interactions between proteins and nanostructured minerals provide a new, broadly applicable mechanism to stabilize proteins in the context of drug delivery and regenerative medicine. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A combined chitosan/nano-size hydroxyapatite system for the controlled release of icariin.

PubMed

Fan, Junjun; Bi, Long; Wu, Tao; Cao, Liangguo; Wang, Dexin; Nan, Kaihui; Chen, Jingdi; Jin, Dan; Jiang, Shan; Pei, Guoxian

2012-02-01

Icariin, a plant-derived flavonol glycoside, has been proved as an osteoinductive agent for bone regeneration. For this reason, we developed an icariin-loaded chitosan/nano-sized hydroxyapatite (IC-CS/HA) system which controls the release kinetics of icariin to enhance bone repairing. First, by Fourier transform infrared spectroscopy, we found that icariin was stable in the system developed without undergoing any chemical changes. On the other hand, X-ray diffraction, scanning electron microscopy and mechanical test revealed that the introduction of icariin did not remarkably change the phase, morphology, porosity and mechanical strength of the CS/HA composite. Then the hydrolytic degradation and drug release kinetics in vitro were investigated by incubation in phosphate buffered saline solution. The results indicated that the icariin was released in a temporally controlled manner and the release kinetics could be governed by degradation of both chitosan and hydroxyapatite matrix. Finally the in vitro bioactivity assay revealed that the loaded icariin was biologically active as evidenced by stimulation of bone marrow derived stroma cell alkaline phosphatase activity and formation of mineralized nodules. This successful IC-CS/HA system offers a new delivery method of osteoinductive agents and a useful scaffold design for bone regeneration.

Design of eudragit RL nanoparticles by nanoemulsion method as carriers for ophthalmic drug delivery of ketotifen fumarate

PubMed Central

Soltani, Saieede; Zakeri-Milani, Parvin; Barzegar-Jalali, Mohammad; Jelvehgari, Mitra

2016-01-01

Objective(s): Ketotifen fumarate (KF) is a selective and noncompetitive histamine antagonist (H1-receptor) that is used topically in the treatment of allergic conditions of rhinitis and conjunctivitis. The aim of this study was to formulate and improve an ophthalmic delivery system of KF. Ocular nanoparticles were prepared with the objective of reducing the frequency of administration and obtaining controlled release to improve the anti-inflammatory drug delivery. Materials and Methods: In the present study, ocular KF loaded Eudragit RL 100 nanoparticles were prepared using O/W solvent diffusion method. The nanoparticles were evaluated for particle size, entrapment efficiency, surface morphology, X-ray diffraction (XRD), Fourier transform spectroscopy (FTIR), and differential scanning calorimetry (DSC). In vitro release and permeation studies were also carried out on nanoparticles. Results: An average size range of 182 to 314.30 nm in diameter was obtained and encapsulation efficiency up to 95.0% was observed for all the formulations. Drug release for all formulations after 24 hr was between 65.51% and 88.82% indicating effective controlled release property of KF. The mechanism of drug release for best formulation was found to be fickian diffusion mechanism. KF nanoparticles containing high polymer concentration (1:15) presented a faster drug release and a higher drug penetration; on the contrary, nanoparticles containing low polymer concentration (1:7.5) were able to give a more sustained release of the drug and thus a slower KF permeation through the cornea. Conclusion: The study revealed that KF NPs were capable of releasing the drug for a prolonged period of time and increasing the ocular bioavailability. PMID:27403262

Development and evaluation of emulsion-liposome blends for resveratrol delivery.

PubMed

Hung, Chi-Feng; Chen, Jan-Kan; Liao, Mei-Hui; Lo, Huey-Ming; Fang, Jia-You

2006-01-01

Nano- and submicron-sized vesicles are beneficial for the controlled delivery of drugs. Resveratrol, the main active polyphenol in red wine, was incorporated into various combinations of emulsions and liposomes to examine its physicochemical characteristics and cardiovascular protection. The blends of emulsion-liposome were composed of coconut oil, soybean lecithin, glycerol formal, and non-ionic surfactants. Multiple systems were assessed by evaluating the droplet size, surface charge, drug encapsulation, release rate, and stability. The vesicle diameter of the systems ranged from 114 to 195 nm. The liposomal vesicles in the systems had smaller diameters (of 43 approximately 56 nm) (F6 and F7). Drug encapsulation of approximately 70% were achieved by the vesicles. The inclusion of resveratrol in these systems retarded the drug release in both the presence and absence of plasma in vitro. The emulsion-liposome blends which incorporated Brij 98 (F5) exhibited the slowest release at zero-order for resveratrol delivery. Treatment using resveratrol in the blended formulations dramatically inhibited vascular intimal thickening, which was tested in an experimental model in which endothelial injury was produced in normal rat carotid arteries. Intraperitoneal injection of the multiple systems was associated with no or negligible liver and kidney toxicity. We concluded that encapsulation by the emulsion-liposome blends is a potent way to enhance the preventative and therapeutic benefits of resveratrol.

pH-controlled drug loading and release from biodegradable microcapsules

PubMed Central

Zhao, Qinghe; Li, Bingyun

2013-01-01

Microcapsules made of biopolymers are of both scientific and technological interest and have many potential applications in medicine including their use as controlled drug delivery devices. The present study employs the electrostatic interaction between polycations and polyanions to form a multilayered microcapsule shell and also to control the loading and release of charged drug molecules inside the microcapsule. Micron-sized CaCO3 particles were synthesized and integrated with chondroitin sulfate (CS) through a reaction between Na2CO3 and Ca(NO3)2 solutions suspended with CS macromolecules. Oppositely-charged biopolymers were alternately deposited onto the synthesized particles using electrostatic layer-by-layer self-assembly, and glutaraldehyde was introduced to crosslink the multilayered shell structure. Microcapsules integrated with CS inside the multilayered shells were obtained after decomposition of the CaCO3 templates. The integration of a matrix, i.e. CS, enabled the subsequent selective control of drug loading and release. The CS integrated microcapsules were loaded with a model drug, i.e. bovine serum albumin labeled with fluorescein isothiocyanate (FITC-BSA), and it was shown that pH was an effective means of controlling the loading and release of FITC-BSA. Such CS integrated microcapsules may be used for controlled localized drug delivery as biodegradable devices, which have advantages in reducing systemic side effects and increasing drug efficacy. PMID:18657478

Development of a multilayered association polymer system for sequential drug delivery

NASA Astrophysics Data System (ADS)

Chinnakavanam Sundararaj, Sharath kumar

As all the physiological processes in our body are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the primary objective of this research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. This particular device was designed aimed at the treatment of periodontitis, a highly prevalent oral inflammatory disease that affects 90% of the world population. This condition is caused by bacterial biofilm on the teeth, resulting in a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The polymers used for the fabrication of this multilayered device consists of cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion property of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. After the initial characterization of the CAPP system, the device was specifically modified to achieve sequential release of drugs aimed at the treatment of periodontitis. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. To obtain different erosion times and achieve appropriate release profiles specific to the disease condition, the device was modified by increasing the number of layers or by inclusion of a slower eroding polymer layer. In all the cases, the device was able to release the four different drugs in the designed temporal sequence. Analysis of antibiotic and antiinflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. Following extensive studies on the in vitro sequential drug release from these devices, the in vivo drug release profiles were investigated. The CAPP devices with different release rates and dosage formulations were implanted in a rat calvarial onlay model, and the in vivo drug release and erosion was compared with in vitro results. In vivo studies showed sequential release of drugs comparable to those measured in vitro, with some difference in drug release rates observed. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule. KEYWORDS: Multiple drug delivery, Periodontitis, Cellulose acetate phthalate, Pluronic F-127, Sequential drug release, in vitro drug release, in vivo drug release.

Controlled poorly soluble drug release from solid self-microemulsifying formulations with high viscosity hydroxypropylmethylcellulose.

PubMed

Yi, Tao; Wan, Jiangling; Xu, Huibi; Yang, Xiangliang

2008-08-07

The objective of this work was the development of a controlled release system based on self-microemulsifying mixture aimed for oral delivery of poorly water-soluble drugs. HPMC-based particle formulations were prepared by spray drying containing a model drug (nimodipine) of low water solubility and hydroxypropylmethylcellulose (HPMC) of high viscosity. One type of formulations contained nimodipine mixed with HPMC and the other type of formulations contained HPMC and nimodipine dissolved in a self-microemulsifying system (SMES) consisting of ethyl oleate, Cremophor RH 40 and Labrasol. Based on investigation by transmission electron microscopy (TEM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray powder diffraction, differences were found in the particle structure between both types of formulations. In vitro release was performed and characterized by the power law. Nimodipine release from both types of formulations showed a controlled release profile and the two power law parameters, n and K, correlated to the viscosity of HPMC. The parameters were also influenced by the presence of SMES. For the controlled release solid SMES, oil droplets containing dissolved nimodipine diffused out of HPMC matrices following exposure to aqueous media. Thus, it is possible to control the in vitro release of poorly soluble drugs from solid oral dosage forms containing SMES.

GSH- and pH-responsive drug delivery system constructed by water-soluble pillar[5]arene and lysine derivative for controllable drug release.

PubMed

Wu, Xuan; Li, Yan; Lin, Chen; Hu, Xiao-Yu; Wang, Leyong

2015-04-21

Novel GSH- and pH-responsive supramolecular vesicles constructed by an amphiphilic inclusion complex formed from water-soluble pillar[5]arene and lysine derivative have been successfully developed, which can efficiently encapsulate anticancer drug MTZ and show rapid MTZ-release in a simulated acidic tumor environment with high GSH concentration, and exhibit potent antitumor activity.

An Overview On Various Approaches And Recent Patents On Gastroretentive Drug Delivery Systems.

PubMed

Kumar, Manoj; Kaushik, Deepak

2018-03-08

Drugs having absorption window in the stomach or upper small intestine has restricted bioavailability with conventional dosage forms. The gastric residence time of these dosage forms is usually short and they do not show drug release for prolonged period of time. To avoid these problems and to enhance the bioavailability and gastric retention time of these drugs, controlled drug delivery systems with prolonged gastric retention time are currently being developed. This review highlights the various pharmaceutical approaches for gastroretention such as floating drug delivery systems, mucoadhesive systems, high density systems, expandable and swelling systems, superporous hydrogels systems, magnetic systems, ion exchange resin system and recent patents filed or granted for these approaches. Recently some patents are also reported where a combination of various approaches are being employed to achieve very effective gastroretention. The various patent search sites were used to collect and analyze the information on gastroretentive drug delivery systems. The present study provides valuable information, advantages, limitations and future outlook of various gastroretentive drug delivery systems. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A smart multifunctional nanocomposite for intracellular targeted drug delivery and self-release

NASA Astrophysics Data System (ADS)

Wang, Chan; Lv, Piping; Wei, Wei; Tao, Shengyang; Hu, Tao; Yang, Jingbang; Meng, Changgong

2011-10-01

A multifunctional 'all-in-one' nanocomposite is fabricated using a colloid, template and surface-modification method. This material encompasses magnetic induced target delivery, cell uptake promotion and controlled drug release in one system. The nanocomposite is characterized by scanning electron microscopy, transmission electron microscopy, x-ray diffraction, N2 adsorption and vibrating sample magnetometry. The prepared material has a diameter of 350-400 nm, a high surface area of 420.29 m2 g - 1, a pore size of 1.91 nm and a saturation magnetization of 32 emu g - 1. Doxorubicin (DOX) is loaded in mesopores and acid-sensitive blockers are introduced onto the orifices of the mesopores by a Schiff base linker to implement pH-dependent self-release. Folate was also introduced to improve DOX targeted delivery and endocytosis. The linkers remained intact to block pores with ferrocene valves and inhibit the diffusion of DOX at neutral pH. However, in lysosomes of cancer cells, which have a weak acidic pH, hydrolysis of the Schiff base group removes the nanovalves and allows the trapped DOX to be released. These processes are demonstrated by UV-visible absorption spectra, confocal fluorescence microscopy images and methyl thiazolyl tetrazolium assays in vitro, which suggest that the smart nanocomposite successfully integrates targeted drug delivery with internal stimulus induced self-release and is a potentially useful material for nanobiomedicine.

Drug release from and hydrolytic degradation of a poly(ethylene glycol) grafted poly(3-hydroxyoctanoate).

PubMed

Kim, Hyung Woo; Chung, Chung Wook; Hwang, Sung Joo; Rhee, Young Ha

2005-07-01

Monoacrylate-poly(ethylene glycol)-grafted poly(3-hydroxyoctanoate) (PEGMA-g-PHO) copolymers were synthesized to develop a swelling-controlled release delivery system for ibuprofen as a model drug. The in vitro hydrolytic degradation of and the drug release from a film made of the PEGMA-g-PHO copolymer were carried out in a phosphate buffer saline (pH 7.4) medium. The hydrolytic degradation of the copolymer was strongly dependent on the degree of grafting (DG) of the PEGMA group. The degradation rate of the copolymer films in vitro increased with increasing DG of the PEGMA group on the PHO chain. The copolymer films showed a controlled delivery of ibuprofen to the medium in periods of time that depend on the composition, hydrophilic/hydrophobic characteristics, initial drug loading amount and film thickness of the graft copolymer support. The drug release rate from the grafted copolymer films was faster than the rate of weight loss of the films themselves. In particular, a combination of the low DG of the PEGMA group in the PHO chains with the low ibuprofen solubility in water led to long-term constant release from these matrices in vitro.

Chitosan/alginate multilayer film for controlled release of IDM on Cu/LDPE composite intrauterine devices.

PubMed

Tian, Kuan; Xie, Changsheng; Xia, Xianping

2013-09-01

To reduce such side effects as pain and bleeding caused by copper-containing intrauterine device (Cu-IUD), a novel medicated intrauterine device, which is coated with an indomethacin (IDM) delivery system on the surface of copper/low-density polyethylene (Cu/LDPE) composite intrauterine device, has been proposed and developed in the present work. The IDM delivery system is a polyelectrolyte multilayer film, which is composed of IDM containing chitosan and alginate layer by layer, is prepared by using self-assembled polyelectrolyte multilayer method, and the number of the layers of this IDM containing chitosan/alginate multilayer film can be tailored by controlling the cyclic repetition of the deposition process. After the IDM containing chitosan/alginate multilayer film is obtained on the surface of Cu/LDPE composite intrauterine device, its release behavior of both IDM and cupric ion has been studied in vitro. The results show that the release duration of IDM increase with the increasing of thickness of the IDM containing chitosan/alginate multilayer film, and the initial burst release of cupric ion cannot be found in this novel medicated Cu/LDPE composite IUD. These results can be applied to guide the design of novel medicated Cu-IUD with minimal side effects for the future clinical use. Copyright © 2013 Elsevier B.V. All rights reserved.

Local sustained-release delivery systems of the antibiofilm agent thiazolidinedione-8 for prevention of catheter-associated urinary tract infections.

PubMed

Shenderovich, Julia; Feldman, Mark; Kirmayer, David; Al-Quntar, Abed; Steinberg, Doron; Lavy, Eran; Friedman, Michael

2015-05-15

Thiazolidinedione-8 (TZD-8) is an anti-quorum-sensing molecule that has the potential to effectively prevent catheter-associated urinary tract infections, a major healthcare challenge. Sustained-release drug-delivery systems can enhance drugs' therapeutic potential, by maintaining their therapeutic level and reducing their side effects. Varnishes for sustained release of TZD-8 based on ethylcellulose or ammonio methacrylate copolymer type A (Eudragit(®) RL) were developed. The main factors affecting release rate were found to be film thickness and presence of a hydrophilic or swellable polymer in the matrix. The release mechanism of ethylcellulose-based systems matched the Higuchi model. Selected varnishes were retained on catheters for at least 8 days. Sustained-release delivery systems of TZD-8 were active against Candida albicans biofilms. The present study demonstrates promising results en route to developing applications for the prevention of catheter-associated infections. Copyright © 2015 Elsevier B.V. All rights reserved.

The potential of magneto-electric nanocarriers for drug delivery

PubMed Central

Kaushik, Ajeet; Jayant, Rahul Dev; Sagar, Vidya; Nair, Madhavan

2015-01-01

Introduction The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concentration at the target site, novel nanocarriers (NCs) were designed, for example, magneto-electric (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery. Areas covered This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood-brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted. Expert opinion Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of electrical–magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance. PMID:24986772

The potential of magneto-electric nanocarriers for drug delivery.

PubMed

Kaushik, Ajeet; Jayant, Rahul Dev; Sagar, Vidya; Nair, Madhavan

2014-10-01

The development and design of personalized nanomedicine for better health quality is receiving great attention. In order to deliver and release a therapeutic concentration at the target site, novel nanocarriers (NCs) were designed, for example, magneto-electric (ME) which possess ideal properties of high drug loading, site-specificity and precise on-demand controlled drug delivery. This review explores the potential of ME-NCs for on-demand and site-specific drug delivery and release for personalized therapeutics. The main features including effect of magnetism, improvement in drug loading, drug transport across blood-brain barriers and on-demand controlled release are also discussed. The future directions and possible impacts on upcoming nanomedicine are highlighted. Numerous reports suggest that there is an urgent need to explore novel NC formulations for safe and targeted drug delivery and release at specific disease sites. The challenges of formulation lie in the development of NCs that improve biocompatibility and surface modifications for optimum drug loading/preservation/transmigration and tailoring of electrical-magnetic properties for on-demand drug release. Thus, the development of novel NCs is anticipated to overcome the problems of targeted delivery of therapeutic agents with desired precision that may lead to better patient compliance.

Heparin-based hydrogels with tunable sulfation & degradation for anti-inflammatory small molecule delivery.

PubMed

Peng, Yifeng; Tellier, Liane E; Temenoff, Johnna S

2016-08-16

Sustained release of anti-inflammatory agents remains challenging for small molecule drugs due to their low molecular weight and hydrophobicity. Therefore, the goal of this study was to control the release of a small molecule anti-inflammatory agent, crystal violet (CV), from hydrogels fabricated with heparin, a highly sulfated glycosaminoglycan capable of binding positively-charged molecules such as CV. In this system, both electrostatic interactions between heparin and CV and hydrogel degradation were tuned simultaneously by varying the level of heparin sulfation and varying the amount of dithiothreitol within hydrogels, respectively. It was found that heparin sulfation significantly affected CV release, whereby more sulfated heparin hydrogels (Hep and Hep(-N)) released CV with near zero-order release kinetics (R-squared values between 0.96-0.99). Furthermore, CV was released more quickly from fast-degrading hydrogels than slow-degrading hydrogels, providing a method to tune total CV release between 5-15 days while maintaining linear release kinetics. In particular, N-desulfated heparin hydrogels exhibited efficient CV loading (∼90% of originally included CV), near zero-order CV release kinetics, and maintenance of CV bioactivity after release, making this hydrogel formulation a promising CV delivery vehicle for a wide range of inflammatory diseases.

Optimization of tetracycline hydrochloride adsorption on amino modified SBA-15 using response surface methodology.

PubMed

Hashemikia, Samaneh; Hemmatinejad, Nahid; Ahmadi, Ebrahim; Montazer, Majid

2015-04-01

Several researchers are focused on preparation of mesoporous silica as drug carriers with high loading efficiency to control or sustain the drug release. Carriers with highly loaded drug are utilized to minimize the time of drug intake. In this study, amino modified SBA-15 was synthesized through grafting with amino propyl triethoxy silane and then loaded with tetracycline hydrochloride. The drug loading was optimized by using the response surface method considering various factors including drug to silica ratio, operation time, and temperature. The drug to silica ratio indicated as the most influential factor on the drug loading yield. Further, a quadratic polynomial equation was developed to predict the loading percentage. The experimental results indicated reasonable agreement with the predicted values. The modified and drug loaded mesoporous particles were characterized by FT-IR, SEM, TEM, X-ray diffraction (XRD), elemental analysis and N2 adsorption-desorption. The release profiles of tetracycline-loaded particles were studied in different pH. Also, Higuchi equation was used to analyze the release profile of the drug and to evaluate the kinetic of drug release. The drug release rate followed the conventional Higuchi model that could be controlled by amino-functionalized SBA-15. Further, the drug delivery system based on amino modified SBA-15 exhibits novel features with an appropriate usage as an anti-bacterial drug delivery system with effective management of drug adsorption and release. Copyright © 2014 Elsevier Inc. All rights reserved.

Film coatings for oral pulsatile release.

PubMed

Maroni, Alessandra; Zema, Lucia; Loreti, Giulia; Palugan, Luca; Gazzaniga, Andrea

2013-12-05

Pulsatile delivery is generally intended as a release of the active ingredient that is delayed for a programmable period of time to meet particular chronotherapeutic needs and, in the case of oral administration, also target distal intestinal regions, such as the colon. Most oral pulsatile delivery platforms consist in coated formulations wherein the applied polymer serves as the release-controlling agent. When exposed to aqueous media, the coating initially performs as a protective barrier and, subsequently, undergoes a timely failure based on diverse mechanisms depending on its physico-chemical and formulation characteristics. Indeed, it may be ruptured because of the gradual expansion of the core, swell and/or erode due to the glassy-rubbery polymer transition or become permeable thus allowing the drug molecules to diffuse outwards. Otherwise, when the coating is a semipermeable membrane provided with one or more orifices, the drug is released through the latter as a result of an osmotic water influx. The vast majority of pulsatile delivery systems described so far have been prepared by spray-coating, which offers important versatility and feasibility advantages over other techniques such as press- and dip-coating. In the present article, the design, manufacturing and performance of spray-coated pulsatile delivery platforms is thus reviewed. Copyright © 2013 Elsevier B.V. All rights reserved.

Hierarchical design of a polymeric nanovehicle for efficient tumor regression and imaging

NASA Astrophysics Data System (ADS)

An, Jinxia; Guo, Qianqian; Zhang, Peng; Sinclair, Andrew; Zhao, Yu; Zhang, Xinge; Wu, Kan; Sun, Fang; Hung, Hsiang-Chieh; Li, Chaoxing; Jiang, Shaoyi

2016-04-01

Effective delivery of therapeutics to disease sites significantly contributes to drug efficacy, toxicity and clearance. Here we designed a hierarchical polymeric nanoparticle structure for anti-cancer chemotherapy delivery by utilizing state-of-the-art polymer chemistry and co-assembly techniques. This novel structural design combines the most desired merits for drug delivery in a single particle, including a long in vivo circulation time, inhibited non-specific cell uptake, enhanced tumor cell internalization, pH-controlled drug release and simultaneous imaging. This co-assembled nanoparticle showed exceptional stability in complex biological media. Benefiting from the synergistic effects of zwitterionic and multivalent galactose polymers, drug-loaded nanoparticles were selectively internalized by cancer cells rather than normal tissue cells. In addition, the pH-responsive core retained their cargo within their polymeric coating through hydrophobic interaction and released it under slightly acidic conditions. In vivo pharmacokinetic studies in mice showed minimal uptake of nanoparticles by the mononuclear phagocyte system and excellent blood circulation half-lives of 14.4 h. As a result, tumor growth was completely inhibited and no damage was observed for normal organ tissues. This newly developed drug nanovehicle has great potential in cancer therapy, and the hierarchical design principle should provide valuable information for the development of the next generation of drug delivery systems.Effective delivery of therapeutics to disease sites significantly contributes to drug efficacy, toxicity and clearance. Here we designed a hierarchical polymeric nanoparticle structure for anti-cancer chemotherapy delivery by utilizing state-of-the-art polymer chemistry and co-assembly techniques. This novel structural design combines the most desired merits for drug delivery in a single particle, including a long in vivo circulation time, inhibited non-specific cell uptake, enhanced tumor cell internalization, pH-controlled drug release and simultaneous imaging. This co-assembled nanoparticle showed exceptional stability in complex biological media. Benefiting from the synergistic effects of zwitterionic and multivalent galactose polymers, drug-loaded nanoparticles were selectively internalized by cancer cells rather than normal tissue cells. In addition, the pH-responsive core retained their cargo within their polymeric coating through hydrophobic interaction and released it under slightly acidic conditions. In vivo pharmacokinetic studies in mice showed minimal uptake of nanoparticles by the mononuclear phagocyte system and excellent blood circulation half-lives of 14.4 h. As a result, tumor growth was completely inhibited and no damage was observed for normal organ tissues. This newly developed drug nanovehicle has great potential in cancer therapy, and the hierarchical design principle should provide valuable information for the development of the next generation of drug delivery systems. Electronic supplementary information (ESI) available: Experimental details, 1H NMR spectra and GPC of polymers. See DOI: 10.1039/c6nr01595f

Investigation of Fragment Antibody Stability and Its Release Mechanism from Poly(Lactide-co-Glycolide)-Triacetin Depots for Sustained-Release Applications.

PubMed

Chang, Debby P; Garripelli, Vivek Kumar; Rea, Jennifer; Kelley, Robert; Rajagopal, Karthikan

2015-10-01

Achieving long-term drug release from polymer-based delivery systems continues to be a challenge particularly for the delivery of large hydrophilic molecules such as therapeutic antibodies and proteins. Here, we report on the utility of an in situ-forming and injectable polymer-solvent system for the long-term release of a model antibody fragment (Fab1). The delivery system was prepared by dispersing a spray-dried powder of Fab1 within poly(lactide-co-glycolide) (PLGA)-triacetin solution. The formulation viscosity was within the range 1.0 ± 0.3 Pa s but it was injectable through a 27G needle. The release profile of Fab1, measured in phosphate-buffered saline (PBS), showed a lag phase followed by sustained-release phase for close to 80 days. Antibody degradation during its residence within the depot was comparable to its degradation upon long-term incubation in PBS. On the basis of temporal changes in surface morphology, stiffness, and depot mass, a mechanism to account for the drug release profile has been proposed. The unprecedented release profile and retention of greater than 80% of antigen-binding capacity even after several weeks demonstrates that PLGA-triacetin solution could be a promising system for the long-term delivery of biologics. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Characteristics and degradation of chitosan/cellulose acetate microspheres with different model drugs

NASA Astrophysics Data System (ADS)

Zhou, Hui-yun; Chen, Xi-guang

2008-12-01

In this study, chitosan/cellulose acetate microspheres (CCAM) were prepared by W/O/W emulsification and solvent evaporation as a drug delivery system. The microspheres were spherical, free-flowing and non-aggregated. The CCAM had good flow and suspension ability. The loading efficiency of different model drugs increased with the increasing hydrophobicity of the drug. The loading efficiency of 6-mercaptopurine (6-MP) was more than 30% whereas that of ranitidine hydrochloride (RT) or acetaminophen (ACP) was only 10%. The pH values of solution affected the swelling ability of CCAM and the relative humidity had little effect on the characteristics of CCAM when it was not more than 75%. The CCAM system had a good effect on the controlled release of different model drugs. However, the release rate became slower with the increase of the hydrophobicity of drugs. The release rate of CCAM loaded with hydrophilic RT was almost 60% during 48 h and the release rate of CCAM loaded with hydrophobic drug of 6-MP was not more than 30%. In the meantime, the CCAM system was degradable in vitro and the degradation rate was faster in lysozyme solution than that in the medium of PBS. So the CCAM system was a degradable promising drug delivery system especially for hydrophobic drugs.

Marine structure derived calcium phosphate-polymer biocomposites for local antibiotic delivery.

PubMed

Macha, Innocent J; Cazalbou, Sophie; Ben-Nissan, Besim; Harvey, Kate L; Milthorpe, Bruce

2015-01-20

Hydrothermally converted coralline hydroxyapatite (HAp) particles loaded with medically active substances were used to develop polylactic acid (PLA) thin film composites for slow drug delivery systems. The effects of HAp particles within PLA matrix on the gentamicin (GM) release and release kinetics were studied. The gentamicin release kinetics seemed to follow Power law Korsmeyer Peppas model with mainly diffusional process with a number of different drug transport mechanisms. Statistical analysis shows very significant difference on the release of gentamicin between GM containing PLA (PLAGM) and GM containing HAp microspheres within PLA matrix (PLAHApGM) devices, which PLAHApGM displays lower release rates. The use of HAp particles improved drug stabilization and higher drug encapsulation efficiency of the carrier. HAp is also the source of Ca2+ for the regeneration and repair of diseased bone tissue. The release profiles, exhibited a steady state release rate with significant antimicrobial activity against Staphylococcus aureus (S. aureus) (SH1000) even at high concentration of bacteria. The devices also indicated significant ability to control the growth of bacterial even after four weeks of drug release. Clinical release profiles can be easily tuned from drug-HAp physicochemical interactions and degradation kinetics of polymer matrix. The developed systems could be applied to prevent microbial adhesion to medical implant surfaces and to treat infections mainly caused by S. aureus in surgery.

Marine Structure Derived Calcium Phosphate–Polymer Biocomposites for Local Antibiotic Delivery

PubMed Central

Macha, Innocent J.; Cazalbou, Sophie; Ben-Nissan, Besim; Harvey, Kate L.; Milthorpe, Bruce

2015-01-01

Hydrothermally converted coralline hydroxyapatite (HAp) particles loaded with medically active substances were used to develop polylactic acid (PLA) thin film composites for slow drug delivery systems. The effects of HAp particles within PLA matrix on the gentamicin (GM) release and release kinetics were studied. The gentamicin release kinetics seemed to follow Power law Korsmeyer Peppas model with mainly diffusional process with a number of different drug transport mechanisms. Statistical analysis shows very significant difference on the release of gentamicin between GM containing PLA (PLAGM) and GM containing HAp microspheres within PLA matrix (PLAHApGM) devices, which PLAHApGM displays lower release rates. The use of HAp particles improved drug stabilization and higher drug encapsulation efficiency of the carrier. HAp is also the source of Ca2+ for the regeneration and repair of diseased bone tissue. The release profiles, exhibited a steady state release rate with significant antimicrobial activity against Staphylococcus aureus (S. aureus) (SH1000) even at high concentration of bacteria. The devices also indicated significant ability to control the growth of bacterial even after four weeks of drug release. Clinical release profiles can be easily tuned from drug-HAp physicochemical interactions and degradation kinetics of polymer matrix. The developed systems could be applied to prevent microbial adhesion to medical implant surfaces and to treat infections mainly caused by S. aureus in surgery. PMID:25608725

Electrospun Nanofibrous Silk Fibroin Membranes Containing Gelatin Nanospheres for Controlled Delivery of Biomolecules.

PubMed

Song, Jiankang; Klymov, Alexey; Shao, Jinlong; Zhang, Yang; Ji, Wei; Kolwijck, Eva; Jansen, John A; Leeuwenburgh, Sander C G; Yang, Fang

2017-07-01

Development of novel and effective drug delivery systems for controlled release of bioactive molecules is of critical importance in the field of regenerative medicine. Here, oppositely charged gelatin nanospheres are incorporated into silk fibroin nanofibers through a colloidal electrospinning technique. A novel fibrous nano-in-nano drug delivery system is fabricated without the use of any organic solvent. The distribution of fluorescently labeled gelatin A and B nanospheres inside the nanofibers can be fine-tuned by simple adjustment of the weight ratio between the nanospheres and the relative feeding rate of core and shell solutions containing nanospheres by using single and coaxial nozzle electrospinning, respectively. Incorporation of vancomycin-loaded gelatin B nanospheres into the silk fibroin nanofibrous membranes results in a more sustained release of vancomycin, compared to the gelatin nanospheres free membranes. In addition, these membranes exhibit excellent and prolonged antibacterial effects against Staphylococcus aureus. Moreover, these membranes support the attachment, spreading, and proliferation of periodontal ligament cells. These results suggest that the beneficial properties of gelatin nanospheres can be exploited to improve the biological functionality of electrospun nanofibrous silk fibroin membranes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

ADVANCED MOLECULAR DESIGN OF BIOPOLYMERS FOR TRANSMUCOSAL AND INTRACELLULAR DELIVERY OF CHEMOTHERAPEUTIC AGENTS AND BIOLOGICAL THERAPEUTICS

PubMed Central

Liechty, William B.; Caldorera-Moore, Mary; Phillips, Margaret A.; Schoener, Cody; Peppas, Nicholas A.

2011-01-01

Hydrogels have been instrumental in the development of polymeric systems for controlled release of therapeutic agents. These materials are attractive for transmucosal and intracellular drug delivery because of their facile synthesis, inherent biocompatibility, tunable physicochemical properties, and capacity to respond to various physiological stimuli. In this contribution, we outline a multifaceted hydrogel-based approach for expanding the range of therapeutics in oral formulations from classical small-molecule drugs to include proteins, chemotherapeutics, and nucleic acids. Through judicious materials selection and careful design of copolymer composition and molecular architecture, we can engineer systems capable of responding to distinct physiological cues, with tunable physicochemical properties that are optimized to load, protect, and deliver valuable macromolecular payloads to their intended site of action. These hydrogel carriers, including complexation hydrogels, tethered hydrogels, interpenetrating networks, nanoscale hydrogels, and hydrogels with decorated structures are investigated for their ability respond to changes in pH, to load and release insulin and fluorescein, and remain non-toxic to Caco-2 cells. Our results suggest these novel hydrogel networks have great potential for controlled delivery of proteins, chemotherapeutics, and nucleic acids. PMID:21699934

The effect of glutathione as chain transfer agent in PNIPAAm-based thermo-responsive hydrogels for controlled release of proteins.

PubMed

Drapala, Pawel W; Jiang, Bin; Chiu, Yu-Chieh; Mieler, William F; Brey, Eric M; Kang-Mieler, Jennifer J; Pérez-Luna, Victor H

2014-03-01

To control degradation and protein release using thermo-responsive hydrogels for localized delivery of anti-angiogenic proteins. Thermo-responsive hydrogels derived from N-isopropylacrylamide (NIPAAm) and crosslinked with poly(ethylene glycol)-co-(L-lactic acid) diacrylate (Acry-PLLA-b-PEG-b-PLLA-Acry) were synthesized via free radical polymerization in the presence of glutathione, a chain transfer agent (CTA) added to modulate their degradation and release properties. Immunoglobulin G (IgG) and the recombinant proteins Avastin® and Lucentis® were encapsulated in these hydrogels and their release was studied. The encapsulation efficiency of IgG was high (75-87%) and decreased with CTA concentration. The transition temperature of these hydrogels was below physiological temperature, which is important for minimally invasive therapies involving these materials. The toxicity from unreacted monomers and free radical initiators was eliminated with a minimum of three buffer extractions. Addition of CTA accelerated degradation and resulted in complete protein release. Glutathione caused the degradation products to become solubilized even at 37°C. Hydrogels prepared without glutathione did not disintegrate nor released protein completely after 3 weeks at 37°C. PEGylation of IgG postponed the burst release effect. Avastin® and Lucentis® released from degraded hydrogels retained their biological activity. These systems offer a promising platform for the localized delivery of proteins.

Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy

PubMed Central

Meng, Fanfei; Han, Ning; Yeo, Yoon

2017-01-01

Introduction Chemotherapeutic drugs are used in combination to target multiple mechanisms involved in cancer cell survival and proliferation. Carriers are developed to deliver drug combinations to common target tissues in optimal ratios and desirable sequences. Nanoparticles (NP) have been a popular choice for this purpose due to their ability to increase the circulation half-life and tumor accumulation of a drug. Areas covered We review organic NP carriers based on polymers, proteins, peptides, and lipids for simultaneous delivery of multiple anticancer drugs, drug/sensitizer combinations, drug/photodynamic- or photothermal therapy combinations, and drug/gene therapeutics with examples in the past three years. Sequential delivery of drug combinations, based on either sequential administration or built-in release control, is introduced with an emphasis on the mechanistic understanding of such control. Expert opinion Recent studies demonstrate how a drug carrier can contribute to co-localizing drug combinations in optimal ratios and dosing sequences to maximize the synergistic effects. We identify several areas for improvement in future research, including the choice of drug combinations, circulation stability of carriers, spatiotemporal control of drug release, and the evaluation and clinical translation of combination delivery. PMID:27476442

Design and mechanistic study of a novel gold nanocluster-based drug delivery system.

PubMed

Li, Qinzhen; Pan, Yiting; Chen, Tiankai; Du, Yuanxin; Ge, Honghua; Zhang, Buchang; Xie, Jianping; Yu, Haizhu; Zhu, Manzhou

2018-05-22

Chemically-triggered drug delivery systems (DDSs) have been extensively studied as they do not require specialized equipment to deliver the drug and can deeply penetrate human tissue. However, their syntheses are complicated and they tend to be cytotoxic, which restricts their clinical utility. In this work, the self-regulated drug loading and release capabilities of peptide-protected gold nanoclusters (Pep-Au NCs) are investigated using vancomycin (Van) as the model drug. Gold nanoclusters (Au NCs) coated with a custom-designed pentapeptide are synthesized as drug delivery nanocarriers and loaded with Van - a spontaneous process reliant on the specific binding between Van and the custom-designed peptide. The Van-loaded Au NCs show comparable antimicrobial activity with Van on its own, and the number of Van released by the Pep-Au NCs is found to be proportional to the amount of bacteria present. The controlled nature of the Van release is very encouraging, and predominantly due to the stronger binding affinity of Van with bacteria than that with Au NCs. In addition, these fluorescent Au NCs could also be used to construct temperature sensors, which enable the in vitro and in vivo bioimaging.

A Reactive 1O2 - Responsive Combined Treatment System of Photodynamic and Chemotherapy for Cancer

NASA Astrophysics Data System (ADS)

Wang, Xiaojun; Meng, Guoqing; Zhang, Song; Liu, Xinli

2016-07-01

The development of reactive oxygen species (ROS)-responsive drug delivery and drug release has gradually attracted much attention in recent years as a promising therapeutic strategy. Singlet oxygen (1O2) as the major ROS species is widely used in photodynamic therapy (PDT) of cancer. In the present study, we introduce a combined treatment using ROS-sensitive thioketal (TK) linkage as a linker between upconversion nanoparticles (UNs)-based PDT and doxorubicin (DOX)-based chemotherapy. UNs can not only play a role in PDT, but can also be used as a nanocarrier for drug delivery of DOX. Moreover, the products of 1O2 during PDT are able to cleave TK linker inducing the release of DOX which can further achieve the goal of chemotherapy. By using this 1O2-responsive nanocarrier delivery system, DOX can easily reach the tumor site and be accumulated in the nuclei to effectively kill the cancer cells, and therefore decreasing the side effects of chemotherapy on the body. Thus, PDT also has the function of controlling drug release in this combination treatment strategy. Compared with monotherapy, the combination of PDT with chemotherapy also possesses excellent drug loading capability and anticancer efficiency.

Final Environmental Assessment for the Joint Integrated Fires Exercise at Avon Park Air Force Range, Florida

DTIC Science & Technology

2005-04-01

Tactical Operations Center TRI-DDS................ Toxic Release Inventory Data Delivery System US...Emissions from ordnance are tracked by the Toxic Release Inventory Data Delivery System (TRI-DDS) (URS 2001). Emission releases by ordnance at...listed threatened plant (pigeonwing) and one federally listed endangered plant (hairy jointweed or wireweed ) are known to occur on APAFR. Surveys have

Newly Engineered Magnetic Erythrocytes for Sustained and Targeted Delivery of Anti-Cancer Therapeutic Compounds

PubMed Central

Taranta, Monia; Naldi, Ilaria

2011-01-01

Cytotoxic chemotherapy of cancer is limited by serious, sometimes life-threatening, side effects that arise from toxicities to sensitive normal cells because the therapies are not selective for malignant cells. So how can they be selectively improved? Alternative pharmaceutical formulations of anti-cancer agents have been investigated in order to improve conventional chemotherapy treatment. These formulations are associated with problems like severe toxic side effects on healthy organs, drug resistance and limited access of the drug to the tumor sites suggested the need to focus on site-specific controlled drug delivery systems. In response to these concerns, we have developed a new drug delivery system based on magnetic erythrocytes engineered with a viral spike fusion protein. This new erythrocyte-based drug delivery system has the potential for magnetic-controlled site-specific localization and highly efficient fusion capability with the targeted cells. Here we show that the erythro-magneto-HA virosomes drug delivery system is able to attach and fuse with the target cells and to efficiently release therapeutic compounds inside the cells. The efficacy of the anti-cancer drug employed is increased and the dose required is 10 time less than that needed with conventional therapy. PMID:21373641

Multilayered materials based on biopolymers as drug delivery systems.

PubMed

Vilela, Carla; Figueiredo, Ana R P; Silvestre, Armando J D; Freire, Carmen S R

2017-02-01

The design of efficient therapeutic delivery devices has become a tremendously active area of research with a strong contribution from the layer-by-layer (LbL) technology. The application of this simple yet firmly established technique for the design of drug reservoirs originates a multitude of multilayered systems of tailored architecture and with a high level of control of drug administration. Areas covered: This review will focus on the most recent and original research on LbL assemblies based on biopolymers including polysaccharides, polypeptides and proteins, with potential use in drug delivery. Herein, drug reservoirs consisting of multilayered planar films and capsules will be examined with emphasis on the ones benefiting from the non-cytotoxic and biocompatible nature of biopolymers, which are suitable to load, protect and release a high payload of toxic and fragile drugs. Expert opinion: The combination of biopolymers with LbL technology has undergone extensive research, still, there is a multitude of R&D opportunities for the design of smart drug delivery systems with distinct multilayered morphologies, low immunological response, non-invasive drug release devices, as well as the design of theranostic systems combining diagnostics and therapeutic features. Further developments in terms of scaling towards mass production in the pharmaceutical industry are expected in the long-term.

Self-Assembly Assisted Fabrication of Dextran-Based Nanohydrogels with Reduction-Cleavable Junctions for Applications as Efficient Drug Delivery Systems

PubMed Central

Wang, Hao; Dai, Tingting; Zhou, Shuyan; Huang, Xiaoxiao; Li, Songying; Sun, Kang; Zhou, Guangdong; Dou, Hongjing

2017-01-01

In order to overcome the key challenge in improving both fabrication efficiency and their drug delivery capability of anti-cancer drug delivery systems (ACDDS), here polyacrylic acid (PAA) grafted dextran (Dex) nanohydrogels (NGs) with covalent crosslinked structure bearing redox sensitive disulfide crosslinking junctions (Dex-SS-PAA) were synthesized efficiently through a one-step self-assembly assisted methodology (SAA). The Dex-SS-PAA were subsequently conjugated with doxorubicin through an acid-labile hydrazone bond (Dex-SS-PAA-DOX). The in vitro drug release behavior, anti-cancer effects in vivo, and biosafety of the as-prepared acid- and redox-dual responsive biodegradable NGs were systematically investigated. The results revealed that the Dex-SS-PAA-DOX exhibited pH- and redox-controlled drug release, greatly reduced the toxicity of free DOX, while exhibiting a strong ability to inhibit the growth of MDA-MB-231 tumors. Our study demonstrated that the Dex-SS-PAA-DOX NGs are very promising candidates as ACDDS for anti-cancer therapeutics. PMID:28071743

Self-Assembly Assisted Fabrication of Dextran-Based Nanohydrogels with Reduction-Cleavable Junctions for Applications as Efficient Drug Delivery Systems

NASA Astrophysics Data System (ADS)

Wang, Hao; Dai, Tingting; Zhou, Shuyan; Huang, Xiaoxiao; Li, Songying; Sun, Kang; Zhou, Guangdong; Dou, Hongjing

2017-01-01

In order to overcome the key challenge in improving both fabrication efficiency and their drug delivery capability of anti-cancer drug delivery systems (ACDDS), here polyacrylic acid (PAA) grafted dextran (Dex) nanohydrogels (NGs) with covalent crosslinked structure bearing redox sensitive disulfide crosslinking junctions (Dex-SS-PAA) were synthesized efficiently through a one-step self-assembly assisted methodology (SAA). The Dex-SS-PAA were subsequently conjugated with doxorubicin through an acid-labile hydrazone bond (Dex-SS-PAA-DOX). The in vitro drug release behavior, anti-cancer effects in vivo, and biosafety of the as-prepared acid- and redox-dual responsive biodegradable NGs were systematically investigated. The results revealed that the Dex-SS-PAA-DOX exhibited pH- and redox-controlled drug release, greatly reduced the toxicity of free DOX, while exhibiting a strong ability to inhibit the growth of MDA-MB-231 tumors. Our study demonstrated that the Dex-SS-PAA-DOX NGs are very promising candidates as ACDDS for anti-cancer therapeutics.

Sol-gel Derived Warfarin - Silica Composites for Controlled Drug Release.

PubMed

Dolinina, Ekaterina S; Parfenyuk, Elena V

2017-01-01

Warfarin, commonly used anticoagulant in clinic, has serious shortcomings due to its unsatisfactory pharmacodynamics. One of the efficient ways for the improvement of pharmacological and consumer properties of drugs is the development of optimal drug delivery systems. The aim of this work is to synthesize novel warfarin - silica composites and to study in vitro the drug release kinetics to obtain the composites with controlled release. The composites of warfarin with unmodified (UMS) and mercaptopropyl modified silica (MPMS) were synthesized by sol-gel method. The composite formation was confirmed by FTIR spectra. The concentrations of warfarin released to media with pH 1.6, 6.8 and 7.4 were measured using UV spectroscopy. The drug release profiles from the solid composites were described by a series of kinetic models which includes zero order kinetics, first order kinetics, the modified Korsmeyer-Peppas model and Hixson-Crowell model. The synthesized sol-gel composites have different kinetic behavior in the studied media. In contrast to the warfarin composite with unmodified silica, the drug release from the composite with mercaptopropyl modified silica follows zero order kinetics for 24 h irrespective to the release medium pH due to mixed mechanism (duffusion + degradation and/or disintegration of silica matrix). The obtained results showed that warfarin - silica sol-gel composites have a potential application for the development of novel oral formulation of the drug with controlled delivery. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Microspheres Assembled from Chitosan-Graft-Poly(lactic acid) Micelle-Like Core-Shell Nanospheres for Distinctly Controlled Release of Hydrophobic and Hydrophilic Biomolecules.

PubMed

Niu, Xufeng; Liu, Zhongning; Hu, Jiang; Rambhia, Kunal J; Fan, Yubo; Ma, Peter X

2016-07-01

To simultaneously control inflammation and facilitate dentin regeneration, a copolymeric micelle-in-microsphere platform is developed in this study, aiming to simultaneously release a hydrophobic drug to suppress inflammation and a hydrophilic biomolecule to enhance odontogenic differentiation of dental pulp stem cells in a distinctly controlled fashion. A series of chitosan-graft-poly(lactic acid) copolymers is synthesized with varying lactic acid and chitosan weight ratios, self-assembled into nanoscale micelle-like core-shell structures in an aqueous system, and subsequently crosslinked into microspheres through electrostatic interaction with sodium tripolyphosphate. A hydrophobic biomolecule either coumarin-6 or fluocinolone acetonide (FA) is encapsulated into the hydrophobic cores of the micelles, while a hydrophilic biomolecule either bovine serum albumin or bone morphogenetic protein 2 (BMP-2) is entrapped in the hydrophilic shells and the interspaces among the micelles. Both hydrophobic and hydrophilic biomolecules are delivered with distinct and tunable release patterns. Delivery of FA and BMP-2 simultaneously suppresses inflammation and enhances odontogenesis, resulting in significantly enhanced mineralized tissue regeneration. This result also demonstrates the potential for this novel delivery system to deliver multiple therapeutics and to achieve synergistic effects. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A review of drug delivery systems for capsule endoscopy.

PubMed

Munoz, Fredy; Alici, Gursel; Li, Weihua

2014-05-01

The development of a highly controllable drug delivery system (DDS) for capsule endoscopy has become an important field of research due to its promising applications in therapeutic treatment of diseases in the gastrointestinal (GI) tract and drug absorption studies. Several factors need to be considered to establish the minimum requirements for a functional DDS. Environmental factors of the GI tract and also pharmaceutical factors can help determine the requirements to be met by a DDS in an endoscopic capsule. In order to minimize the influence of such factors on the performance of an effective DDS, at least two mechanisms should be incorporated into a capsule endoscope: an anchoring mechanism to control the capsule position and a drug release mechanism to control variables such as the drug release rate, number of doses and amount of drug released. The implementation of such remotely actuated mechanisms is challenging due to several constraints, including the limited space available in a swallowable capsule endoscope and the delicate and complex environment within the GI tract. This paper presents a comprehensive overview of existing DDS. A comparison of such DDS for capsule endoscopy based on the minimum DDS requirements is presented and future work is also discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Controlled Release Oral Delivery of Apigenin Containing Pellets with Antioxidant Activity.

PubMed

Pápay, Zsófia Edit; Kállai-Szabó, Nikolett; Balogh, Emese; Ludányi, Krisztina; Klebovich, Imre; Antal, István

2017-01-01

Drug delivery of phytochemicals has gained interest recently due to their remarkable health effects. Apigenin, a plant flavonoid, has antioxidant, anti-inflammatory and anticancer activities but its delivery is challenging. It could be absorbed through the whole intestine, however, it has poor bioavailability due to its low aqueous solubility. In Europe, the daily intake was estimated to be as low as 3 ± 1 mg. Pellets offer several advantages such as improved bioavailability and various resultant drug release profiles can be obtained by simply mixing pellets with different coatings. The objective of our study was to develop a carrier system containing 20 mg apigenin thus enhancing intake and to offer reduction of oxidative stress which can cause inflammation in the intestine. The apigenin powder was dispersed in aqueous solution of binding material and layered onto the inert cores in a fluidized bed apparatus. The layered cores were further coated with enteric polymers and the process parameters were optimized. The prepared pellets met with the requirements and have good physical characteristic. 10% (w/w) Eudragit® L was suitable for enteric coating with a complete release at pH 6.8 within 1 hour. 15% (w/w) Eudragit® FS coating ensured acid resistance ability and colonic delivery. The therapeutic efficiency was confirmed with antioxidant activity measurement by using DPPH* assay. Enteric coated spheres allow targeted delivery into the intestine and colon thus reaching the main absorption site. Pellets were proved to be an optimal delivery system for apigenin thus providing enhanced apigenin intake. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Mechanisms of monoclonal antibody stabilization and release from silk biomaterials

PubMed Central

Guziewicz, Nicholas A.; Massetti, Andrew J.; Perez-Ramirez, Bernardo J.; Kaplan, David L.

2013-01-01

The availability of stabilization and sustained delivery systems for antibody therapeutics remains a major clinical challenge, despite the growing development of antibodies for a wide range of therapeutic applications due to their specificity and efficacy. A mechanistic understanding of protein-matrix interactions is critical for the development of such systems and is currently lacking as a mode to guide the field. We report mechanistic insight to address this need by using well-defined matrices based on silk gels, in combination with a monoclonal antibody. Variables including antibody loading, matrix density, charge interactions, hydrophobicity and water access were assessed to clarify mechanisms involved in the release of antibody from the biomaterial matrix. The results indicate that antibody release is primarily governed by hydrophobic interactions and hydration resistance, which are controlled by silk matrix chemistry, peptide domain distribution and protein density. Secondary ionic repulsions are also critical in antibody stabilization and release. Matrix modification by free methionine incorporation was found to be an effective strategy for mitigating encapsulation induced antibody oxidation. Additionally, these studies highlight a characterization approach to improve the understanding and development of other protein sustained delivery systems, with broad applicability to the rapidly developing monoclonal antibody field. PMID:23859659

Preservation of Anticancer and Immunosuppressive Properties of Rapamycin Achieved Through Controlled Releasing Particles.

PubMed

Fan, Yan Liang; Hou, Han Wei; Tay, Hui Min; Guo, Wei Mei; Berggren, Per-Olof; Loo, Say Chye Joachim

2017-10-01

Rapamycin is commonly used in chemotherapy and posttransplantation rejection suppression, where sustained release is preferred. Conventionally, rapamycin has to be administered in excess due to its poor solubility, and this often leads to cytotoxicity and undesirable side effects. In addition, rapamycin has been shown to be hydrolytically unstable, losing its bioactivity within a few hours. The use of drug delivery systems is hypothesized to preserve the bioactivity of rapamycin, while providing controlled release of this otherwise potent drug. This paper reports on the use of microparticles (MP) as a means to tune and sustain the delivery of bioactive rapamycin for up to 30 days. Rapamycin was encapsulated (100% efficiency) in poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), or a mixture of both via an emulsion method. The use of different polymer types and mixture was shown to achieve a variety of release kinetics and profile. Released rapamycin was subsequently evaluated against breast cancer cell (MCF-7) and human lymphocyte cell (Jurkat). Inhibition of cell proliferation was in good agreement with in vitro release profiles, which confirmed the intact bioactivity of rapamycin. For Jurkat cells, the suppression of cell growth was proven to be effective up to 20 days, a duration significantly longer than free rapamycin. Taken together, these results demonstrate the ability to tune, sustain, and preserve the bioactivity of rapamycin using MP formulations. The sustained delivery of rapamycin could lead to better therapeutic effects than bolus dosage, at the same time improving patient compliance due to its long-acting duration.

Development and optimization of buspirone oral osmotic pump tablet

PubMed Central

Derakhshandeh, K.; berenji, M. Ghasemnejad

2014-01-01

The aim of the current study was to design a porous osmotic pump–based drug delivery system for controlling the release of buspirone from the delivery system. The osmotic pump was successfully developed using symmetric membrane coating. The core of the tablets was prepared by direct compression technique and coated using dip-coating technique. Drug release from the osmotic system was studied using USP paddle type apparatus. The effect of various processing variables such as the amount of osmotic agent, the amount of swellable polymer, concentration of the core former, concentration of the plasticizer, membrane thickness, quantum of orifice on drug release from osmotic pump were evaluated. Different kinetic models (zero order, first order and Higuchi model) were applied to drug release data in order to establish the kinetics of drug release. It was found that the drug release was mostly affected by the amount of NaCl as osmotic agent, the swellable polymer; hydroxy propyl methyl cellulose (HPMC), the amount of PEG-400 and cellulose acetate in the coating solution and thickness of the semipermeable membrane. The optimized formulation released buspirone independent of pH and orifice quantum at the osmogen amount of 42%, hydrophilic polymer of 13% and pore size of 0.8 mm on the tablet surface. The drug release of osmotic formulation during 24 h showed zero order kinetics and could be suggested that this formulation as a once-daily regimen improves pharmacokinetic parameters of the drug and enhances patient compliance. PMID:25657794

Development and optimization of buspirone oral osmotic pump tablet.

PubMed

Derakhshandeh, K; Berenji, M Ghasemnejad

2014-01-01

The aim of the current study was to design a porous osmotic pump-based drug delivery system for controlling the release of buspirone from the delivery system. The osmotic pump was successfully developed using symmetric membrane coating. The core of the tablets was prepared by direct compression technique and coated using dip-coating technique. Drug release from the osmotic system was studied using USP paddle type apparatus. The effect of various processing variables such as the amount of osmotic agent, the amount of swellable polymer, concentration of the core former, concentration of the plasticizer, membrane thickness, quantum of orifice on drug release from osmotic pump were evaluated. Different kinetic models (zero order, first order and Higuchi model) were applied to drug release data in order to establish the kinetics of drug release. It was found that the drug release was mostly affected by the amount of NaCl as osmotic agent, the swellable polymer; hydroxy propyl methyl cellulose (HPMC), the amount of PEG-400 and cellulose acetate in the coating solution and thickness of the semipermeable membrane. The optimized formulation released buspirone independent of pH and orifice quantum at the osmogen amount of 42%, hydrophilic polymer of 13% and pore size of 0.8 mm on the tablet surface. The drug release of osmotic formulation during 24 h showed zero order kinetics and could be suggested that this formulation as a once-daily regimen improves pharmacokinetic parameters of the drug and enhances patient compliance.

Incorporation of beads into oral films for buccal and oral delivery of bioactive molecules.

PubMed

Castro, Pedro M; Sousa, Flávia; Magalhães, Rui; Ruiz-Henestrosa, Victor Manuel Pizones; Pilosof, Ana M R; Madureira, Ana Raquel; Sarmento, Bruno; Pintado, Manuela E

2018-08-15

The association of alginate beads and guar-gum films in a single delivery system was idealized to promote a more effective buccal and oral delivery of bioactive molecules. A response surface method (experimental design approach) was performed to obtain optimal formulations of alginate beads to be incorporated into guar gum oral films as combined buccal and oral delivery systems for caffeine delivery. The combined formulation was further characterized regarding physicochemical properties, drug release, cell viability and buccal permeability. Beads average size, determined by dynamic light scattering (DLS), was of 3.37 ± 6.36 μm. Film thickness was set to 62 μm. Scanning electron microscopy micrographs revealed that beads were evenly distributed onto the film matrix and beads size was in accordance to data obtained from DLS analysis. Evaluation of Fourier-transform infrared spectra did not indicate the formation of new covalent bonds between the matrix of guar-gum films, alginate beads and caffeine. In vitro release assays by dialysis membrane allowed understanding that the combination of guar-gum films and alginate beads assure a slower release of caffeine when compared with the delivery profile of free caffeine from alginate beads or guar-gum films alone. MTT assay, performed on human buccal carcinoma TR146 cell line, allowed concluding that neither guar-gum film, alginate beads nor guar-gum film incorporated into alginate beads significantly compromised cell viability after 12 h of exposure. As demonstrated by in vitro permeability assay using TR146 human buccal carcinoma cell lines, combination of guar-gum films and alginate beads also promoted a slower release and, thus, lower apparent permeability (1.15E-05 ± 3.50E-06) than for caffeine solution (2.68E-05 ± 7.30E-06), guar-gum film (3.12E-05 ± 4.70E-06) or alginate beads (2.01E-05 ± 3.90E-06). The conjugation of alginate beads within an orodispersible film matrix represents an effective oral/buccal delivery system that induces a controlled release along with an enhanced intimate contact with cell layers that may promote higher in vivo bioavailability of carried drugs. Copyright © 2018. Published by Elsevier Ltd.

Nanobiotechnology and its applications in drug delivery system: a review.

PubMed

Khan, Imran; Khan, Momin; Umar, Muhammad Naveed; Oh, Deog-Hwan

2015-12-01

Nanobiotechnology holds great potential in various regimes of life sciences. In this review, the potential applications of nanobiotechnology in various sectors of nanotechnologies, including nanomedicine and nanobiopharmaceuticals, are highlighted. To overcome the problems associated with drug delivery, nanotechnology has gained increasing interest in recent years. Nanosystems with different biological properties and compositions have been extensively investigated for drug delivery applications. Nanoparticles fabricated through various techniques have elevated therapeutic efficacy, provided stability to the drugs and proved capable of targeting the cells and controlled release inside the cell. Polymeric nanoparticles have shown increased development and usage in drug delivery as well as in diagnostics in recent decades.

Microfluidic assembly of a nano-in-micro dual drug delivery platform composed of halloysite nanotubes and a pH-responsive polymer for colon cancer therapy.

PubMed

Li, Wei; Liu, Dongfei; Zhang, Hongbo; Correia, Alexandra; Mäkilä, Ermei; Salonen, Jarno; Hirvonen, Jouni; Santos, Hélder A

2017-01-15

Harsh conditions of the gastrointestinal tract hinder the oral delivery of many drugs. Developing oral drug delivery systems based on commercially available materials is becoming more challenging due to the demand for simultaneously delivering physicochemically different drugs for treating complex diseases. A novel architecture, namely nanotube-in-microsphere, was developed as a drug delivery platform by encapsulating halloysite nanotubes (HNTs) in a pH-responsive hydroxypropyl methylcellulose acetate succinate polymer using microfluidics. HNTs were selected as orally acceptable clay mineral and their lumen was enlarged by selective acid etching. Model drugs (atorvastatin and celecoxib) with different physicochemical properties and synergistic effect on colon cancer prevention and inhibition were simultaneously incorporated into the microspheres at a precise ratio, with atorvastatin and celecoxib being loaded in the HNTs and polymer matrix, respectively. The microspheres showed spherical shape, narrow particle size distribution and pH-responsive dissolution behavior. This nanotube/pH-responsive polymer composite protected the loaded drugs from premature release at pH⩽6.5, but allowed their fast release and enhanced the drug permeability, and the inhibition of colon cancer cell proliferation at pH 7.4. Overall, the nano-in-micro drug delivery composite fabricated by microfluidics is a promising and flexible platform for the delivery of multiple drugs for combination therapy. Halloysite nanotubes (HNTs) are attracting increasing attention for drug delivery applications. However, conventional HNTs-based oral drug delivery systems are lack of the capability to precisely control the drug release at a desired site in the gastrointestinal tract. In this study, a nanotube-in-microsphere drug delivery platform is developed by encapsulating HNTs in a pH-responsive polymer using microfluidics. Drugs with different physicochemical properties and synergistic effect on colon cancer therapy were simultaneously incorporated in the microspheres. The prepared microspheres prevented the premature release of the loaded drugs after exposure to the harsh conditions of the gastrointestinal tract, but allowed their simultaneously fast release, and enhanced the drug permeability and the inhibition of colon cancer cell proliferation in response to the colon pH. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Controlled Release from Recombinant Polymers

PubMed Central

Price, Robert; Poursaid, Azadeh; Ghandehari, Hamidreza

2014-01-01

Recombinant polymers provide a high degree of molecular definition for correlating structure with function in controlled release. The wide array of amino acids available as building blocks for these materials lend many advantages including biorecognition, biodegradability, potential biocompatibility, and control over mechanical properties among other attributes. Genetic engineering and DNA manipulation techniques enable the optimization of structure for precise control over spatial and temporal release. Unlike the majority of chemical synthetic strategies used, recombinant DNA technology has allowed for the production of monodisperse polymers with specifically defined sequences. Several classes of recombinant polymers have been used for controlled drug delivery. These include, but are not limited to, elastin-like, silk-like, and silk-elastinlike proteins, as well as emerging cationic polymers for gene delivery. In this article, progress and prospects of recombinant polymers used in controlled release will be reviewed. PMID:24956486

Alginate nanoparticles protect ferrous from oxidation: Potential iron delivery system.

PubMed

Katuwavila, Nuwanthi P; Perera, A D L C; Dahanayake, Damayanthi; Karunaratne, V; Amaratunga, Gehan A J; Karunaratne, D Nedra

2016-11-20

A novel, efficient delivery system for iron (Fe 2+ ) was developed using the alginate biopolymer. Iron loaded alginate nanoparticles were synthesized by a controlled ionic gelation method and was characterized with respect to particle size, zeta potential, morphology and encapsulation efficiency. Successful loading was confirmed with Fourier Transform Infrared spectroscopy and Thermogravimetric Analysis. Electron energy loss spectroscopy study corroborated the loading of ferrous into the alginate nanoparticles. Iron encapsulation (70%) was optimized at 0.06% Fe (w/v) leading to the formation of iron loaded alginate nanoparticles with a size range of 15-30nm and with a negative zeta potential (-38mV). The in vitro release studies showed a prolonged release profile for 96h. Release of iron was around 65-70% at pH of 6 and 7.4 whereas it was less than 20% at pH 2.The initial burst release upto 8h followed zero order kinetics at all three pH values. All the release profiles beyond 8h best fitted the Korsmeyer-Peppas model of diffusion. Non Fickian diffusion was observed at pH 6 and 7.4 while at pH 2 Fickian diffusion was observed. Copyright © 2016 Elsevier B.V. All rights reserved.

Formulation and evaluation of gastroretentive microballoons containing baclofen for a floating oral controlled drug delivery system.

PubMed

Dube, T S; Ranpise, N S; Ranade, A N

2014-01-01

The objective of the present study was to fabricate and evaluate a multiparticulate oral gastroretentive dosage form of baclofen characterized by a central large cavity (hollow core) promoting unmitigated floatation with practical applications to alleviate the signs and symptoms of spasticity and muscular rigidity. Solvent diffusion and evaporation procedure were applied to prepare floating microspheres with a central large cavity using various combinations of ethylcellulose (release retardant) and HPMC K4M (release modifier) dissolved in a mixture of dichloromethane and methanol (2:1). The obtained microspheres (700-1000 µm) exhibit excellent floating ability (86 ± 2.00%) and release characteristics with entrapment efficiency of 95.2 ± 0.32%. Microspheres fabricated with ethylcellulose to HPMC K4M in the ratio 8.5:1.5 released 98.67% of the entrapped drug in 12 h. Muscle relaxation caused by baclofen microspheres impairs the rotarod performance for more than 12 h. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate- labeled microspheres was no less than 10 h. The buoyant baclofen microspheres provide a promising gastroretentive drug delivery system to deliver baclofen in spastic patients with a sustained release rate.

Preparation and characterization of metoprolol tartrate containing matrix type transdermal drug delivery system.

PubMed

Malipeddi, Venkata Ramana; Awasthi, Rajendra; Ghisleni, Daniela Dal Molim; de Souza Braga, Marina; Kikuchi, Irene Satiko; de Jesus Andreoli Pinto, Terezinha; Dua, Kamal

2017-02-01

The present study aimed to develop matrix-type transdermal drug delivery system (TDDS) of metoprolol tartrate using polyvinyl pyrrolidone (PVP) and polyvinyl alcohol (PVA). The transdermal films were evaluated for physical parameters, Fourier transform infrared spectroscopy analysis (FTIR), differential scanning calorimetry (DSC), in vitro drug release, in vitro skin permeability, skin irritation test and stability studies. The films were found to be tough, non-sticky, easily moldable and possess good tensile strength. As the concentration of PVA was increased, the tensile strength of the films was also increased. Results of FTIR spectroscopy and DSC revealed the absence of any drug-polymer interactions. In vitro release of metoprolol followed zero-order kinetics and the mechanism of release was found to be diffusion rate controlled. In vitro release studies of metoprolol using Keshary-Chein (vertical diffusion cell) indicated 65.5 % drug was released in 24 h. In vitro skin permeation of metoprolol transdermal films showed 58.13 % of the drug was released after 24 h. In vitro skin permeation of metoprolol followed zero-order kinetics in selected formulations. The mechanism of release was found to be diffusion rate controlled. In a 22-day skin irritation test, tested formulation of transdermal films did not exhibit any allergic reactions, inflammation, or contact dermatitis. The transdermal films showed good stability in the 180-day stability study. It can be concluded that the TDDS of MPT can help in bypassing the first-pass effect and will provide patient improved compliance, without sacrificing the therapeutic advantages of the drugs.

Pharmaceutical Additive Manufacturing: a Novel Tool for Complex and Personalized Drug Delivery Systems.

PubMed

Zhang, Jiaxiang; Vo, Anh Q; Feng, Xin; Bandari, Suresh; Repka, Michael A

2018-06-25

Inter-individual variability is always an issue when treating patients of different races, genders, ages, pharmacogenetics, and pharmacokinetic characteristics. However, the development of novel dosage forms is limited by the huge investments required for production line modifications and dosages diversity. Additive manufacturing (AM) or 3D printing can be a novel alternative solution for the development of controlled release dosages because it can produce personalized or unique dosage forms and more complex drug-release profiles. The primary objective of this manuscript is to review the 3D printing processes that have been used in the pharmaceutical area, including their general aspects, materials, and the operation of each AM technique. Advantages and shortcomings of the technologies are discussed with respect to practice and practical applications. Thus, this review will provide an overview and discussion on advanced pharmaceutical AM technologies, which can be used to produce unique controlled drug delivery systems and personalized dosages for the future of personalized medicine.

Cubic and Hexagonal Liquid Crystals as Drug Delivery Systems

PubMed Central

Chen, Yulin; Ma, Ping; Gui, Shuangying

2014-01-01

Lipids have been widely used as main constituents in various drug delivery systems, such as liposomes, solid lipid nanoparticles, nanostructured lipid carriers, and lipid-based lyotropic liquid crystals. Among them, lipid-based lyotropic liquid crystals have highly ordered, thermodynamically stable internal nanostructure, thereby offering the potential as a sustained drug release matrix. The intricate nanostructures of the cubic phase and hexagonal phase have been shown to provide diffusion controlled release of active pharmaceutical ingredients with a wide range of molecular weights and polarities. In addition, the biodegradable and biocompatible nature of lipids demonstrates the minimum toxicity and thus they are used for various routes of administration. Therefore, the research on lipid-based lyotropic liquid crystalline phases has attracted a lot of attention in recent years. This review will provide an overview of the lipids used to prepare cubic phase and hexagonal phase at physiological temperature, as well as the influencing factors on the phase transition of liquid crystals. In particular, the most current research progresses on cubic and hexagonal phases as drug delivery systems will be discussed. PMID:24995330

The Effect of Single, Binary and Ternary Anions of Chloride, Carbonate and Phosphate on the Release of 2,4-Dichlorophenoxyacetate Intercalated into the Zn-Al-layered Double Hydroxide Nanohybrid

NASA Astrophysics Data System (ADS)

Hussein, Mohd Zobir; Jaafar, Adila Mohamad; Yahaya, Asmah Hj.; Zainal, Zulkarnain

2009-11-01

Intercalation of beneficial anion into inorganic host has lead to an opportunity to synthesize various combinations of new organic-inorganic nanohybrids with various potential applications; especially, for the controlled release formulation and storage purposes. Investigation on the release behavior of 2,4-dichlorophenoxyacetate (2,4-D) intercalated into the interlayer of Zn-Al-layered double hydroxide (ZAN) have been carried out using single, binary and ternary aqueous systems of chloride, carbonate and phosphate. The release behavior of the active agent 2,4-D from its double-layered hydroxide nanohybrid ZANDI was found to be of controlled manner governed by pseudo-second order kinetics. It was found that carbonate medium yielded the highest accumulated release of 2,4-D, while phosphate in combination with carbonate and/or nitrate speeds up the release rate of 2,4-D. These results indicate that it is possible to design and develop new delivery system of latex stimulant compound with controlled release property based on 2,4-D that is known as a substance to increase latex production of rubber tree, Hevea brasiliensis.

Time-controlled release pseudoephedrine tablets: bioavailability and in vitro/in vivo correlations.

PubMed

Halsas, M; Penttinen, T; Veski, P; Jürjenson, H; Marvola, M

2001-09-01

In chronopharmacotherapy, circadian changes in disease symptoms are taken into account. Press-coated, time-controlled release tablets containing pseudoephedrine hydrochloride as a model drug have been formulated and the suitability of this highly soluble drug in relation to the new drug delivery system was evaluated. Hydroxypropylmethylcellulose was used in the coat of the tablet to adjust drug release. If such a formulation was administered in the evening it would have maximal effect in the early morning, and would be useful for the treatment of nocturnal symptoms. Two cross-over, single-dose bioavailability studies were carried out on eight healthy volunteers. A dissolution test method was developed to establish level A and level C in vitro/in vivo correlation for four formulations. With a low viscosity grade of polymer, peak concentrations were achieved after five hours. The drug was absorbed much more slowly from tablets containing a high viscosity grade polymer, with a plasma peak at ten hours. For further development of the drug delivery system described, a dissolution test method at pH 7.2 at a rotation speed of 150 min-1 is recommended on the basis of level A in vitro/in vivo correlation.

Enzyme-Responsive Nanomaterials for Controlled Drug Delivery

PubMed Central

Hu, Quanyin; Katti, Prateek S.; Gu, Zhen

2015-01-01

Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials for controlled drug release have achieved significant development and been studied as an important class of drug delivery devices in nanomedicine. In this review, we describe enzymes such as proteases, phospholipase and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area. PMID:25251024

Enzyme-responsive nanomaterials for controlled drug delivery

NASA Astrophysics Data System (ADS)

Hu, Quanyin; Katti, Prateek S.; Gu, Zhen

2014-10-01

Enzymes underpin physiological function and exhibit dysregulation in many disease-associated microenvironments and aberrant cell processes. Exploiting altered enzyme activity and expression for diagnostics, drug targeting, and drug release is tremendously promising. When combined with booming research in nanobiotechnology, enzyme-responsive nanomaterials used for controlled drug release have achieved significant development and have been studied as an important class of drug delivery strategies in nanomedicine. In this review, we describe enzymes such as proteases, phospholipases and oxidoreductases that serve as delivery triggers. Subsequently, we explore recently developed enzyme-responsive nanomaterials with versatile applications for extracellular and intracellular drug delivery. We conclude by discussing future opportunities and challenges in this area.

S-protected thiolated chitosan: synthesis and in vitro characterization.

PubMed

Dünnhaupt, Sarah; Barthelmes, Jan; Thurner, Clemens C; Waldner, Claudia; Sakloetsakun, Duangkamon; Bernkop-Schnürch, Andreas

2012-10-01

Purpose of the present study was the generation and evaluation of novel thiolated chitosans, so-named S-protected thiolated chitosans as mucosal drug delivery systems. Stability of all conjugates concerning swelling and disintegration behavior as well as drug release was examined. Mucoadhesive properties were evaluated in vitro on intestinal mucosa. Different thiolated chitosans were generated displaying increasing amounts of attached free thiol groups on the polymer, whereby more than 50% of these thiol groups were linked with 6-mercaptonicotinamide. Based on the implementation of this hydrophobic residue, the swelling behavior was 2-fold decreased, whereas stability was essentially improved. Their mucoadhesive properties were 2- and 14-fold increased compared to corresponding thiolated and unmodified chitosans, respectively. Release studies out of matrix tablets comprising the novel conjugates revealed a controlled release of a model peptide. Accordingly, S-protected thiomers represent a promising type of mucoadhesive polymers for the development of various mucosal drug delivery systems. Copyright © 2012 Elsevier Ltd. All rights reserved.

Biophysical characterization of hydrogel-core, lipid-shell nanoparticles (nanolipogels) for HIV chemoprophylaxis

NASA Astrophysics Data System (ADS)

Mahadevan, Reena

Nanoparticles are emerging as versatile vehicles for drug delivery, providing targeting, protection, and controlled-release capabilities to encapsulated cargo. Polymeric nanoparticles made from poly(lactide-co-glycolide) (PLGA) are biodegradable, exhibit tunable drug release, and have encapsulated a wide variety of biological agents. However, PLGA nanoparticles are relatively inefficient at encapsulating small-molecule hydrophilic drugs. Liposomes encapsulate greater amounts of hydrophilic agents and demonstrate good cellular affinity; however, they lack controlled-release functionality. Hydrogel-core lipid-shell nanoparticles, or nanolipogels, combine the controlled-release capability of polymeric nanocarriers with the hydrophilic and cellular affinity of liposomes into a single drug delivery vehicle. This study establishes a facile, reproducible synthetic protocol for nanolipogels and evaluates hydrogel swelling as a mechanism for release of the small hydrophilic antiretroviral azidothymidine from nanolipogels.

Biopolymers as transdermal drug delivery systems in dermatology therapy.

PubMed

Basavaraj, K H; Johnsy, George; Navya, M A; Rashmi, R; Siddaramaiah

2010-01-01

The skin is considered a complex organ for drug delivery because of its structure. Drug delivery systems are designed for the controlled release of drugs through the skin into the systemic circulation, maintaining consistent efficacy and reducing the dose of the drugs and their related side effects. Transdermal drug delivery represents one of the most rapidly advancing areas of novel drug delivery. The excellent impervious nature of the skin is the greatest challenge that must be overcome for successful drug delivery. Today, polymers have been proven to be successful for long-term drug delivery applications as no single polymer can satisfy all of the requirements. Biopolymers in the field of dermal application are rare and the mechanisms that affect skin absorption are almost unknown. Biopolymers are widely used as drug delivery systems, but as such the use of biopolymers as drug delivery systems in dermatologic therapy is still in progress. Commonly used biopolymers include hydrocolloids, alginates, hydrogels, polyurethane, collagen, poly(lactic-co-glycolic acid), chitosan, proteins and peptides, pectin, siRNAs, and hyaluronic acid. These new and exciting methods for drug delivery are already increasing the number and quality of dermal and transdermal therapies. This article reviews current research on biopolymers and focuses on their potential as drug carriers, particularly in relation to the dermatologic aspects of their use.

Evaluation of a Perforated Drug Delivery System in Mice for Prolonged and Constant Release of a Hydrophilic Drug

DTIC Science & Technology

2012-02-17

A drug delivery system (DDS) consisting of a perforated microtube ( polyimide , inside diameter= 1.8 mm, tube length= 20 mm, hole size= 0.15 mm) was... biocompatible and capable of long-term constant release of hydrophilic drugs such as sodium fluorescein.

Development of Ocular Delivery System for Glaucoma Therapy Using Natural Hydrogel as Film Forming Agent and Release Modifier.

PubMed

Kulkarni, Giriraj T; Sethi, Nitin; Awasthi, Rajendra; Pawar, Vivek Kumar; Pahuja, Vineet

2016-01-01

Glaucoma is characterized by increased intraocular pressure, which results in damage to the optic nerve. The existing therapy with conventional eye drops is inefficient due to nasolachrymal drainage, resulting in a reduced corneal residence of the drug. The objective was to develop controlled-release ocular films of timolol maleate using natural hydrogel from Tamarindus indica seeds as a sustaining and film-forming agent, to overcome the problems associated with eye drops. The hydrogel was isolated using hot aqueous extraction followed by precipitation with ethanol. Six batches of ocular films were prepared and evaluated for drug content, weight variation, thickness, diameter and in vitro release profile. The ideal batch of the films was subjected to stability, pharmacodynamic and ocular safety studies. The yield of the hydrogel was 58.29%. The thickness of the ocular films was in the range of 0.17 to 0.25 mm and the weight of the films was found to increase with the increase in polymer content. The drug release from the films was found to be controlled over a period of 8 h. The films were found to be stable and were able to reduce the intraocular pressure for 24 h in a more efficient manner than the eye drops. The films were found to be practically non-irritating to the eye. It can be concluded that the hydrogel from tamarind seeds can be used as a film-forming and release-controlling agent for the development of an ocular drug delivery system for the effective therapy of glaucoma.

Nanocarrier-Integrated Microspheres: Nanogel Tectonic Engineering for Advanced Drug-Delivery Systems.

PubMed

Tahara, Yoshiro; Mukai, Sada-Atsu; Sawada, Shin-Ichi; Sasaki, Yoshihiro; Akiyoshi, Kazunari

2015-09-09

A nanocarrier-integrated bottom-up method is a promising strategy for advanced drug-release systems. Self-assembled nanogels, which are one of the most beneficial nanocarriers for drug-delivery systems, are tectonically integrated to prepare nanogel-crosslinked (NanoClik) microspheres. NanoClik microspheres consisting of nanogel-derived structures (observed by STED microscopy) release "drug-loaded nanogels" after hydrolysis, resulting in successful sustained drug delivery in vivo. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Viruses, Artificial Viruses and Virus-Based Structures for Biomedical Applications.

PubMed

van Rijn, Patrick; Schirhagl, Romana

2016-06-01

Nanobiomaterials such as virus particles and artificial virus particles offer tremendous opportunities to develop new biomedical applications such as drug- or gene-delivery, imaging and sensing but also improve understanding of biological mechanisms. Recent advances within the field of virus-based systems give insights in how to mimic viral structures and virus assembly processes as well as understanding biodistribution, cell/tissue targeting, controlled and triggered disassembly or release and circulation times. All these factors are of high importance for virus-based functional systems. This review illustrates advances in mimicking and enhancing or controlling these aspects to a high degree toward delivery and imaging applications. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Methylphenidate and dexmethylphenidate formulations for children with attention-deficit/hyperactivity disorder.

PubMed

Sugrue, David; Bogner, Robin; Ehret, Megan J

2014-07-15

Current literature on the safety and efficacy of various intermediate- and long-acting preparations of methylphenidate and dexmethylphenidate for pediatric attention-deficit/hyperactivity disorder (ADHD) is reviewed. The efficacy of methylphenidate in controlling ADHD symptoms is firmly established. Given the drug's relatively short half-life in pediatric patients (about 2.5 hours), a number of intermediate- and long-acting products have been developed; these extended-release methylphenidate products provide the same efficacy as immediate-release (IR) formulations, with the convenience of less frequent dosing. Intermediate-acting methylphenidate preparations have effects lasting as long as 8 hours, but peak concentrations are not attained for up to 5 hours, and many patients may require twice-daily dosing. Long-acting methylphenidate products developed to address these challenges include a controlled-release tablet and bimodal-delivery capsules containing mixtures of IR and extended-release beads (durations of effect, 8-12 hours). Options for patients with difficulty swallowing tablets or capsules include a once-daily transdermal delivery system and a once-daily liquid formulation. Dexmethylphenidate (the more pharmacologically active d-isomer of racemic methylphenidate) can provide efficacy comparable to that of IR methylphenidate at half the dose; an extended-release form of dexmethylphenidate can provide less fluctuation in peak and trough concentrations than the IR form. Methylphenidate and dexmethylphenidate products in capsule form can be opened and sprinkled on applesauce. The various formulations of IR and intermediate- and extended-release methylphenidate and dexmethylphenidate can be useful options in satisfying patients' individual needs in the management of ADHD. All are equally efficacious in controlling ADHD symptoms. Copyright © 2014 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Micromachined devices: the impact of controlled geometry from cell-targeting to bioavailability.

PubMed

Tao, Sarah L; Desai, Tejal A

2005-12-05

Advances in microelectomechanical systems (MEMS) have allowed the microfabrication of polymeric substrates and the development of a novel class of controlled delivery devices. These vehicles have specifically tailored three-dimensional physical and chemical features which, together, provide the capacity to target cells, promote unidirectional controlled release, and enhance permeation across the intestinal epithelial barrier. Examining the biological response at the microdevice biointerface may provide insight into the benefits of customized surface chemistry and structure in terms of complex drug delivery vehicle design. Therefore, the aim of this work was to determine the interfacial effects of selective surface chemistry and architecture of tomato lectin (TL)-modified poly(methyl methacrylate) (PMMA) drug delivery microdevices on the Caco-2 cell line, a model of the gastrointestinal tract.

Spatiotemporally and Sequentially-Controlled Drug Release from Polymer Gatekeeper-Hollow Silica Nanoparticles

NASA Astrophysics Data System (ADS)

Palanikumar, L.; Jeena, M. T.; Kim, Kibeom; Yong Oh, Jun; Kim, Chaekyu; Park, Myoung-Hwan; Ryu, Ja-Hyoung

2017-04-01

Combination chemotherapy has become the primary strategy against cancer multidrug resistance; however, accomplishing optimal pharmacokinetic delivery of multiple drugs is still challenging. Herein, we report a sequential combination drug delivery strategy exploiting a pH-triggerable and redox switch to release cargos from hollow silica nanoparticles in a spatiotemporal manner. This versatile system further enables a large loading efficiency for both hydrophobic and hydrophilic drugs inside the nanoparticles, followed by self-crosslinking with disulfide and diisopropylamine-functionalized polymers. In acidic tumour environments, the positive charge generated by the protonation of the diisopropylamine moiety facilitated the cellular uptake of the particles. Upon internalization, the acidic endosomal pH condition and intracellular glutathione regulated the sequential release of the drugs in a time-dependent manner, providing a promising therapeutic approach to overcoming drug resistance during cancer treatment.

Simultaneous expression and transportation of insulin by supramolecular polysaccharide nanocluster

NASA Astrophysics Data System (ADS)

Zhang, Yu-Hui; Zhang, Ying-Ming; Zhao, Qi-Hui; Liu, Yu

2016-03-01

Drug/gene transportation systems with stimuli-responsive release behaviors are becoming research hotspots in biochemical and biomedical fields. In this work, a glucose-responsive supramolecular nanocluster was successfully constructed by the intermolecular complexation of phenylboronic acid modified β-cyclodextrin with adamantane modified polyethylenimine, which could be used as a biocompatible carrier for insulin and pCMV3-C-GFPSpark-Ins DNA which could express insulin co-delivery. Benefiting from the response capability of phenylboronic acid moiety toward glucose, the encapsulated insulin could be specifically released and the corresponding targeted DNA could efficiently express insulin in HepG2 cell, accompanied by the high-level insulin release in vitro. Our results demonstrate that the simultaneous insulin drug delivery and insulin gene transfection in a controlled mode may have great potential in the clinical diabetes treatments.

Delivery of S1P Receptor-Targeted Drugs via Biodegradable Polymer Scaffolds Enhances Bone Regeneration in a Critical Size Cranial Defect*

PubMed Central

Das, Anusuya; Tanner, Shaun; Barker, Daniel A.; Green, David; Botchwey, Edward A.

2014-01-01

Biodegradable polymer scaffolds can be used to deliver soluble factors to enhance osseous remodeling in bone defects. To this end, we designed a poly(lactic-co-glycolic acid) (PLAGA) microsphere scaffold to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors. The microsphere scaffolds were created from fast degrading 50:50 PLAGA and/or from slow-degrading 85:15 PLAGA. Temporal and spatial regulation of bone remodeling depended on the use of appropriate scaffolds for drug delivery. The release profiles from the scaffolds were used to design an optimal delivery system to treat critical size cranial defects in a rodent model. The ability of local FTY720 delivery to maximize bone regeneration was evaluated with microcomputed tomography (microCT) and histology. Following 4 weeks of defect healing, FTY720 delivery from 85:15 PLAGA scaffolds resulted in a significant increase in bone volumes in the defect region compared to the controls. 85:15 microsphere scaffolds maintain their structural integrity over a longer period of time, and cause an initial burst release of FTY720 due to surface localization of the drug. This encourages cellular in-growth and an increase in new bone formation. PMID:23640833

Delivery of S1P receptor-targeted drugs via biodegradable polymer scaffolds enhances bone regeneration in a critical size cranial defect.

PubMed

Das, Anusuya; Tanner, Shaun; Barker, Daniel A; Green, David; Botchwey, Edward A

2014-04-01

Biodegradable polymer scaffolds can be used to deliver soluble factors to enhance osseous remodeling in bone defects. To this end, we designed a poly(lactic-co-glycolic acid) (PLAGA) microsphere scaffold to sustain the release of FTY720, a selective agonist for sphingosine 1-phosphate (S1P) receptors. The microsphere scaffolds were created from fast degrading 50:50 PLAGA and/or from slow-degrading 85:15 PLAGA. Temporal and spatial regulation of bone remodeling depended on the use of appropriate scaffolds for drug delivery. The release profiles from the scaffolds were used to design an optimal delivery system to treat critical size cranial defects in a rodent model. The ability of local FTY720 delivery to maximize bone regeneration was evaluated with micro-computed tomography (microCT) and histology. Following 4 weeks of defect healing, FTY720 delivery from 85:15 PLAGA scaffolds resulted in a significant increase in bone volumes in the defect region compared to the controls. A 85:15 microsphere scaffolds maintain their structural integrity over a longer period of time, and cause an initial burst release of FTY720 due to surface localization of the drug. This encourages cellular in-growth and an increase in new bone formation. Copyright © 2013 Wiley Periodicals, Inc.

pH-sensitive nanomicelles for controlled and efficient drug delivery to human colorectal carcinoma LoVo cells.

PubMed

Feng, Shi-Ting; Li, Jingguo; Luo, Yanji; Yin, Tinghui; Cai, Huasong; Wang, Yong; Dong, Zhi; Shuai, Xintao; Li, Zi-Ping

2014-01-01

The triblock copolymers PEG-P(Asp-DIP)-P(Lys-Ca) (PEALCa) of polyethylene glycol (PEG), poly(N-(N',N'-diisopropylaminoethyl) aspartamide) (P(Asp-DIP)), and poly (lysine-cholic acid) (P(Lys-Ca)) were synthesized as a pH-sensitive drug delivery system. In neutral aqueous environment such as physiological environment, PEALCa can self-assemble into stable vesicles with a size around 50-60 nm, avoid uptake by the reticuloendothelial system (RES), and encase the drug in the core. However, the PEALCa micelles disassemble and release drug rapidly in acidic environment that resembles lysosomal compartments. The anticancer drug Paclitaxel (PTX) and hydrophilic superparamagnetic iron oxide (SPIO) were encapsulated inside the core of the PEALCa micelles and used for potential cancer therapy. Drug release study revealed that PTX in the micelles was released faster at pH 5.0 than at pH 7.4. Cell culture studies showed that the PTX-SPIO-PEALCa micelle was effectively internalized by human colon carcinoma cell line (LoVo cells), and PTX could be embedded inside lysosomal compartments. Moreover, the human colorectal carcinoma (CRC) LoVo cells delivery effect was verified in vivo by magnetic resonance imaging (MRI) and histology analysis. Consequently effective suppression of CRC LoVo cell growth was evaluated. These results indicated that the PTX-SPION-loaded pH-sensitive micelles were a promising MRI-visible drug release system for colorectal cancer therapy.

Progress in the Field of Constructing Near-Infrared Light-Responsive Drug Delivery Platforms.

PubMed

Zhou, Fang; Wang, Hanjie; Chang, Jin

2016-03-01

Stimuli-responsive materials have taken replace of traditional drug carriers due to their ability to achieve controlled release of their encapsulated contents. A variety of sensitive materials, such as polymers that respond to pH, light, and magnetic fields, are widely used to construct drug carriers, and achieved good results. Specifically, near-infrared light (NIR) responsive materials are of particular interest in drug delivery, as NIR can penetrate body tissue and is minimally absorbed by the body's water and hemoglobin and is less harmful to healthy cells than UV or visible light. Thus, the near-infrared excitation drug delivery systems (NIRDDSs) have some essential advantages just like being efficient to kill tumor cells, accurate to achieve the tumor sites and less damage to human body. Also, in the process of building the carriers, we may achieve a combination of controlled release chemotherapy, photothermal therapy (PTT) or photodynamic therapy (PDT). In addition, besides utilizing as drug delivery platforms, some carriers can achieve multifunctional tumor diagnosis and treatment, such as magnetic resonance imaging, optical imaging, drug carriers and PTT. In this review, based on the mechanism of NIR, we highlight diverse near-infrared light-responsive drug delivery platforms and recent advances in the development of NIRDDSs for cancer therapy primarily.

Navigating sticky areas in transdermal product development.

PubMed

Strasinger, Caroline; Raney, Sam G; Tran, Doanh C; Ghosh, Priyanka; Newman, Bryan; Bashaw, Edward D; Ghosh, Tapash; Shukla, Chinmay G

2016-07-10

The benefits of transdermal delivery over the oral route to combat such issues of low bioavailability and limited controlled release opportunities are well known and have been previously discussed by many in the field (Prausnitz et al. (2004) [1]; Hadgraft and Lane (2006) [2]). However, significant challenges faced by developers as a product moves from the purely theoretical to commercial production have hampered full capitalization of the dosage forms vast benefits. While different technical aspects of transdermal system development have been discussed at various industry meetings and scientific workshops, uncertainties have persisted regarding the pharmaceutical industry's conventionally accepted approach for the development and manufacturing of transdermal systems. This review provides an overview of the challenges frequently faced and the industry's best practices for assuring the quality and performance of transdermal delivery systems and topical patches (collectively, TDS). The topics discussed are broadly divided into the evaluation of product quality and the evaluation of product performance; with the overall goal of the discussion to improve, advance and accelerate commercial development in the area of this complex controlled release dosage form. Published by Elsevier B.V.

In vitro-ex vivo correlations between a cell-laden hydrogel and mucosal tissue for screening composite delivery systems

PubMed Central

Blakney, Anna K.; Little, Adam B.; Jiang, Yonghou; Woodrow, Kim A.

2017-01-01

Composite delivery systems where drugs are electrospun in different layers and vary the drug stacking-order are posited to affect bioavailability. We evaluated how the formulation characteristics of both burst- and sustained-release electrospun fibers containing three physicochemically diverse drugs: dapivirine (DPV), maraviroc (MVC) and tenofovir (TFV) affect in vitro and ex vivo release. We developed a poly(hydroxyethyl methacrylate) (pHEMA) hydrogel release platform for the rapid, inexpensive in vitro evaluation of burst- and sustained-release topical or dermal drug delivery systems with varying microarchitecture. We investigated properties of the hydrogel that could recapitulate ex vivo release into nonhuman primate vaginal tissue. Using a DMSO extraction protocol and HPLC analysis, we achieved >93% recovery from the hydrogels and >88% recovery from tissue explants for all three drugs. We found that DPV loading, but not stacking order (layers of fiber containing a single drug) or microarchitecture (layers with isolated drug compared to all drugs in the same layer) impacted the burst release in vitro and ex vivo. Our burst-release formulations showed a correlation for DPV accumulation between the hydrogel and tissue (R2=0.80), but the correlation was not significant for MVC or TFV. For the sustained release formulations, the PLGA/PCL content did not affect TFV release in vitro or ex vivo. Incorporation of cells into the hydrogel matrix improved the correlation between hydrogel and tissue explant release for TFV. We expect that this hydrogel tissue mimic maybe a promising preclinical model to evaluate topical or transdermal drug delivery systems with complex microarchitectures. PMID:28222612

Controlled dexamethasone delivery via double-walled microspheres to enhance long-term adipose tissue retention

PubMed Central

Kelmendi-Doko, Arta; Rubin, J Peter; Klett, Katarina; Mahoney, Christopher; Wang, Sheri; Marra, Kacey G

2017-01-01

Current materials used for adipose tissue reconstruction have critical shortcomings such as suboptimal volume retention, donor-site morbidity, and poor biocompatibility. The aim of this study was to examine a controlled delivery system of dexamethasone to generate stable adipose tissue when mixed with disaggregated human fat in an athymic mouse model for 6 months. The hypothesis that the continued release of dexamethasone from polymeric microspheres would enhance both adipogenesis and angiogenesis more significantly when compared to the single-walled microsphere model, resulting in long-term adipose volume retention, was tested. Dexamethasone was encapsulated within single-walled poly(lactic-co-glycolic acid) microspheres (Dex SW MS) and compared to dexamethasone encapsulated in a poly(lactic-co-glycolic acid) core surrounded by a shell of poly-l-lactide. The double-walled polymer microsphere system in the second model was developed to create a more sustainable drug delivery process. Dexamethasone-loaded poly(lactic-co-glycolic acid) microspheres (Dex SW MS) and dexamethasone-loaded poly(lactic-co-glycolic acid)/poly-l-lactide double-walled microspheres (Dex DW MS) were prepared using single and double emulsion/solvent techniques. In vitro release kinetics were determined. Two doses of each type of microsphere were examined; 50 and 27 mg of Dex MS and Dex DW MS were mixed with 0.3 mL of human lipoaspirate. Additionally, 50 mg of empty MS and lipoaspirate-only controls were examined. Samples were analyzed grossly and histologically after 6 months in vivo. Mass and volume were measured; dexamethasone microsphere-containing samples demonstrated greater adipose tissue retention compared to the control group. Histological analysis, including hematoxylin and eosin and CD31 staining, indicated increased vascularization (p < 0.05) within the Dex MS-containing samples. Controlled delivery of adipogenic factors, such as dexamethasone via polymer microspheres, significantly affects adipose tissue retention by maintaining healthy tissue formation and vascularization. Dex DW MS provide an improved model to former Dex SW MS, resulting in notably longer release time and, consequently, larger volumes of adipose retained in vivo. The use of microspheres, specifically double-walled, as vehicles for controlled drug delivery of adipogenic factors therefore present a clinically relevant model of adipose retention that has the potential to greatly improve soft tissue repair. PMID:29051810

Nanoencapsulation of dietary flavonoid fisetin: Formulation and in vitro antioxidant and α-glucosidase inhibition activities.

PubMed

Sechi, Mario; Syed, Deeba N; Pala, Nicolino; Mariani, Alberto; Marceddu, Salvatore; Brunetti, Antonio; Mukhtar, Hasan; Sanna, Vanna

2016-11-01

The bioactive flavonoid fisetin (FS) is a diet-derived antioxidant that is being increasingly investigated for its health-promoting effects. Unfortunately, the poor physicochemical and pharmacokinetic properties affect and limit the clinical application. In this study, novel polymeric nanoparticles (NPs), based on Poly-(ε-caprolactone) (PCL) and PLGA-PEG-COOH, encapsulating FS were formulated as suitable oral controlled release systems. Results showed NPs having a mean diameter of 140-200nm, and a percent loading of FS ranging from 70 to 82%. In vitro release studies revealed that NPs are able to protect and preserve the release of FS in gastric simulated conditions, also controlling the release in the intestinal medium. Moreover, the DPPH and ABTS scavenging capacity of FS, as well as α-glucosidase inhibition activity, that resulted about 20-fold higher than commercial Acarbose, were retained during nanoencapsulation process. In summary, our developed NPs can be proposed as an attractive delivery system to control the release of antioxidant and anti-hyperglycemic FS for nutraceutical and/or therapeutic application. Copyright © 2016 Elsevier B.V. All rights reserved.

Multifunctional halloysite nanotubes for targeted delivery and controlled release of doxorubicin in-vitro and in-vivo studies

NASA Astrophysics Data System (ADS)

Hu, Yuwei; Chen, Jian; Li, Xiufang; Sun, Yanhua; Huang, Shen; Li, Yuqing; Liu, Hui; Xu, Jiangfeng; Zhong, Shian

2017-09-01

The current state of cancer therapy encourages researchers to develop novel efficient nanocarriers. Halloysite nanotubes (HNTs) are good nanocarrier candidates due to their unique nanoscale (40-80 nm in diamter and 200-500 nm in length) and hollow lumen, as well as good biocompatibility and low cost. In our study, we prepared a type of folate-mediated targeting and redox-triggered anticancer drug delivery system, so that Doxorubicin (DOX) can be specifically transported to tumor sites due to the over-expressed folate-receptors on the surface of cancer cells. Furthermore, it can then be released by the reductive agent glutathione (GSH) in cancer cells where the content of GSH is nearly 103-fold higher than in the extracellular matrix. A series of methods have demonstrated that per-thiol-β-cyclodextrin (β-CD-(SH)7) was successfully combined with HNTs via a redox-responsive disulfide bond, and folic acid-polyethylene glycol-adamantane (FA-PEG-Ad) was immobilized on the HNTs through the strong complexation between β-CD/Ad. In vitro studies indicated that the release rate of DOX raised sharply in dithiothreitol (DTT) reducing environment and the amount of released DOX reached 70% in 10 mM DTT within the first 10 h, while only 40% of DOX was released in phosphate buffer solution (PBS) even after 79 h. Furthermore, the targeted HNTs could be specifically endocytosed by over-expressed folate-receptor cancer cells and significantly accelerate the apoptosis of cancer cells compared to non-targeted HNTs. In vivo studies further verified that the targeted HNTs had the best therapeutic efficacy and no obvious side effects for tumor-bearing nude mice, while free DOX showed damaging effects on normal tissues. In summary, this novel nanocarrier system shows excellent potential for targeted delivery and controlled release of anticancer drugs and provides a potential platform for tumor therapy.

Stimuli sensitive polymers and self regulated drug delivery systems: a very partial review.

PubMed

Siegel, Ronald A

2014-09-28

Since the early days of the Journal of Controlled Release, there has been considerable interest in materials that can release drug on an "on-demand" basis. So called "stimuli-responsive" and "intelligent" systems have been designed to deliver drug at various times or at various sites in the body, according to a stimulus that is either endogenous or externally applied. In the past three decades, research along these lines has taken numerous directions, and each new generation of investigators has discovered new physicochemical principles and chemical schemes by which the release properties of materials can be altered. No single review could possibly do justice to all of these approaches. In this article, some general observations are made, and a partial history of the field is presented. Both open loop and closed loop systems are discussed. Special emphasis is placed on stimuli-responsive hydrogels, and on systems that can respond repeatedly. It is argued that the most success at present and in the foreseeable future is with systems in which biosensing and actuation (i.e. drug delivery) are separated, with a human and/or cybernetic operator linking the two. Copyright © 2014 Elsevier B.V. All rights reserved.

Stimuli Sensitive Polymers and Self Regulated Drug Delivery Systems: A Very Partial Review

PubMed Central

Siegel, Ronald A.

2014-01-01

Since the early days of the Journal of Controlled Release, there has been considerable interest in materials that can release drug on an “on-demand” basis. So called “stimuli-responsive” and “intelligent” systems have been designed to deliver drug at various times or at various sites in the body, according to a stimulus that is either endogenous or externally applied. In the past three decades, research along these lines has taken numerous directions, and each new generation of investigators has discovered new physicochemical principles and chemical schemes by which the release properties of materials can be altered. No single review could possibly do justice to all of these approaches. In this article, some general observations are made, and a partial history of the field is presented. Both open loop and closed loop systems are discussed. Special emphasis is placed on stimuli-responsive hydrogels, and on systems that can respond repeatedly. It is argued that the most success at present and in the foreseeable future is with systems in which biosensing and actuation (i.e. drug delivery) are separated, with a human and/or cybernetic operator linking the two. PMID:24984012

Radiation synthesis of poly[(dimethylaminoethyl methacrylate)-co-(ethyleneglycol dimethacrylate)] hydrogels and its application as a carrier for anticancer delivery

NASA Astrophysics Data System (ADS)

Mazied, Nabila A.; Ismail, Sahar A.; Abou Taleb, Manal F.

2009-11-01

The use of hydrogels as carriers for anticancer delivery has been a subject of significant recent research. In our recent work, we have shown that diffusion-controlled delivery of flutamide from hydrogels containing poly (dimethylaminoethyl methacrylate (DMAEMA)/ethyleneglycol dimethacrylate (EGDMA)) can be possible and controlled by the three-dimensional structure. Hydrogels based essentially on dimethylaminoethyl methacrylate and different ratios of ethyleneglycol dimethacrylate monomers were synthesized using gamma radiation copolymerization. The influence of copolymer composition and pH value of the surrounding medium on swelling behavior into the glassy polymer were discussed. The results showed that the ratio of EGDMA in the comonomer feeding solution has a great effect on the gel fraction and water content in the final hydrogel. In this regard, it was observed that the increase of EGDMA ratio decreased these properties. The ability of the prepared copolymer to be used as drug carrier for anticancer drug-delivery system was estimated using flutamide as a model drug. In vitro drug-release studies in different buffer solutions show that the basic parameters affecting the drug release behavior of hydrogel are the pH of the solution and DMAEMA content of hydrogel.

Investigating the Release of a Hydrophobic Peptide from Matrices of Biodegradable Polymers: An Integrated Method Approach

PubMed Central

Gubskaya, Anna V.; Khan, I. John; Valenzuela, Loreto M.; Lisnyak, Yuriy V.; Kohn, Joachim

2013-01-01

The objectives of this work were: (1) to select suitable compositions of tyrosine-derived polycarbonates for controlled delivery of voclosporin, a potent drug candidate to treat ocular diseases, (2) to establish a structure-function relationship between key molecular characteristics of biodegradable polymer matrices and drug release kinetics, and (3) to identify factors contributing in the rate of drug release. For the first time, the experimental study of polymeric drug release was accompanied by a hierarchical sequence of three computational methods. First, suitable polymer compositions used in subsequent neural network modeling were determined by means of response surface methodology (RSM). Second, accurate artificial neural network (ANN) models were built to predict drug release profiles for fifteen polymers located outside the initial design space. Finally, thermodynamic properties and hydrogen-bonding patterns of model drug-polymer complexes were studied using molecular dynamics (MD) technique to elucidate a role of specific interactions in drug release mechanism. This research presents further development of methodological approaches to meet challenges in the design of polymeric drug delivery systems. PMID:24039300

Design and evaluation of a dry coated drug delivery system with floating-pulsatile release.

PubMed

Zou, Hao; Jiang, Xuetao; Kong, Lingshan; Gao, Shen

2008-01-01

The objective of this work was to develop and evaluate a floating-pulsatile drug delivery system intended for chronopharmacotherapy. Floating-pulsatile concept was applied to increase the gastric residence of the dosage form having lag phase followed by a burst release. To overcome limitations of various approaches for imparting buoyancy, we generated the system which consisted of three different parts, a core tablet, containing the active ingredient, an erodible outer shell and a top cover buoyant layer. The dry coated tablet consists in a drug-containing core, coated by a hydrophilic erodible polymer which is responsible for a lag phase in the onset of pulsatile release. The buoyant layer, prepared with Methocel K4M, Carbopol 934P and sodium bicarbonate, provides buoyancy to increase the retention of the oral dosage form in the stomach. The effect of the hydrophilic erodible polymer characteristics on the lag time and drug release was investigated. Developed formulations were evaluated for their buoyancy, dissolution and pharmacokinetic, as well gamma-scintigraphically. The results showed that a certain lag time before the drug released generally due to the erosion of the dry coated layer. Floating time was controlled by the quantity and composition of the buoyant layer. Both pharmacokinetic and gamma-scintigraphic data point out the capability of the system of prolonged residence of the tablets in the stomach and releasing drugs after a programmed lag time. (c) 2007 Wiley-Liss, Inc.

Liquid Crystalline Systems Based on Glyceryl Monooleate and Penetration Enhancers for Skin Delivery of Celecoxib: Characterization, In Vitro Drug Release, and In Vivo Studies.

PubMed

Dante, Mariane de Cássia Lima; Borgheti-Cardoso, Livia Neves; Fantini, Marcia Carvalho de Abreu; Praça, Fabíola Silva Garcia; Medina, Wanessa Silva Garcia; Pierre, Maria Bernadete Riemma; Lara, Marilisa Guimarães

2018-03-01

Celecoxib (CXB) is a widely used anti-inflammatory drug that also acts as a chemopreventive agent against several types of cancer, including skin cancer. As the long-term oral administration of CXB has been associated with severe side effects, the skin delivery of this drug represents a promising alternative for the treatment of skin inflammatory conditions and chemoprevention of skin cancer. We prepared and characterized liquid crystalline systems based on glyceryl monooleate and water containing penetration enhancers which were primarily designed to promote skin delivery of CXB. Analysis of their phase behavior revealed the formation of cubic and hexagonal phases depending on the systems' composition. The systems' structure and composition markedly affected the in vitro CXB release profile. Oleic acid reduced CXB release rate, but association oleic acid/propylene glycol increased the drug release rate. The developed systems significantly reduced inflammation in an aerosil-induced rat paw edema model. The systems' composition and liquid crystalline structure influenced their anti-inflammatory potency. Cubic phase systems containing oleic acid/propylene glycol association reduced edema in a sustained manner, indicating that they modulate CXB release and permeation. Our findings demonstrate that the developed liquid crystalline systems are potential carriers for the skin delivery of CXB. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Towards Optimal Design of Cancer Nanomedicines: Multi-stage Nanoparticles for the Treatment of Solid Tumors.

PubMed

Stylianopoulos, Triantafyllos; Economides, Eva-Athena; Baish, James W; Fukumura, Dai; Jain, Rakesh K

2015-09-01

Conventional drug delivery systems for solid tumors are composed of a nano-carrier that releases its therapeutic load. These two-stage nanoparticles utilize the enhanced permeability and retention (EPR) effect to enable preferential delivery to tumor tissue. However, the size-dependency of the EPR, the limited penetration of nanoparticles into the tumor as well as the rapid binding of the particles or the released cytotoxic agents to cancer cells and stromal components inhibit the uniform distribution of the drug and the efficacy of the treatment. Here, we employ mathematical modeling to study the effect of particle size, drug release rate and binding affinity on the distribution and efficacy of nanoparticles to derive optimal design rules. Furthermore, we introduce a new multi-stage delivery system. The system consists of a 20-nm primary nanoparticle, which releases 5-nm secondary particles, which in turn release the chemotherapeutic drug. We found that tuning the drug release kinetics and binding affinities leads to improved delivery of the drug. Our results also indicate that multi-stage nanoparticles are superior over two-stage nano-carriers provided they have a faster drug release rate and for high binding affinity drugs. Furthermore, our results suggest that smaller nanoparticles achieve better treatment outcome.

Interpreting the Weibull fitting parameters for diffusion-controlled release data

NASA Astrophysics Data System (ADS)

Ignacio, Maxime; Chubynsky, Mykyta V.; Slater, Gary W.

2017-11-01

We examine the diffusion-controlled release of molecules from passive delivery systems using both analytical solutions of the diffusion equation and numerically exact Lattice Monte Carlo data. For very short times, the release process follows a √{ t } power law, typical of diffusion processes, while the long-time asymptotic behavior is exponential. The crossover time between these two regimes is determined by the boundary conditions and initial loading of the system. We show that while the widely used Weibull function provides a reasonable fit (in terms of statistical error), it has two major drawbacks: (i) it does not capture the correct limits and (ii) there is no direct connection between the fitting parameters and the properties of the system. Using a physically motivated interpolating fitting function that correctly includes both time regimes, we are able to predict the values of the Weibull parameters which allows us to propose a physical interpretation.

Simultaneously Load and Extended Release of Betamethasone and Ciprofloxacin from Vitamin E-Loaded Silicone-Based Soft Contact Lenses.

PubMed

Rad, Maryam Shayani; Mohajeri, Seyed Ahmad

2016-09-01

The purpose of the present study was to evaluate the efficacy of commercial soft contact lenses, loaded with vitamin E, as ocular drug delivery systems for simultaneous loading and release of ciprofloxacin (Cipro) and betamethasone (BMZ) in artificial tears. In this study, we applied vitamin E as a barrier to increase BMZ-Cipro loading into three commercial silicone-based soft contact lenses and control their simultaneous release into the artificial lachrymal fluid. Two different concentrations of vitamin E solution (0.1 and 0.2 g/ml) were used, and various parameters including changes in lens diameter, water content, ultraviolet-visible light (UV-Vis) transmittance, drug-binding properties, and drug release profile were investigated. The obtained results indicated that vitamin E significantly reduced the swelling properties of contact lenses in aqueous media, while it enhanced the lens diameter in both dry and hydrated states. Vitamin E had no significant effects on visible transmittance, while it blocked UV radiation, which could be harmful for the eye surface. Our findings revealed that vitamin E improved the simultaneous loading amount of BMZ-Cipro into soft contact lenses. Additionally, BMZ and Cipro release rates significantly reduced after using vitamin E as a hydrophobic diffusion barrier. After soaking the lenses in 0.1 and 0.2 g/ml of vitamin E solution, BMZ release time increased by 28.8-81.6 and 182.4-201 folds, respectively. Moreover, Cipro release time increased by 12-18 and 1152-2313 folds, respectively. The results of the present study indicated the efficacy of vitamin E as a diffusion barrier in developing a controlled drug delivery system for the simultaneous loading of BMZ and Cipro and sustaining their release from soft contact lenses.

Controlled delivery of antimicrobial gallium ions from phosphate-based glasses.

PubMed

Valappil, S P; Ready, D; Abou Neel, E A; Pickup, D M; O'Dell, L A; Chrzanowski, W; Pratten, J; Newport, R J; Smith, M E; Wilson, M; Knowles, J C

2009-05-01

Gallium-doped phosphate-based glasses (PBGs) have been recently shown to have antibacterial activity. However, the delivery of gallium ions from these glasses can be improved by altering the calcium ion concentration to control the degradation rate of the glasses. In the present study, the effect of increasing calcium content in novel gallium (Ga2O3)-doped PBGs on the susceptibility of Pseudomonas aeruginosa is examined. The lack of new antibiotics in development makes gallium-doped PBG potentially a highly promising new therapeutic agent. The results show that an increase in calcium content (14, 15 and 16 mol.% CaO) cause a decrease in degradation rate (17.6, 13.5 and 7.3 microg mm(-2) h(-1)), gallium ion release and antimicrobial activity against planktonic P. aeruginosa. The most potent glass composition (containing 14 mol.% CaO) was then evaluated for its ability to prevent the growth of biofilms of P. aeruginosa. Gallium release was found to reduce biofilm growth of P. aeruginosa with a maximum effect (0.86 log(10) CFU reduction compared to Ga2O3-free glasses) after 48 h. Analysis of the biofilms by confocal microscopy confirmed the anti-biofilm effect of these glasses as it showed both viable and non-viable bacteria on the glass surface. Results of the solubility and ion release studies show that this glass system is suitable for controlled delivery of Ga3+. 71Ga NMR and Ga K-edge XANES measurements indicate that the gallium is octahedrally coordinated by oxygen atoms in all samples. The results presented here suggest that PBGs may be useful in controlled drug delivery applications, to deliver gallium ions in order to prevent infections due to P. aeruginosa biofilms.

Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers.

PubMed

Nair, Madhavan; Guduru, Rakesh; Liang, Ping; Hong, Jeongmin; Sagar, Vidya; Khizroev, Sakhrat

2013-01-01

Although highly active anti-retroviral therapy has resulted in remarkable decline in the morbidity and mortality in AIDS patients, inadequately low delivery of anti-retroviral drugs across the blood-brain barrier results in virus persistence. The capability of high-efficacy-targeted drug delivery and on-demand release remains a formidable task. Here we report an in vitro study to demonstrate the on-demand release of azidothymidine 5'-triphosphate, an anti-human immunodeficiency virus drug, from 30 nm CoFe2O4@BaTiO3 magneto-electric nanoparticles by applying a low alternating current magnetic field. Magneto-electric nanoparticles as field-controlled drug carriers offer a unique capability of field-triggered release after crossing the blood-brain barrier. Owing to the intrinsic magnetoelectricity, these nanoparticles can couple external magnetic fields with the electric forces in drug-carrier bonds to enable remotely controlled delivery without exploiting heat. Functional and structural integrity of the drug after the release was confirmed in in vitro experiments with human immunodeficiency virus-infected cells and through atomic force microscopy, spectrophotometry, Fourier transform infrared and mass spectrometry studies.

Development and optimization of methotrexate-loaded lipid-polymer hybrid nanoparticles for controlled drug delivery applications.

PubMed

Tahir, Nayab; Madni, Asadullah; Balasubramanian, Vimalkumar; Rehman, Mubashar; Correia, Alexandra; Kashif, Prince Muhammad; Mäkilä, Ermei; Salonen, Jarno; Santos, Hélder A

2017-11-25

Lipid-polymer hybrid nanoparticles (LPHNPs) are emerging platforms for drug delivery applications. In the present study, methotrexate loaded LPHNPs consisted of PLGA and Lipoid S100 were fabricated by employing a single-step modified nanoprecipitation method combined with self-assembly. A three factor, three level Box Behnken design using Design-Expert ® software was employed to access the influence of three independent variables on the particle size, drug entrapment and percent drug release. The optimized formulation was selected through numeric optimization approach. The results were supported with the ANOVA analysis, regression equations and response surface plots. Transmission electron microscope images indicated the nanosized and spherical shape of the LPHNPs with fair size distribution. The nanoparticles ranged from 176 to 308nm, which increased with increased polymer concentration. The increase in polymer and lipid concentration also increased the drug entrapment efficiency. The in vitro drug release was in range 70.34-91.95% and the release mechanism follow the Higuchi model (R 2 =0.9888) and Fickian diffusion (n<0.5). The in vitro cytotoxicity assay and confocal microscopy of the optimized formulation demonstrate the good safety and better internalization of the LPHNPs. The cell antiproliferation showed the spatial and controlled action of the nanoformulation as compared to the plain drug solution. The results suggest that LPHNPs can be a promising delivery system envisioned to safe, stable and potentially controlled delivery of methotrexate to the cancer cells to achieve better therapeutic outcomes. Copyright © 2017 Elsevier B.V. All rights reserved.

Design and in vitro evaluation of multiparticulate floating drug delivery system of zolpidem tartarate.

PubMed

Amrutkar, P P; Chaudhari, P D; Patil, S B

2012-01-01

Zolpidem tartarate is a non-benzodiazepine, sedative-hypnotic, which finds its major use in various types of insomnia. The present work relates to development of multiparticulate floating drug delivery system based on gas generation technique to prolong the gastric residence time and to increase the overall bioavailability. Modified release dosage form of zolpidem tartarate adapted to release over a predetermined time period, according to biphasic profile of dissolution, where the first phase is immediate release phase for inducing the sleep and the second phase is modified release phase for maintaining the sleep up to 10 h. The system consists of zolpidem tartarate layered pellets coated with effervescent layer and polymeric membrane. The floating ability and in vitro drug release of the system were dependent on amount of the effervescent agent (sodium bicarbonate) layered onto the drug layered pellets, and coating level of the polymeric membrane (Eudragit(®) NE 30D). The system could float completely within 5 min and maintain the floating over a period of 10 h. The multiparticulate floating delivery system of zolpidem tartarate with rapid floating and modified drug release was obtained. Copyright © 2011 Elsevier B.V. All rights reserved.

Lyophilized Silk Fibroin Hydrogels for the Sustained Local Delivery of Therapeutic Monoclonal Antibodies

PubMed Central

Guziewicz, Nicholas; Best, Annie; Perez-Ramirez, Bernardo; Kaplan, David L.

2011-01-01

The development of sustained delivery systems compatible with protein therapeutics continues to be a significant unmet need. A lyophilized silk fibroin hydrogel matrix (lyogel) for the sustained release of pharmaceutically relevant monoclonal antibodies is described. Sonication of silk fibroin prior to antibody incorporation avoids exposing the antibody to the sol-gel transition inducing shear stress. Fourier Transform Infrared (FTIR) analysis showed no change in silk structural composition between hydrogel and lyogel or with increasing silk fibroin concentration. Antibody release from hydrogels occurred rapidly over 10 days regardless of silk concentration. Upon lyophilization, sustained antibody release was observed over 38 days from lyogels containing 6.2% (w/w) silk fibroin and above. In 3.2% (w/w) silk lyogels, antibody release was comparable to hydrogels. Swelling properties of lyogels followed a similar threshold behavior. Lyogels at 3.2% (w/w) silk recovered approximately 90% of their fluid mass upon rehydration, while approximately 50% fluid recovery was observed at 6.2% (w/w) silk and above. Antibody release was primarily governed by hydrophobic/hydrophilic silk-antibody interactions and secondarily altered by the hydration resistance of the lyogel. Hydration resistance was controlled by altering β-sheet (crystalline) density of the matrix. The antibody released from lyogels maintained biological activity. Silk lyogels offer an advantage as a delivery matrix over other hydrogel materials for the slow release of the loaded protein, making lyogels suitable for long-term sustained release applications. PMID:21216004

In Vitro and In Vivo Evaluation of a Hydrogel Reservoir as a Continuous Drug Delivery System for Inner Ear Treatment

PubMed Central

Hessler, Roland; Stöver, Timo; Esser, Karl-Heinz; Möller, Martin; Lenarz, Thomas; Jolly, Claude; Groll, Jürgen; Scheper, Verena

2014-01-01

Fibrous tissue growth and loss of residual hearing after cochlear implantation can be reduced by application of the glucocorticoid dexamethasone-21-phosphate-disodium-salt (DEX). To date, sustained delivery of this agent to the cochlea using a number of pharmaceutical technologies has not been entirely successful. In this study we examine a novel way of continuous local drug application into the inner ear using a refillable hydrogel functionalized silicone reservoir. A PEG-based hydrogel made of reactive NCO-sP(EO-stat-PO) prepolymers was evaluated as a drug conveying and delivery system in vitro and in vivo. Encapsulating the free form hydrogel into a silicone tube with a small opening for the drug diffusion resulted in delayed drug release but unaffected diffusion of DEX through the gel compared to the free form hydrogel. Additionally, controlled DEX release over several weeks could be demonstrated using the hydrogel filled reservoir. Using a guinea-pig cochlear trauma model the reservoir delivery of DEX significantly protected residual hearing and reduced fibrosis. As well as being used as a device in its own right or in combination with cochlear implants, the hydrogel-filled reservoir represents a new drug delivery system that feasibly could be replenished with therapeutic agents to provide sustained treatment of the inner ear. PMID:25105670

Design and evaluation of novel fast forming pilocarpine-loaded ocular hydrogels for sustained pharmacological response

PubMed Central

Anumolu, SivaNaga S.; Singh, Yashveer; Gao, Dayuan; Stein, Stanley; Sinko, Patrick J.

2009-01-01

Fast forming hydrogels prepared by crosslinking a poly(ethylene glycol) (PEG)-based copolymer containing multiple thiol (SH) groups were evaluated for the controlled ocular delivery of pilocarpine and subsequent pupillary constriction. Physical properties of the hydrogels were characterized using UV-Vis spectrophotometry, transmission electron microscopy (TEM), rheometry, and swelling kinetics. Pilocarpine loading efficiency and release properties were measured in simulated tear fluid. The hydrogel formulations exhibited high drug loading efficiency (~74%). Pilocarpine release was found to be biphasic with release half times of ~2 and 94 h, respectively, and 85–100% of the drug was released over 8-days. Pilocarpine-loaded (2% w/v) hydrogels were evaluated in a rabbit model and compared to a similar dose of drug in aqueous solution. The hydrogels were retained in the eye for the entire period of the study with no observed irritation. Pilocarpine-loaded hydrogels sustained pupillary constriction for 24 h after administration as compared to 3 h for the solution, an 8-fold increase in duration of action. A strong correlation between pilocarpine release and pupillary response was observed. In conclusion, the current studies demonstrate that in situ forming PEG hydrogels possess the viscoelastic, retention, and sustained delivery properties required for an efficient ocular drug delivery system. PMID:19341773

Dual-body magnetic helical robot for drilling and cargo delivery in human blood vessels

NASA Astrophysics Data System (ADS)

Lee, Wonseo; Jeon, Seungmun; Nam, Jaekwang; Jang, Gunhee

2015-05-01

We propose a novel dual-body magnetic helical robot (DMHR) manipulated by a magnetic navigation system. The proposed DMHR can generate helical motions to navigate in human blood vessels and to drill blood clots by an external rotating magnetic field. It can also generate release motions which are relative rotational motions between dual-bodies to release the carrying cargos to a target region by controlling the magnitude of an external magnetic field. Constraint equations were derived to selectively manipulate helical and release motions by controlling external magnetic fields. The DMHR was prototyped and various experiments were conducted to demonstrate its motions and verify its manipulation methods.

Bile Acid-Based Drug Delivery Systems for Enhanced Doxorubicin Encapsulation: Comparing Hydrophobic and Ionic Interactions in Drug Loading and Release.

PubMed

Cunningham, Alexander J; Robinson, Mattieu; Banquy, Xavier; Leblond, Jeanne; Zhu, X X

2018-03-05

Doxorubicin (Dox) is a drug of choice in the design of drug delivery systems directed toward breast cancers, but is often limited by loading and control over its release from polymer micelles. Bile acid-based block copolymers present certain advantages over traditional polymer-based systems for drug delivery purposes, since they can enable a higher drug loading via the formation of a reservoir through their aggregation process. In this study, hydrophobic and electrostatic interactions are compared for their influence on Dox loading inside cholic acid based block copolymers. Poly(allyl glycidyl ether) (PAGE) and poly(ethylene glycol) (PEG) were grafted from the cholic acid (CA) core yielding a star-shaped block copolymer with 4 arms (CA-(PAGE- b-PEG) 4 ) and then loaded with Dox via a nanoprecipitation technique. A high Dox loading of 14 wt % was achieved via electrostatic as opposed to hydrophobic interactions with or without oleic acid as a cosurfactant. The electrostatic interactions confer a pH responsiveness to the system. 50% of the loaded Dox was released at pH 5 in comparison to 12% at pH 7.4. The nanoparticles with Dox loaded via hydrophobic interactions did not show such a pH responsiveness. The systems with Dox loaded via electrostatic interactions showed the lowest IC 50 and highest cellular internalization, indicating the pre-eminence of this interaction in Dox loading. The blank formulations are biocompatible and did not show cytotoxicity up to 0.17 mg/mL. The new functionalized star block copolymers based on cholic acid show great potential as drug delivery carriers.