Engineering Biomimetic Platesomes for pH‐Responsive Drug Delivery and Enhanced Antitumor Activity

Biomimetic camouflage, i.e., using natural cell membranes for drug delivery, has demonstrated advantages over synthetic materials in both pharmacokinetics and biocompatibility, and so represents a promising solution for the development of safe nanomedicine. However, only limited efforts have been dedicated to engineering such camouflage to endow it with optimized or additional properties, in particular properties critical to a “smart” drug delivery system, such as stimuli‐responsive drug release. A pH‐responsive biomimetic “platesome” for specific drug delivery to tumors and tumor‐triggered drug release is described. This platesome nanovehicle is constructed by merging platelet membranes with functionalized synthetic liposomes and exhibits enhanced tumor affinity, due to its platelet membrane–based camouflage, and selectively releases its cargo in response to the acidic microenvironment of lysosomal compartments. In mouse cancer models, it shows significantly better antitumor efficacy than nanoformulations based on a platesome without pH responsiveness or those based on traditional pH‐sensitive liposomes. A convenient way to incorporate stimuli‐responsive features into biomimetic nanoparticles is described, demonstrating the potential of engineered cell membranes as biomimetic camouflages for a new generation of biocompatible and efficient nanocarriers.     

Mechanistic analysis of drug release from theophylline pellets coated by films containing pectin, chitosan and Eudragit RS

The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit® RS. Pellets (710-840 μm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit® L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.     

Calcium alginate nanocarriers as possible vehicles for oral delivery of insulin

In the present investigation, alginate nanoparticles have been prepared and characterised by various techniques such as FTIR, SEM, particle size analysis and surface charge measurements. It was found from both the SEM and particle size analysis that average size of the particle was about 40?nm. The particles were loaded with insulin and the release kinetics of insulin was studied in PBS medium. The results indicated that when percent loading increases from 11.7 to 38.9, the released amount of insulin increased from 18% to 60% of the loaded drug. The effect of composition of nanoparticles, pH and temperature of the release medium was examined on the amount of released insulin. It was observed when that amount of alginate in the feed mixture was varied from 1.0 to 2.0?g, the prepared nanoparticles showed a decreasing tendency to release insulin. Similarly, upon increasing the concentration of crosslinker in the range 0.5–1.1?mM, the release of insulin constantly decreased. The chemical stability of the loaded drug was assessed especially under highly acidic conditions of artificial gastric juice and it was noticed that even in harsh acidic environment (pH 1.2) the insulin remains chemically stable. The invitro blood compatibility of nanoparticles was also investigated and it was found that for a definite composition of nanoparticles, protein adsorption and percent haemolysis were minimum which suggested for an optimum blood compatibility of alginate nanoparticles of definite composition. Thus, it can be conclusively stated that the calcium alginate nanoparticles prepared by emulsion crosslinking method show potential to be developed as oral formulation for insulin delivery.     

Mechanistic Analysis of Drug Release from Theophylline Pellets Coated by Films Containing Pectin,Chitosan and Eudragit® RS

The objective of this study was to obtain detailed information on the mechanism of drug release from mixed-film of pectin-chitosan/Eudragit® RS. Pellets (710–840 μm in diameter) containing 60% theophylline and 40% microcrystalline cellulose were prepared by extrusion-spheronization method. Eudragit® L100-55 enteric coating capsules included film-coated pellets of theophylline in theoretical coating weight gains of 10, 15, and 20%, with pectin-chitosan complex contents of 5, 10, 15, and 20% for each level of weight gain were prepared and subjected to in vitro drug release. Drug release from this system showed a bimodal release profile characteristic with the drug release enhancement, being triggered (burst release) in the colonic medium. The reason for burst drug release may be due to the enzymatic degradation of pectin via pectinolytic enzymes in the simulated colonic medium. The mechanism of drug release from each formulation was evaluated in the terms of zero-order, first-order, Higuchi and Korsmeyer-Peppas models. It was observed that none of the enteric coating capsules showed any drug release in the simulated gastric medium (phase I). The analysis of release profiles showed that zero-order kinetics was found as the better fitting model for all formulations in the simulated small intestine (phase II) and it could be due to the pectin-chitosan swelling and subsequent formation of aqueous channels. In the colonic medium (phase III), due to degradation of pectin and its leaching from the mixed-film, there was a modification in drug release kinetics from swelling-controlled at phase II to anomalous at phase III. It also was found that both zero-order and Higuchi models contributed in colonic drug release from most of the formulations.     

Investigating a New Approach to Film Casting for Enhanced Drug Content Uniformity in Polymeric Films

Films prepared by conventional casting onto trays such as teflon-coated perspex trays (TCPTs) suffer from poor drug content uniformity. The aim of this study was to prepare a silicone-molded tray (SMT) with individual wells for film casting and to evaluate it in terms of enhancing drug content uniformity. Films were prepared by solvent evaporation or emulsification and cast onto TCPT and SMT. Preparation of films by the SMT method was superior in terms of meeting drug content uniformity requirements. As compared with the TCPT method, the SMT casting method also reduced the variability in mucoadhesivity, drug release, and film thickness. Reproducibility of the SMT method was demonstrated in terms of drug content, mucoadhesion, and drug release.     

The role of fillers and sodium metabisulfite on drug release from aged polyox tablets

Polyethylene oxides (PEOs) are extensively used to control the release rate of drugs from matrices. Unfortunately, polyox polymers are prone to oxidation under high temperature and relative humidity. The aim of this study was to investigate the effect of sodium metabisulfite as an antioxidant to overcome the drug release changes from polyox matrices (PEO 301 and 303) when stored at 40?°C. The effect of different types of fillers (lactose, mannitol and dicalcium phosphate dihydrate) on stability of diltiazem HCl release profiles was also investigated. Generally, the presence of sodium metabisulfite stabilized the release of drug from PEO matrices stored at 40?°C for 8 weeks. Whilst the absence of metabisulfite caused an increase in drug release from polyox matrices when stored at 40?°C. The results indicate that all three concentrations (0.25, 0.5 and 1% w/w) of sodium metabisulfite were able to overcome structural changes of polyox samples hence stabilizing the drug release. The results also showed that the incorporation of fillers in polyox matrices reduced the sensitivity of drug release when stored at elevated temperature. This indicates that when these excipients were used there was no need to incorporate additional antioxidant. DSC results showed that there was no difference in the melting points of fresh polyox samples and aged polyox samples containing sodium metabisulfite, whereas the melting point of aged polyox samples without sodium metabisulfite were lower than fresh polyox samples. This indicates that the presence of metabisulfite is essential to stabilize polyox samples.     

环糊精水凝胶的研究进展

综述了环糊精水凝胶的合成方法及环糊精单元的引入对水凝胶的包合性能、响应速率及不同药物释放性能的影响。结果表明,将具有包合作用的环糊精单元引入到水凝胶基质中,不仅改善了水凝胶的载药能力,而且改变了药物-聚合物之间的作用力及药物在聚合物基体中的状态,从而改变了药物的控制释放性能。     

聚乙二醇1000维生素E琥珀酸酯在高分子药物释放体系的应用进展

许多由高分子药物释放体系给药的药物,由于载药量不够、或者由于癌细胞的多药耐药性导致药物外排等种种原因,不能以有效的药物浓度作用于目的器官,从而导致治疗效果不理想。人们已经尝试以不同方式添加聚乙二醇1000维生素E琥珀酸酯(D-α-tocopheryl polyethylene glycol 1000succinate,TPGS)来改良高分子药物释放体系中的各种不足。总结了近几年来各种添加TPGS的高分子药物释放体系的研究进展,对所有TPGS的添加情况进行了分类,从包埋率和载药量的测量,细胞检测以及动物实验等进行概述。以不同的方式添加TPGS均可大大提高高分子药物释放体系的载药量和包埋率,抑制多药耐药性,甚至使抗癌药物达到口服的效果,可从多方面改善高分子释放体系给药的性能。     

壳聚糖水凝胶的制备及其在药物释放中的应用

水凝胶作为性能良好的载体,在药物的控释、组织工程等领域有着广泛的应用。壳聚糖是一类天然的带正电荷的碱性多糖,由其形成的水凝胶具有较好的生物相容性、生物降解性、抗菌和低细胞毒性,因此,壳聚糖水凝胶有着良好的生物应用前景。本文综述了壳聚糖水凝胶的制备方法(包括物理交联法和化学交联法),在物理交联法部分着重介绍了离子化合物及聚电解质分子与壳聚糖通过离子交联形成水凝胶,以及利用分子链间的疏水作用形成壳聚糖水凝胶的方法;而在化学交联法部分介绍了合成壳聚糖水凝胶的化学手段,包括交联剂、光照辐射和酶的使用。继而概述了壳聚糖水凝胶在药物缓释应用方面的研究进展,包括温度、pH值和电场响应的药物控释体系。最后展望了壳聚糖水凝胶未来的发展前景。     

Microfluidic Synthesis of pH‐Sensitive Multicompartmental Microparticles for Multimodulated Drug Release

Stimuli‐responsive carriers releasing multiple drugs have been researched for synergistic combinatorial cancer treatment with reduced side‐effects. However, previously used drug carriers have limitations in encapsulating multiple drug components in a single carrier and releasing each drug independently. In this work, pH‐sensitive, multimodulated, anisotropic drug carrier particles are synthesized using an acid‐cleavable polymer and stop‐flow lithography. The particles exhibit a faster drug release rate at the acidic pH of tumors than at physiological pH, demonstrating their potential for tumor‐selective drug release. The drug release rate of the particles can be adjusted by controlling the monomer composition. To accomplish multimodulated drug release, multicompartmental particles are synthesized. The drug release profile of each compartment is programmed by tailoring the monomer composition. These pH‐sensitive, multicompartmental particles are promising drug carriers enabling tumor‐selective and multimodulated release of multiple drugs for synergistic combination cancer therapy.     

生物降解高分子材料--聚酸酐的研究进展

聚酸酐由于其具有良好的表面溶蚀性能，作为药物控释体材料得到广泛的应用。文中综述了生物降解医用高分子材料——聚酸酐的分类、制备方法、研究进展及应用等．并提出了今后的发展方向。     

静电喷射法制备聚合物微球和微粒

介绍了静电喷射制备微球、微粒的原理、装置及所用聚合物。总结了静电喷射制备微球、微粒的影响因素及所制备微球、微粒的用途。静电喷射制备微球、微粒的影响因素主要包括电压、聚合物溶液流量、聚合物溶液浓度及电导率。已通过静电喷射制备微球、微粒的聚合物有聚己内酯、聚乳酸、聚丙交酯乙交酯、聚膦腈、聚乙烯基吡咯烷酮、壳聚糖等,主要用于药物、蛋白质、酶等生物活性分子的包埋研究。     

基于角膜接触镜的眼药缓释水凝胶材料研究进展

常用的眼用药物制剂为滴眼剂或者眼膏剂,具有使用不方便、药物利用效率低、易引起副作用、需频繁施用、影响视力等缺点.采用角膜接触镜缓释的眼用药物制剂可克服这些缺点,因而受到研究人员的重视.综述了基于角膜接触镜、适于缓释眼用药物的poly-HEMA(聚甲基丙烯酸羟乙酯)水凝胶、硅氧烷水凝胶、分子印迹聚合物水凝胶以及含离子配体水凝胶的研究进展,并展望了适于角膜接触镜缓释的眼用制剂的水凝胶材料的发展前景.     

Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability

The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.     

分子印迹技术在药物缓释领域的研究进展

分子印迹技术是制备对特定分子结构具特异性识别功能的聚合物的一项重要技术,其在药物缓释领域的应用越来越引起研究者们的重视。在介绍了分子印迹技术的概念及原理的基础上,提出了应用于药物传输领域的分子印迹聚合物所应当具备的特性,综述了近年来分子印迹技术在药物传输领域的研究进展。并指出:为提高聚合物作为药物载体的生物顺应性,在水相中对聚合物的合成、可控自由基聚合制备规格统一的聚合物及将分子印迹聚合物应用于智能医用材料领域将成为日后研究的主流。     

Subcellular tracking of drug release from carbon nanotube vehicles in living cells

The direct observation of drug release from carbon nanotube vehicles in living cells is realized through a unique two-dye labeling approach. Single-walled carbon nanotubes (SWNTs) are firstly marked with fluorescein isothiocyanate (FITC) to track their location and movement inside the cell. Then a fluorescent anticancer drug doxorubicin (DOX) is attached by means of π-stacking onto SWNTs. Delivered by SWNTs into cells, DOX will detach from the vehicle in an acidic environment due to the pH-dependent π-π stacking interaction between DOX and SWNTs. From observation of the two different kinds of fluorescence (green and red) that respectively represent the carrier SWNTs and drug DOX, the process of drug release inside the living cell can be monitored under a confocal microscope. Results show that the drug DOX detaches from SWNTs inside the lysosomes to yield free molecules and escape into the cytoplasm and finally into the nucleus, while the vehicle SWNTs are trapped inside the lysosomes, without entering the nucleus. The current observations confirm previously proposed mechanisms for drug/DOX release inside cells. The experimental establishment of drug-release mechanisms in living cells here might provide important insights for future design of new drug-delivery and release systems.