Synthesis of theophylline-polyrotaxane conjugates and their drug release via supramolecular dissociation.

Theophylline-polyrotaxane conjugates were synthesized by coupling theophylline with alpha-cyclodextrins (alpha-CDs) in the polyrotaxane. The polyrotaxane is a molecular assembly in which many alpha-CDs are threaded onto a poly(ethylene glycol) (PEG) chain capped with L-phenylalanine (L-Phe). Theophylline-7-acetic acid was activated by coupling with 4-nitrophenol, and then ethylenediamine was allowed to react with the active ester in order to obtain N-aminoethyl-theophylline-7-acetoamide. This derivative was coupled with a 4-nitrophenyl chloroformate-activated polyrotaxane to obtain the theophylline-polyrotaxane conjugates. The conjugates formed a specific association under physiological conditions, depending upon interactions between the theophylline molecules and/or the terminal l-Phe moiety in the conjugates. In vitro degradation of the conjugates revealed that theophylline-immobilized alpha-CDs were completely released by hydrolysis of the terminal peptide linkage in the polyrotaxane. This result indicates that the association of the conjugates does not induce the steric hindrance but rather enhances the accessibility of enzymes to the terminal peptide linkages. It is suggested that our designed drug-polyrotaxane conjugates can release the drugs via the dissociation of the supramolecular structure without steric hindrance of enzymatic accessibility to the terminal peptide linkages.     

Electrolyte and pH-sensitive amphiphilic alginate: synthesis,self-assembly and controlled release of acetamiprid

In this study, a pH-responsive amphiphilic alginate (Ugi-Alg) was synthesized via Ugi reaction without using a catalyst. The structure of Ugi-Alg was confirmed by FT-IR and ¹H NMR spectroscopy. Amphiphilic alginate can form micelles in an aqueous medium due to it''s amphiphilic nature.. The impacts of Na⁺ concentration and pH on the micelle size were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The dynamic light scattering observations showed that micelle size increases with the decrease in Na⁺ concentration in aqueous solution. However, the micelle size decreases first and then increases as the pH value decreases from 5.3 to 2.0. Transmission electron microscopy confirmed that the mean size of micelles is 30–200 nm. In addition, a model hydrophobic pesticide (acetamiprid) was loaded in the micelles. The encapsulation efficiency and release behavior of micelles were studied, which could be controlled by Na⁺ concentration and pH. The results indicated that encapsulation efficiency of acetamiprid increases from 55% to 96% due to the increase in Na⁺ concentration from 0.01 M to 0.3 M. Moreover, with the decrease in pH from 5.3 to 2.0, encapsulation efficiency increases from 55% to 80%. Furthermore, the data of acetamiprid release kinetics could be well-fitted by the Weibull model.

Schematic of Ugi-Alg aggregation in aqueous solution of different NaCl concentrations and pH values.     

Microspheres for controlled release drug delivery

Controlled release drug delivery employs drug-encapsulating devices from which therapeutic agents may be released at controlled rates for long periods of time, ranging from days to months. Such systems offer numerous advantages over traditional methods of drug delivery, including tailoring of drug release rates, protection of fragile drugs and increased patient comfort and compliance. Polymeric microspheres are ideal vehicles for many controlled delivery applications due to their ability to encapsulate a variety of drugs, biocompatibility, high bioavailability and sustained drug release characteristics. Research discussed in this review is focused on improving large-scale manufacturing, maintaining drug stability and enhancing control of drug release rates. This paper describes methods of microparticle fabrication and the major factors controlling the release rates of encapsulated drugs. Furthermore, recent advances in the use of polymer microsphere-based systems for delivery of single-shot vaccines, plasmid DNA and therapeutic proteins are discussed, as well as some future directions of microsphere research.     

药物控释载体材料的性质

学术背景:将药物或其他的活性物质与适当的载体按一定的形式制成的药物控释制剂已成为药学领域的重要发展方向,然而不同性质的药物载体材料具有不同的药物释放行为,为了获得令人满意的释药速率,新型药物载体材料的研究成为近年来的研究重点.目的:介绍几种用作药物载体的材料,分析材料的性质及其在药物控释中的应用.检索策略:由该论文作者应用计算机检索中国期刊全文数据库1998-01/2007-06的相关文献,检索词:"高分子水凝胶,聚乳酸,壳聚糖,丝素蛋白,药物控释,药物载体",限定文章语言种类为中文.纳入标准:①不同类型药物载体材料的制备及性能;②不同类型药物载体材料的药物控释性研究.排除标准:较陈旧的文献.文献评价:共检索到86篇相关文章, 28篇符合标准,其中10篇为综述,其余为临床或基础实验研究.资料综合:①目前用作药物载体的材料主要包括高分子凝胶、聚乳酸(PLA)/乳酸-羟基乙酸(PLGA)、壳聚糖及其衍生物、丝素蛋白等.②智能高分子水凝胶对温度、酸度、压力、光等引起的刺激,能及时地作出溶胀和收缩应答的智能效应,这种特殊的环境敏感性使它被广泛地应用于药物缓释体系.③聚乳酸和聚乳酸-羟基乙酸是一种生物可降解高分子材料,具有生物相容性、生物可降解性、降解产物无毒等优点,用作药物控释载体材料时,可通过调节聚乳酸的降解速率改变释放速率,提高药效.④壳聚糖具有很好的吸附性、成膜性和通透性,较低相对分子质量的水溶性壳聚糖更易在体内降解,不易积聚, 以壳聚糖为载体材料制备纳米粒、微球等给药系统是近年来的研究热点.⑤天然高分子材料丝素蛋白无毒、无刺激,具有良好的物理、化学、生物学性能,与人体有较好的组织相容性,在负载与释放药物时, 具有一定程度的pH 值响应性和酶分解性.一般通过化学修饰、添加其他化合物等方法, 提高丝素蛋白的性质,增加丝素蛋白质对药物的吸附释放功能.结论:不同类型药物载体材料均具有很好的生物相容性、生物可降解性、理化及生物稳定性和极低的毒性,且有较高的载药性,但在实际应用过程中还需要对材料的性能进行合成和改进,使其具有特定性能、结构,满足不同药物制剂释放的要求.     

药物控释载体材料的性质

学术背景：将药物或其他的活性物质与适当的载体按一定的形式制成的药物控释制剂己成为药学领域的重要发展方向，然而不同性质的药物载体材料具有不同的药物释放行为，为了获得令人满意的释药速率，新型药物载体材料的研究成为近年来的研究重点。目的：介绍几种用作药物载体的材料，分析材料的性质及其在药物控释中的应用。检索策略：由该论文作者应用计算机检索中国期刊全文数据库1998—01／2007—06的相关文献，检索词：“高分子水凝胶，聚乳酸，壳聚糖，丝素蛋白，药物控释，药物载体”，限定文章语言种类为中文。纳入标准：①不同类型药物载体材料的制备及性能：②不同类型药物载体材料的药物控释性研究。排除标准：较陈旧的文献。文献评价：共检索到86篇相关文章，28篇符合标准，其中10篇为综述，其余为临床或基础实验研究。资料综合：①目前用作药物载体的材料主要包括高分子凝胶、聚乳酸（PLA），乳酸-羟基乙酸（PLGA）、壳聚糖及其衍生物、丝素蛋白等。②智能高分子水凝胶对温度、酸度、压力、光等引起的刺激，能及时地作出溶胀和收缩应答的智能效应，这种特殊的环境敏感性使它被广泛地应用于药物缓释体系。③聚乳酸和聚乳酸-羟基乙酸是一种生物可降解高分子材料，具有生物相容性、生物可降解性、降解产物无毒等优点，用作药物控释载体材料时，可通过调节聚乳酸的降解速率改变释放速率，提高药效。④壳聚糖具有很好的吸附性、成膜性和通透性，较低相对分子质量的水溶性壳聚糖更易在体内降解，不易积聚，以壳聚糖为载体材料制备纳米粒、微球等给药系统是近年来的研究热点。⑤天然高分子材料丝素蛋白无毒、无刺激，具有良好的物理、化学、生物学性能，与人体有较好的组织相?     

pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery.

The aim of this study was to develop a pH-sensitive chitosan/polyvinyl pyrrolidone (PVP) based controlled drug release system for antibiotic delivery. The hydrogels were synthesised by crosslinking chitosan and PVP blend with glutaraldehyde to form a semi-interpenetrating polymer network (semi-IPN). The semi-IPN formation was confirmed by Fourier transform infrared spectroscopic (FTIR) analysis. Semi-IPNs, viz, air-dried and freeze-dried, were compared for their surface morphology, wettability, swelling properties and pH-dependent swelling. Air- and freeze-dried membranes were also incorporated with amoxicillin and antibiotic release was studied. Porous freeze-dried hydrogels (pore diameter, 39.20+/-2.66 microm) exhibited superior pH-dependent swelling properties over non-porous air-dried hydrogels. A high octane contact angle (144.20+/-0.580) of hydrogel was indicative of its hydrophilic nature. Increased swelling of hydrogels, under acidic conditions, was due to the protonation of a primary amino group on chitosan, as confirmed by FTIR analysis. Freeze-dried membranes released around 73% of the amoxicillin (33% by air-dried) in 3 h at pH 1.0 and, thus, had superior drug-release properties to air-dried hydrogels. Freeze-dried membranes could serve as potent candidates for antibiotic delivery in an acidic environment.     

ATRP-based synthesis of a pH-sensitive amphiphilic block polymer and its self-assembled micelles with hollow mesoporous silica as DOX carriers for controlled drug release

The atom transfer radical polymerization (ATRP)-based synthesis of a pH-sensitive fluorescent polymer (PSDMA-b-POEGMA) was successfully prepared using 3,6-dibromo-isobutyramide acridine (DIA), an initiator with a fluorescent chromophore, to initiate a lipophilic monomer 2-styryl-1,3-dioxan-5-yl methacrylate (SDMA) and a hydrophilic monomer oligo(ethylene glycol) methyl ether (OEGMA), which contained a cinnamic aldehyde acetal structure. With the addition of hollow mesoporous silicon (HMS@C18), the pH-sensitive core–shell nanoparticles (HMS@C18@PSDMA-b-POEGMA) were developed via a self-assembly process as carriers for the anticancer drug doxorubicin (DOX) for drug loading and controlled release. The nanocomposites showed a higher drug loading capacity which was much higher than that observed using common micelles. At the same time, the polymer coated on the surface of the nanoparticles contains the fluorescent segment of an initiator, which can be used for fluorescence contrast of the cells. The nanocomposite carrier selectively inhibits human melanoma cell A375 relative to human normal fibroblasts GM. The in vitro results suggested that a smart pH sensitive nanoparticles drug delivery system was successfully prepared for potential applications in cancer diagnosis and therapy.

A pH-sensitive core–shell nanoparticle (HMS@C18@PSDMA-b-POEGMA) was developed via a self-assembly process as the carrier of anticancer drug doxorubicin (DOX) for drug loading and controlled release.     

Spermine modified polymeric micelles with pH-sensitive drug release for targeted and enhanced antitumor therapy

Tumor targeting delivery of chemotherapeutic drugs by nanocarriers has been demonstrated to be a promising strategy for cancer therapy with improved therapeutic efficacy. In this work, we reported a novel type of active targeting micelle with pH-responsive drug release by using biodegradable poly(lactide)-poly(2-ethyl-2-oxazoline) di-block copolymers functionalized with spermine (SPM). SPM has been considered as a tumor binding ligand through its specific interaction with the polyamine transport system (PTS), a transmembrane protein overexpressed on various types of cancer cell, while its application in nano-drug delivery systems has rarely been explored. The micelles with spherical shape (∼110 nm) could load hydrophobic paclitaxel (PTX) with high capacity, and release the payload much faster at acidic pH (4.5–6.5) than at pH 7.4. This pH-responsive property assisted the rapid escape of drug from the endo/lysosome after internalization as demonstrated by confocal laser scanning microscopy images using coumarin-6 (Cou-6) as a fluorescent probe. With surface SPM modification, the micelles displayed much higher cellular uptake than SPM lacking micelles in various types of cancer cells, demonstrating tumor targeting ability. The uptake mechanism of SPM modified micelles was explored by flow cytometry, which suggested an energy-consuming sag vesicle-mediated endocytosis pathway. As expected, the micelles displayed significantly enhanced anti-cancer activity. This work demonstrates that SPM modified pH-sensitive micelles may be potential drug delivery vehicles for targeting and effective cancer therapy.

Tumor targeting delivery of SPM functionalized micelles via PTS binding and their endocytosis and pH-triggered endo/lysosome drug release for anti-cancer therapy.     

小檗碱磁性药物微球的制备及控制释放

背景:国内外对磁性药物微球的研究进展十分迅速,实践和理论研究均有不少报道.过去的工作多以葡聚糖、壳聚糖、聚酯等为包裹层,明胶包裹磁性材料和药物的相关报道相对较少,而用明胶包裹的小檗碱药物微球尚未见报道.目的:制备小檗碱明胶磁性复合药物微球,用动态透析法,光电显微镜等考察药物的释放、负载和交联行为.设计、时间及地点:微球的制备及性质表征.实验于2004-02/2006-05在贵州大学和贵州益康制药有限公司完成.材料:主要材料为明胶、小檗碱、戊二醛、液体石蜡和铁盐.方法:利用明胶的生物相容性及经戊二醛处理可使其固化的特性,以Fe_3O_4作为磁性内核,液体石蜡为有机分散介质,通过反相悬液冷冻凝聚法制备出磁性小檗碱明胶核壳微球.主要观察指标:药物微球的结构和外观形貌,以及药物微球载药率、包裹率及体外释放情况.结果:磁性药物微球的颗粒直径在20 μm以下,通过扫描电镜可以看出,Fe_3O_4粒子和小檗碱已经被明胶复合成堆积状的球体,达到微米级.将药物包裹前后的紫外吸收和红外相结合分析说明所制备的明胶磁性混合药物微球能保持原药的结构和药学性质.小檗碱微球载药率为7.2%,Fe_3O_4的含量为20.8%,微球包裹率为62.6%.微球的缓释性能良好,7 h内释放的药物占总含药量的83.5%.结论:用反相悬液冷冻凝聚法制备的小檗碱磁性明胶药物微球,制备方法简便,微球的粒径小,形状规则,缓释效果良好.     

Nano-encapsulation of furosemide microcrystals for controlled drug release.

Furosemide microcrystals were encapsulated with polyions and gelatin to control the release of the drug in aqueous solutions. Charged linear polyions and gelatin were alternatively deposited on 5-microm drug microcrystals through layer-by-layer (LbL) assembly. Sequential layers of poly(dimethyldiallyl ammonium chloride) (PDDA) and poly(styrenesulfonate) (PSS) were followed by adsorption of two to six gelatin/PSS bilayers with corresponding capsule wall thicknesses ranging from 45 to 115 nm. The release of furosemide from the coated microparticles was measured in aqueous solutions of pH 1.4 and 7.4. At both pH values, the release rate of furosemide from the encapsulated particles was reduced by 50-300 times (for capsules coated with two to six bilayers) compared to uncoated furosemide. The results provide a method of achieving prolonged drug release through self-assembly of polymeric shells on drug microcrystals.     

Gradual hydrophobization of silica aerogel for controlled drug release

We report on the successful fine-tuning of silica aerogel hydrophobicity, through a gas-phase surface modification process. Aerogel hydrophobicity is a widely discussed matter, as it contributes to the aerogel''s preservation and determines its functionality. Still, a general procedure for tuning the hydrophobicity, without affecting other aerogel properties was missing. In the developed procedure, silica aerogel was modified with trimethylchlorosilane vapor for varying durations, resulting in gradual hydrophobicity, determined by solid-state NMR and contact angle measurements. The generality of this post-synthesis treatment allows its application on a variety of aerogel materials, while having minimum effect on their porosity and transparency. We demonstrate the applicability of the gradual hydrophobization by tuning drug release rates from the silica aerogel. Two chlorhexidine salts – widely employed as antiseptic agents – were used as model drugs, one representing a soluble drug, and the other an insoluble drug; they were entrapped in silica aerogel, following hydrophobization to varying degrees. The drug release patterns showed that depending on the degree, hydrophobization can increase or decrease release kinetics, compared to the unmodified aerogel. This arises from the effect of the hydrophobic degree on pore structure, diffusional rates and wetting of the aerogel carrier. We suggest the use of the gradual hydrophobization process for other drug-aerogel systems, as well as for other aerogel applications, such as transparent insulation panels, contaminate sorbents or catalysis supports.

A gradual hydrophobization process of silica aerogel is presented, with minimal impact on porosity and transparency. Applicability is demonstrated in gradual tailoring the release rate of soluble and insoluble variants of a model drug, chlorhexidine.     

药物控释载体材料的研究与应用

背景:作为控制释放体系的药物载体材料大多是高分子材料,但部分纳米无机材料也正逐步应用到药物控释材料体系中并取得了很好的研究成果.因此,药物控释用载体材料的设计与研究应用越来越受到重视.目的:对国内外药物控释载体材料的应用及最新研究进展作一综述.方法:应用计算机检索CNKI和Elsevier SD 数据库中1999-01/2011-01 关于药物控缓释材料的文章,在标题和摘要中以"高分子,介孔材料,无机硅,磷酸盐,控释"或"polymer,mesoporous materials,Inorganic s ilicon,calcium phosphate,controlled release"为检索词进行检索.选择文章内容与药物控缓释有关者,同一领域文献则选择近期发表或发表在权威杂志文章.纳入25 篇文献进行综述.结果与结论:药物控缓释载体材料以用药量小、作用时间长、靶向作用好等特点被广泛关注,但是仍存在载药后药物失活,丧失生物活性等缺陷,目前随着复合药物载体材料和经皮给药装置研究的发展,控缓释材料在临床治疗中的应用必将更加广泛.     

药物控释载体材料的研究与应用

背景：作为控制释放体系的药物载体材料大多是高分子材料,但部分纳米无机材料也正逐步应用到药物控释材料体系中并取得了很好的研究成果。因此,药物控释用载体材料的设计与研究应用越来越受到重视。目的：对国内外药物控释载体材料的应用及最新研究进展作一综述。方法：应用计算机检索CNKI和Elsevier SD数据库中1999-01/2011-01关于药物控缓释材料的文章,在标题和摘要中以＂高分子,介孔材料,无机硅,磷酸盐,控释＂或＂polymer,mesoporous materials,Inorganic silicon,calcium phosphate,controlled release＂为检索词进行检索。选择文章内容与药物控缓释有关者,同一领域文献则选择近期发表或发表在权威杂志文章。纳入25篇文献进行综述。结果与结论：药物控缓释载体材料以用药量小、作用时间长、靶向作用好等特点被广泛关注,但是仍存在载药后药物失活,丧失生物活性等缺陷,目前随着复合药物载体材料和经皮给药装置研究的发展,控缓释材料在临床治疗中的应用必将更加广泛。     

Dual fluorescent HPMA copolymers for passive tumor targeting with pH-sensitive drug release II: Impact of release rate on biodistribution

In recent years, polymer drug carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with pH-triggered drug release have shown enhanced uptake in solid tumors and excellent antitumor activity. Here, the impact of the structure of the acid-labile spacer between the drug and the polymer carrier on the biodistribution of both the drug and the carrier was studied using in vivo noninvasive multispectral optical imaging of dual fluorescently labeled HPMA copolymers. Five different spacers containing a pH-sensitive hydrazone bond were synthesized and used to combine a fluorescent model drug with a polymer backbone, conjugated with another non-releasable fluorescent dye. Two copolymers differing in polymer chain structure (linear and star-like) and molecular weight (30 and 200 kDa) were used to distinguish between carriers with molecular weights above and below the limit for renal filtration. The rate of model drug release from the conjugates was determined in vitro. The biodistributions of the six most promising conjugates were investigated in vivo in athymic nude mice inoculated with human colon carcinoma xenograft. The structure of the spacer in the vicinity of the hydrazone bond significantly influenced the release rate of the model drug. The slow release rate of a pyridyl group bearing spacer resulted in a greater amount of the model drug being transported to the tumor, which was independent of the carrier structure. The results of this study emphasize the importance of careful selection of the structure and appropriate spacer when designing polymer conjugates intended for passive tumor targeting.     

Albumin-based nanoparticles as potential controlled release drug delivery systems

Albumin, a versatile protein carrier for drug delivery, has been shown to be nontoxic, non-immunogenic, biocompatible and biodegradable. Therefore, it is ideal material to fabricate nanoparticles for drug delivery. Albumin nanoparticles have gained considerable attention owing to their high binding capacity of various drugs and being well tolerated without any serious side-effects. The current review embodies an in-depth discussion of albumin nanoparticles with respect to types, formulation aspects, major outcomes of in vitro and in vivo investigations as well as site-specific drug targeting using various ligands modifying the surface of albumin nanoparticles with special insights to the field of oncology. Specialized nanotechnological techniques like desolvation, emulsification, thermal gelation and recently nano-spray drying, nab-technology and self-assembly that have been investigated for fabrication of albumin nanoparticles, are also discussed. Nanocomplexes of albumin with other components in the area of drug delivery are also included in this review.     

Magnetic hydrogel nanocomposites for remote controlled pulsatile drug release

Hydrogel nanocomposites are novel macromolecular biomaterials that promise to impact various applications in medical and pharmaceutical fields. In this paper, magnetic nanocomposites of temperature responsive hydrogels were used to illustrate remote controlled (RC) drug delivery. A high frequency alternating magnetic field (AMF) was used to trigger the on-demand pulsatile drug release from the nanocomposites. Nanocomposites were synthesized by incorporation of superparamagnetic Fe₃O₄ particles in negative temperature sensitive poly (N-isopropylacrylamide) hydrogels. Pulses of AMF were applied to the nanocomposites and the kinetics of collapse and recovery were characterized. Application of AMF resulted in uniform heating within the nanocomposites leading to accelerated collapse and squeezing out large amounts of imbibed drug (release at a faster rate). Remote controlled pulsatile drug release was characterized for different drugs as well as for different ON–OFF durations of the AMF.     

Casein-based formulations as promising controlled release drug delivery systems

Casein, the major milk protein, forms an integral part of the daily diet in many parts of the world. Casein possesses a number of interesting properties that make it a good candidate for conventional and novel drug delivery systems. This article reviews approaches aimed to associate bioactive molecules to casein and analyze the evidence of their efficacy in modifying the release and/or improving the bioavailability of the associated molecules. The ability of casein to modify drug dissolution from compacts was reported. The high tensile strength of casein films, favors its use as an acceptable film-coating for tablets. Naturally occurring genipin and a natural tissue enzyme, transglutaminase, were used as crosslinkers to prepare novel casein-based hydrogels for the controlled release of bioactives. Casein floating beads were developed to increase the residence time of drugs in the stomach based on its emulsifying and bubble-forming properties. Casein-based microparticles entrapping bioactive molecules were prepared via emulsification-chemical crosslinking with glutaraldehyde, enzymatic crosslinking by transglutaminase, simple coacervation and electrostatic complexation. Casein nano-formulations were also prepared to deliver nutraceuticals and synthetic drugs via enzymatic crosslinking, graft copolymerization, heat-gelation and polyelectrolyte ionic complexation. It can be concluded that casein-based formulations are promising materials for controlled drug delivery.     

Uptake and release of budesonide from mucoadhesive, pH-sensitive copolymers and their application to nasal delivery.

Microparticles of novel, bioadhesive graft copolymers of polymethacrylic acid and polyethylene glycol (P(MAA-g-EG)) were prepared. The aims of this study were to investigate the uptake and release kinetics of budesonide from P(MAA-g-EG) in vitro as well as the pharmacokinetics following nasal administration of the polymer contained budesonide. The loading of budesonide into the pH-sensitive polymers was examined using various ethanol solutions. Ethanol was required for drug solubilization but hindered hydrogel swelling at pH 7.2. Maximum loading of the drug in the polymer was obtained using 25% ethanol solutions. The release of budesonide from the polymer swollen in 25% ethanol solutions obeyed classical Fickian release behavior after an initial rapid drug burst. For nasal administration of budesonide-containing P(MAA-g-EG) the plasma concentration of budesonide was kept constant following a peak concentration of the drug approximately 45 min after administration.