温度敏感型聚酯/聚乙二醇三嵌段生物可降解共聚物的降解性能及药物释放的影响因素研究进展

温度敏感型生物可降解水凝胶作为一种注射缓释给药系统的新型载体己受到越来越多的关注,聚酯(A嵌段)/聚乙二醇(B嵌段)三嵌段共聚物是目前最常用的温度敏感型聚合物,具有良好的生物相容性和生物降解性.本文综述了聚乙二醇嵌段含量、聚酯嵌段种类、共聚物凝胶水溶液浓度、处方中添加剂、药物与共聚物分子间的作用力、载药量及制剂形状、介质pH及温度等因素对聚酯/聚乙二醇三嵌段共聚物降解速率及药物释放速率的影响,为聚酯/聚乙二醇三嵌段共聚物水凝胶注射剂开发过程中共聚物降解速率和药物释放速率的调节提供有价值的思路与科学依据.     

嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1的pH和温度敏感性质及体外释药特性考察

目的 为嵌段共聚物磺胺甲嘧啶低聚物-聚-ε-己内酯-丙交酯-聚乙二醇-聚-ε-己内酯-丙交酯-磺胺甲嘧啶低聚物(sulfamerazine oligomers-poly(ε-caprolactone-co-DL-lactide-b-ethyleneglycol-b-ε-caprolactone-co-DL-lactide)-sulfamerazine oligomers,OSM1-PCLA-PEG-PCLA-OSM1)作为缓控释给药系统的载体提供依据.方法 采用激光粒度仪对不同pH和温度下嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1胶束粒径大小、分布进行考察;通过表面张力和相转变温度测定对其临界胶束浓度和溶液-凝胶相转变行为进行考察;以5 -氟尿嘧啶为模型药,通过透射电镜观察载药和空白共聚物胶束形态;采用物理混合法制备5 -氟尿嘧啶载药水凝胶;采用HPLC法测定载药水凝胶中药物释放速率.结果 嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1胶束溶液具有pH和温度双重敏感的性质,在一定pH和温度条件下可发生溶液-凝胶相转变;5 -氟尿嘧啶载药水凝胶体外释放可持续9 d,具有较好的缓释作用.结论 pH和温度双重敏感型嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1作为注射缓释给药系统载体材料具有良好的应用前景.     

嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1的pH和温度敏感性质及体外释药特性考察

目的 为嵌段共聚物磺胺甲嘧啶低聚物-聚-ε-己内酯-丙交酯-聚乙二醇-聚-ε-己内酯-丙交酯-磺胺甲嘧啶低聚物（sulfamerazine oligomers-poly(ε-caprolactone-co-DL-lactide-b-ethyleneglycol-b-ε-caprolactone-co-DL-lactide)-sulfamerazine oligomers,OSM₁-PCLA-PEG-PCLA-OSM1)作为缓控释给药系统的载体提供依据。方法 采用激光粒度仪对不同pH和温度下嵌段共聚物OSM₁-PCLA-PEG-PCLA-OSM₁胶束粒径大小、分布进行考察;通过表面张力和相转变温度测定对其临界胶束浓度和溶液-凝胶相转变行为进行考察;以5-氟尿嘧啶为模型药,通过透射电镜观察载药和空白共聚物胶束形态;采用物理混合法制备5-氟尿嘧啶载药水凝胶;采用HPLC法测定载药水凝胶中药物释放速率。结果 嵌段共聚物OSM₁-PCLA-PEG-PCLA-OSM₁胶束溶液具有pH和温度双重敏感的性质,在一定pH和温度条件下可发生溶液-凝胶相转变;5-氟尿嘧啶载药水凝胶体外释放可持续9 d,具有较好的缓释作用。结论 pH和温度双重敏感型嵌段共聚物OSM₁-PCLA-PEG-PCLA-OSM₁作为注射缓释给药系统载体材料具有良好的应用前景。     

温度/pH双敏感嵌段共聚物胶束的体外性质研究

本文采用透析法制备了新型温度/pH双敏感聚组氨酸-聚乳酸羟基乙酸-聚乙二醇-聚乳酸羟基乙酸-聚组氨酸(PHis-b-PLGA-b-PEG-b-PLGA-b-PHis)嵌段共聚物的空白胶束与阿霉素(DOX)载药胶束。采用荧光探针技术测定其临界胶束浓度(CMC);应用光透射法研究了聚合物胶束的温度和pH敏感性质;测定了阿霉素载药胶束的粒径、形态、包封率和载药量;并对阿霉素载药胶束的温度和pH响应释药行为进行了研究。结果表明,制备的嵌段共聚物的临界胶束浓度为7.5×10-3 g.L-1;随胶束溶液温度升高或pH降低,其透光率升高;载药胶束的包封率为(85.2±3.1)%,载药量为(10.4±4.5)%;载药胶束粒径为(91.1±15.8)nm,为类球形结构;与模拟生理条件下(37℃,pH 7.4)释药行为相比,升高温度(41℃)、降低pH(pH 7.0、pH 6.5、pH 5.0)和同时升温并降低pH(41℃,pH 5.0)后胶束释药行为明显加快,表明该胶束的释药行为具有温度和pH敏感性。研究结果可见,PHis-b-PLGA-b-PEG-b-PLGA-b-PHis共聚物胶束具有pH/温度双重响应性质,有望成为抗肿瘤...     

pH/温度双敏感水凝胶合成与释药性质研究

目的:合成一种同时具有pH和温度敏感性的水凝胶,并研究其载药、释药机理.方法:利用反相悬浮聚合法合成基于温度敏感材料N-异丙基丙烯酰胺、pH敏感材料甲基丙烯酸与N,N'-亚甲基双丙烯酰胺的共聚物,以双氯芬酸钠为模型药,测定在不同溶剂中水凝胶的载药能力;并测定了在不同pH环境(pH1,pH4和pH7)、不同温度下(25℃和37℃),双敏感水凝胶的释放性质.结果:实验表明药物在低温、低pH条件下保持收缩状态,药物基本不能从中释放;在高温、高pH状态下药物迅速释放,凝胶微球有较强的温度/pH敏感性质.结论:所得双敏感水凝胶具有显著的pH/温度敏感性质,可应用于药物口服给药.     

注射用蜂毒多肽温度敏感型缓释凝胶的制备及体外释放研究

目的制备注射用蜂毒多肽的温度敏感型缓释凝胶制剂并对其体外释药进行考察。方法以新型温度敏感聚丙交酯乙交酯聚乙二醇嵌段共聚物(PLGAPEGPLGA)为载体材料制备注射用蜂毒多肽缓释凝胶制剂,采用福林酚试剂法测定制剂在磷酸盐缓冲溶液中(pH7.4)的体外释放度,并对体外释放数据用KorsmeyerPeppas方程进行拟合。结果蜂毒多肽体外持续释放36d,其释药速率随聚合物的质量分数增加而降低,且聚合物分子结构中丙交酯比例增大对释药速率几乎没有影响。蜂毒多肽从凝胶中的释放初期以扩散为主,体外释放行为符合KorsmeyerPeppas方程,后期为凝胶溶蚀和药物扩散结合的作用机制。结论注射用蜂毒多肽的温度敏感型缓释凝胶制剂制备工艺简便,药物释放达到预期要求,同时说明温度敏感PLGAPEGPLGA嵌段共聚物作为注射用缓释给药系统的载体材料具有很好的应用前景。     

嵌段共聚物在给药系统中的应用

嵌段共聚物作为一类重要的高分子材料在药学中应用广泛。本文结合近几年的研究报道，对嵌段共聚物在给药系统中作为水凝胶、微球、纳米球等的应用以及部分嵌段共聚物的生物降解性和生物相容性作出简要综述。     

多西他赛pH敏感嵌段共聚物胶束的制备

本文在合成pH敏感两亲性嵌段共聚物聚(2-乙基-2-噁唑啉)-聚乳酸(PEOz-PDLLA)的基础上，采用薄膜分散法制备多西他赛pH敏感嵌段共聚物胶束，利用芘荧光探针技术测定胶束的临界胶束浓度(CMC)；通过高效液相色谱测定胶束的载药量及包封率；分别利用透射电镜、动态光散射法和zeta电位分析仪对胶束的形态、粒径和表面电位进行了表征；采用透析法考察了载药聚合物胶束的体外释放行为。结果表明，胶束的临界胶束浓度值为1.0×10^-3 g·L^-1；载药量可达15.0%，包封率为91.1%；胶束的粒度分布很窄，平均粒径为28.7nm；胶束粒子为圆球形且分散良好，其表面zeta电位值为(1.19±0.12)mV；在pH 7.4释放介质中，多西他赛胶束具有缓释作用；而在pH 5.0条件下，胶束释药明显加快，体现出PEOz-PDLLA胶束释药行为的pH敏感性。综合上述研究可见，PEOz-PDLLA嵌段共聚物胶束作为疏水性抗肿瘤药物的给药系统具有很好的应用前景。     

温敏性聚乙二醇-聚酯类嵌段共聚物研究进展及在生物医药中的应用

环境敏感水凝胶能随外界环境变化由溶液转变成凝胶,其中温度敏感性水凝胶在不同环境温度刺激下即产生相转变。聚乙二醇-聚酯类嵌段共聚物水溶液室温下是流动的液体,达生理温度时则形成凝胶。该类共聚物有温度敏感性、生物可降解性、生物相容性,可注射性,延长药物的释放时间,作为药物缓释载体被广泛应用于生物医药领域。文章综合国内外文献报道,介绍了聚乙二醇-聚酯类嵌段共聚物的合成、物理凝胶化机理,同时综述了其在生物医药领域中的应用,并对其发展趋势及应用前景作了简单的评述。     

可注射5-氟尿嘧啶缓释凝胶体外释放及其大鼠体内药动学研究

目的:制备可注射5-氟尿嘧啶(FU)缓释凝胶,并研究其体外释药及体内药动学特征。方法:以pH/温度双重敏感生物可降解嵌段共聚物OSM1-PCLA-PEG-PCLA-OSM1为载体材料,采用物理混合法制备5-FU缓释凝胶。考察载药量和共聚物浓度对其体外释药情况的影响。采用高效液相色谱法分别测定大鼠皮下注射5-FU水溶液(参比制剂)及缓释凝胶(受试制剂)后不同时间点的血药浓度,绘制药-时曲线,计算药动学参数。结果:5-FU在载药量为0.5%,共聚物浓度为15%、20%、25%的缓释凝胶中第9天时平均累积释放百分率为89.66%、87.59%、80.85%;载药量为0.2%、0.5%、1%,共聚物浓度为25%的缓释凝胶中第9天时平均累积释放百分率为75.30%、80.85%、86.90%;参比制剂与受试制剂在大鼠体内tmax分别为0.25、0.50h,Cmax分别为72.7、31.1μg·mL-1,AUC(0～)t分别为44.5、342.4mg·h·mL-1,MRT分别为0.57、27.2h。结论:5-FU缓释凝胶中5-FU体外释放呈现Higuchi动力学特征,表现为以扩散控制型为主的释药模式;释药初期,载药量对释药速率影响较大;释药后期,共聚物浓度对释药速率影响较大。皮下注射给药后,与水溶液相比,缓释凝胶可持续释药3d,具有良好的缓释作用。     

Cyclodextrin-based supramolecular architectures: Syntheses, structures, and applications for drug and gene delivery

The supramolecular structures formed between cyclodextrins (CDs) and polymers have inspired interesting developments of novel supramolecular biomaterials. This review will update the recent progress in studies on supramolecular structures based on CDs and block copolymers, followed by the design and synthesis of CD-based supramolecular hydrogels and biodegradable polyrotaxanes for potential controlled drug delivery, and CD-containing cationic polymers and cationic polyrotaxanes for gene delivery. Supramolecular hydrogels based on the self-assembly of the inclusion complexes between CDs with biodegradable block copolymers could be used as promising injectable drug delivery systems for sustained controlled release of macromolecular drugs. Biodegradable polyrotaxanes with drug-conjugated CDs threaded on a polymer chain with degradable end-caps could be interesting supramolecular prodrugs for controlled and targeting delivery of drugs. CD-containing cationic polymers as gene carriers showed reduced cytotoxicity than non-CD-containing polymer counterparts. More importantly, the polyplexes of CD-containing cationic polymers with DNA could be pegylated through a supramolecular process using inclusion complexation between the CD moieties and a modified PEO. Finally, new cationic polyrotaxanes composed of multiple oligoethylenimine-grafted CDs threaded and end-capped on a block copolymer chain were designed and synthesized as a new class of polymeric gene delivery vectors, where the chain-interlocked cationic cyclic units formed an integrated supramolecular entity to function as a macromolecular gene vector. The development of the supramolecular biomaterials through inclusion complexation has opened up a new approach for designing novel drug and gene delivery systems, which may have many advantages over the systems based on the conventional polymeric materials.     

聚乙二醇-聚乳酸嵌段共聚物及其微粒给药系统的研究进展

 综述可生物降解嵌段共聚物聚乙二醇-聚乳酸（PEG-PLA）及其微粒给药系统在药剂学中的研究与应用。该嵌段共聚物微球能提高蛋白、多肽的稳定性,有利于难溶性药物释放。纳米粒可降低网状内皮吞噬系统的识别与吞噬,改变药物体内分布及清除率,连接识别配体后脑靶向作用显著,具有温敏性和pH敏感性,增加难溶性药物溶解度,且生物相容性良好。PEG-PLA嵌段共聚物微粒给药系统将有广阔的发展和应用前景。     

生物降解聚合物PLGA-PEG-PLGA的合成及表征

目的对生物降解聚合物PLGA-PEG-PLGA进行合成及表征。方法以丙交酯、乙交酯及PEG为原料,用开环聚合法合成生物降解聚合物PLGA-PEG-PLGA,并用DSC、GPC和1H-NMR对其结构进行表征。结果合成的聚合物为嵌段聚合物。由1H-NMR可知聚合物数均相对分子质量为6 400~8 000,重均相对分子质量为7 100~9 200。上述制备的聚合物的水溶液具有反向热敏性质。质量分数为30%的PLGA-PEG-PLGA(3)水溶液的胶凝(由溶胶变为凝胶)温度为33℃,符合人体生理温度。结论提供了一种新的生物降解性药物载体材料。     

Controlled delivery of testosterone from smart polymer solution based systems: in vitro evaluation

The objective of this research is to develop injectable polymers solution based controlled release delivery systems for testosterone (TSN), using phase sensitive and thermosensitive polymers. A combination of poly(lactide) (PLA) and solvents mixture of benzyl benzoate (BB) and benzyl alcohol (BA) was used in the phase sensitive polymer delivery system. The effects of solvents system and drug loading on the in vitro TSN release were evaluated. In the case of thermosensitive polymer delivery systems, a series of low-molecular-weight poly(lactide-co-glycolide)-poly(ethylene glycol)-poly(lactide-co-glycolide) (PLGA-PEG-PLGA) triblock copolymers with varying ratio of lactide/glycolide (LA/GA, 2.0-3.5) were studied to control the release of TSN. The effects of varying block length of copolymers 1-4 on the in vitro TSN release were evaluated. Phosphate buffer saline (pH 7.4) containing 0.5% (w/v) Tween-80 was used as in vitro release medium. The amount of the released TSN was determined by an HPLC method. A controlled (zero-order) in vitro release of TSN was observed from both the phase sensitive and thermosensitive polymer delivery systems. Addition of BA (15%, v/v) in solvents system significantly (p<0.05) increased the release rate of TSN (0.33+/-0.01 mg/ml) from phase sensitive delivery system in comparison to solvent without BA (0.27+/-0.00 mg/day). Increasing drug loading also increased release rate. In the case of thermosensitive polymer delivery system, increasing the hydrophobic PLGA block length of copolymers significantly (p<0.05) decreased the release rate of TSN. It is evident from this study that the phase sensitive and thermosensitive polymers are suitable for developing prolong-release injectable implant delivery systems for TSN.     

Advances in the synthesis of amphiphilic block copolymers via RAFT polymerization: stimuli-responsive drug and gene delivery

Controlled/'living' radical polymerization methods, including the versatile reversible addition-fragmentation chain transfer (RAFT) polymerization process, are rapidly moving to the forefront in construction of drug and gene delivery vehicles. The RAFT technique allows an unprecedented latitude in the synthesis of water soluble or amphiphilic architectures with precise dimensions and appropriate functionality for attachment and targeted delivery of diagnostic and therapeutic agents. This review focuses on the chemistry of the RAFT process and its potential for preparing well-defined block copolymers and conjugates capable of stimuli-responsive assembly and release of bioactive agents in the physiological environment. Recent examples of block copolymers with designed structures and segmental compositions responsive to changes in pH or temperature are reviewed and hurdles facing further development of these novel systems are discussed.     

Thermosensitive sol-gel reversible hydrogels.

Aqueous polymer solutions that are transformed into gels by changes in environmental conditions, such as temperature and pH, thus resulting in in situ hydrogel formation, have recently attracted the attention of many investigators for scientific interest and for practical biomedical or pharmaceutical applications. When the hydrogel is formed under physiological conditions and maintains its integrity for a desired period of time, the process may provide various advantages over conventional hydrogels. Because of the simplicity of pharmaceutical formulation by solution mixing, biocompatibility with biological systems, and convenient administration, the pharmaceutical and biomedical uses of the water-based sol-gel transition include solubilization of low-molecular-weight hydrophobic drugs, controlled release, labile biomacromolecule delivery, such as proteins and genes, cell immobilization, and tissue engineering. When the formed gel is proven to be biocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivo applications where degradation is desired. It is timely to summarize the polymeric systems that undergo sol-gel transitions, particularly due to temperature, with emphasis on the underlying transition mechanisms and potential delivery aspects. This review stresses the polymeric systems of natural or modified natural polymers, N-isopropylacrylamide copolymers, poly(ethylene oxide)/poly(propylene oxide) block copolymers, and poly(ethylene glycol)/poly(D,L-lactide-co-glycolide) block copolymers.     

Thermosensitive sol–gel reversible hydrogels

Aqueous polymer solutions that are transformed into gels by changes in environmental conditions, such as temperature and pH, thus resulting in in situ hydrogel formation, have recently attracted the attention of many investigators for scientific interest and for practical biomedical or pharmaceutical applications. When the hydrogel is formed under physiological conditions and maintains its integrity for a desired period of time, the process may provide various advantages over conventional hydrogels. Because of the simplicity of pharmaceutical formulation by solution mixing, biocompatibility with biological systems, and convenient administration, the pharmaceutical and biomedical uses of the water-based sol–gel transition include solubilization of low-molecular-weight hydrophobic drugs, controlled release, labile biomacromolecule delivery, such as proteins and genes, cell immobilization, and tissue engineering. When the formed gel is proven to be biocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivo applications where degradation is desired. It is timely to summarize the polymeric systems that undergo sol–gel transitions, particularly due to temperature, with emphasis on the underlying transition mechanisms and potential delivery aspects. This review stresses the polymeric systems of natural or modified natural polymers, N-isopropylacrylamide copolymers, poly(ethylene oxide)/poly(propylene oxide) block copolymers, and poly(ethylene glycol)/poly(d,l-lactide-co-glycolide) block copolymers.     

Thermodynamic limits on drug loading in nanoparticle cores

Recently, biodegradable nanoparticles based on block copolymers have attracted attention as effective drug delivery vehicles. Maximizing the amount of drug loaded into particle is the desired goal, but loadings of only between 3 to about 25 wt% drug (for paclitaxel) are found experimentally. The reasons for the low loading and variability in loading have not been fully explained. In this study, a model is presented that quantitatively explains the observed phenomena. The thermodynamic model of drug loading is based on the molar free energy of the drug, which depends on the block copolymers size (entropic term), the interaction parameter between the drug and the hydrophobic core (enthalpic term), and the pressure-volume work to load the particle. The pressure-volume work, related directly to the interfacial tension between the core and the corona region, has not been previously considered with respect to drug loading. To validate the model, calculations were compared with experimental results for organic solutes, including paclitaxel, loaded into poly(ethylene glycol)-b-poly(epsilon-caprolactone), PEG-b-PCL block copolymer micelles. The model developed was found to predict the loading values in close agreement with experiments reported in the literature.