聚乙二醇-聚谷氨酸-聚丙氨酸三嵌段共聚物的合成及其胶束的pH-响应性药物控制释放

通过大分子引发剂ω-胺基-α-甲氧基聚乙二醇引发N-羧基-α-氨基环内酸酐开环聚合和酸性水解制备了一种具有pH-响应性的三嵌段共聚物聚乙二醇-聚谷氨酸-聚丙氨酸(mPEG-PLGA-PLAA).通过核磁共振、ζ-电势、动态光散射、电子显微镜等手段表征了此类三嵌段共聚物的自组装过程及所形成胶束的pH-响应性.使用圆二色谱和红外光谱,分析了胶束结构随环境pH值转变过程中聚氨基酸链段二级结构的变化.以阿霉素作为模型药物,研究了三嵌段共聚物的载药能力和在不同pH条件下的药物释放能力.在碱性条件下,PLGA链段去质子化,链段从疏水性变为亲水性,胶束中间层由于水合作用变得松散,药物释放速率增加;在酸性条件下,PLGA链段质子化,不带电荷,与阿霉素药物分子间的静电相互作用消失.同时,PLGA链段α-螺旋含量增加,形成由链内氢键维持的刚性棒状结构,将链段周围包埋的药物分子"挤出",加速了药物的释放.

SYNTHESIS OF POLY( ETHYLENE GLYCOL)-POLY( GLUTAMIC ACID)-POLY(ALANINE ACID) TRIBIOCK COPOLYMER AND THE pH-SENSITIVE DRUG DELIVERY OF NANOPARTICLES THEREFROM

A novel pH-responsive and biodegradable triblock copolymer,poly(ethylene glycol)-poly(L-glutamic acid)-poly(L-Alanine acid)(PEG-PLGA-PLAA),was prepared by N-carboxyl anhydride ring-opening polymerization and acidic hydrolysis.It was found that this amphiphilic copolymer can self-assemble into micelles in aqueous solution.The PLAA,PLGA and mPEG segments serve as a hydrophobic core,a pH-responsive shell and a hydrophilic corona,respectively.The morphology and properties of the micelles such as pH sensitivity,zeta potential,secondary structure and mean diameter were investigated.Doxorubicin(DOX) was encapsulated into the micelles to explore the release profiles,which exhibited in vitro pH-dependence.In acidic environment,with the formation of α-helix secondary structure of poly(L-glutamic acid) segments,the PLGA segments in the triblock copolymers shrank and relocated in the micelles to trigger the release of drugs.As a result,these DOX-loaded polymeric micelles showed rapid release of DOX from the micelles in weakly acidic environments(pH=5.5) but very slow release under physiological condition(pH=7.4).