乙二醇-聚(咪唑丙基-天冬酰胺)-聚丙氨酸三嵌段共聚物的合成及其pH-响应性药物控制释放性能的研究

聚天冬氨酸及其衍生物是一种具有良好生物相容性和可生物降解性的高分子材料, 被广泛应用于生物医药领域. 本研究通过大分子引发剂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N-(3-氨丙基)咪唑侧基改性, 制备了一种侧链含有咪唑丙基的聚乙二醇-聚(咪唑丙基-天冬酰胺)-聚丙氨酸三嵌段共聚物. 在水溶液中, 此聚合物可自组装形成一种核-壳-冠型的三层共聚物胶束, 其中疏水性的聚丙氨酸链段自聚集形成胶束的核, 聚(咪唑丙基-天冬酰胺)链段形成具有pH-响应性的壳层, 用于包埋和释放药物, 外围的聚乙二醇链段可以提供一个稳定的水合冠层, 延长药物的体内循环时间. 利用咪唑环与游离阿霉素之间的π-π相互作用和疏水相互作用可以在自组装的过程中将阿霉素包埋到胶束内. 研究发现, 载药胶束随环境pH 值的降低药物的释放速率显著增加. 这主要是由于咪唑环在酸性条件下的质子化导致链段亲疏水性质发生明显变化.

Preparation and pH-Sensitive Drug Delivery Study of mPEG-poly(Imidazole Propyl-Asparagine)-poly(L-Alanine)

Stimuli-sensitive drug delivery systems have attracted considerable interest in recent years for biomaterials scientists.It is well known that the pH value drops from physiologically 7.4 to that lower than 6.5 in tumor tissues,and such difference can be used as a trigger for drug releasing.Poly(amino acid)s(PAAs) have been studied for decades in the fields of drug delivery system due to their biocompatibility,biodegradability,precise secondary conformation and structural versatility.In this study,a novel biodegrad-able ABC type triblock copolymer mPEG-poly(benzyl L-aspartate)-poly(L-Alanine)(mPEG-PBLA-PLAla) was synthesized by N-carboxyl anhydride ring-opening polymerization.Imidazole groups were tethered to the side chains of poly(L-Asparagine) segments by aminolysis.It was found that this tri-block copolymer can form nano-scale core-shell-corona trilayer micelles in aqueous solution.The PLAla,Poly(L-Asparagine) and mPEG segments serve as a hydrophobic core,a pH-sensitive shell,and a hydrophilic corona,respec-tively.An antitumor agent,doxorubicin(DOX),was successfully loaded into the nanocarrier via combined actions of hydrophobic and π-π interaction.The drug release profiles displayed a pH-dependent behavior.DOX release rate increased significantly as the solution pH dropped from the physiological pH to acidic.This is most likely due to protonation and a change in hydrophilicity of the imidazole groups in the poly(L-Asparagine).