功能化多嵌段-接枝结构生物降解高分子胶束载体材料的研究

Low stability, poor controllable size and lack of functional sites are the main problems for biodegradable polymeric micelles as drug carriers. In this project, a novel functionalized biodegradable polymer with multiblock-graft architecture is synthesized for anticancer drug delivery. The multiblock copolymer backbone is synthesized with ring-opening polymerization of L-lactide (LLA) and β-benzyl malolactonate (β-MLABz) using N-heterocyclic carbene as catalyst. The multiblock poly(L-lactide)-b-poly(β-malic acid) copolymer is received after the deprotection. The pH-sensitive molecule with imidazole ring and targeting moiety iRGD modified poly (ethylene glycol) are immobilized on the pendant carboxyl groups of poly(β-malic acid) blocks. The functionalized copolymers with multiblock-graft architecture are self-assembled into polymeric micelles to load anticancer drug. Both the in vitro and in vivo anticancer activities of the drug loaded micelles are studied systematically. This novel polymeric micelle is expected to have the functions of excellent stability, controllable size, long circulation, active targeting, pH sensitivity and high drug release rate. This project will provide a new polymeric micelle for drug delivery and inspire a new strategy for the design and fabrication of drug delivery systems for chemotherapy.

本项目针对目前生物降解高分子胶束药物载体材料面临的稳定性低、粒径的可控性差、缺乏位点进行功能化等诸多问题，设计构建一种具有多嵌段-接枝结构的新型生物降解高分子胶束载药系统。通过N-杂环卡宾（NHCs）为催化剂，逐步引发丙交酯（LA）和β-苄酯苹果酸内酯（β-MLABz）的开环聚合，合成聚乳酸-b-聚（β-苄酯苹果酸内酯）多嵌段共聚物，脱保护后获得功能侧基——羧基，在羧基上键合pH敏感的带有咪唑环的分子和经iRGD多肽修饰的具有长循环功能的聚乙二醇（PEG-iRGD）制备双亲性高分子，经自组装成为高分子胶束负载抗肿瘤药物，系统研究其体内外抗肿瘤效果。这种多嵌段-接枝结构高分子胶束载药系统具有稳定性好（CMC低）、粒径可控、长循环、靶向、pH敏感、药物释放效率高等多种功能。本项目的实施，将丰富生物降解高分子胶束药物载体材料的类型，为高分子胶束载药系统的设计和构建提供新的思路和方法。

生物降解高分子胶束作为重要的纳米药物载体，已经获得了广泛的认可，然而，目前高分子胶束纳米药物载体面临的稳定性低、粒径的可控性差、缺乏位点进行功能化等三个问题，针对上述问题，本项目设计构建基于聚苹果酸-聚乳酸生物可降解高分子胶束载药系统，该载体同时具有稳定性好、长循环、粒径可控、pH敏感、可控释放等多种功能。首先，合成卞酯苹果酸内酯（MLABz），通过与丙交酯进行开环聚合合成聚乳酸-聚苹果酸共聚物，利用聚苹果酸侧链的羧基键合具有pH和氧化还原敏感的聚合物，构建pH/氧化还原双重敏感的高分子胶束载药系统，系统的研究了载体材料的组成、结构、性能对胶束的形貌、粒径、药物负载性能、释放性能、氧化还原及pH敏感的影响，揭示了载药胶束的入胞途径及其对肿瘤细胞的体内外抑制效果。研究结果表明： pH/氧化还原双重敏感的高分子胶束载药系统由于其接枝型结构赋予其良好的稳定性，相比无规或嵌段型聚合物，其临界胶束浓度低1个数量级；且对疏水药物具有较高的包载量；所形成的胶束粒径可控；在胞内内涵体或溶酶体的环境中显示pH响应性，可实现氧化还原响应性释药；体内外结果显示出良好的抗肿瘤效果。通过本项目的实施，为高分子胶束载药系统的设计和构建提供新的思路和方法。