含磷脂酰胆碱超支化星形共聚物纳米胶束体内长循环机制研究

Long-circulation in blood is one of the necessary properties for the targeting delivery of drug, and zwitterionic nanomicelles have showed their superiorities as the long circulating drug carriers. In previous study, we found that the hyperbranched star polymer micelles containing phosphorylcholine exhibited superior circulation capability compared with that made of mPEG-PLA. Based on this discovery, a (AB3)4 hyperbranched star polymer containing phosphorylcholine will be synthesized by the combination of atom transfer radical polymerization and click chemistry. With the (AB)4 and (AB2)4 hyperbranched star polymer as control groups, the influence of copolymer structures on self-assembly behavior and surface physicochemical properties of the self-assemble micelles will be investigated. And meanwhile, the escape mechanism of the micelles from reticuloendothelial system will be revealed through the study of the interaction between micelles and opsonins. The project will provide a significant theoretical reference for reasonable design of long-circulating polymer micelles.

血液中长循环是纳米微粒靶向药物投递的重要性质之一，表面含两性离子的纳米胶束被认为是长循环载体的优选材料。本项目前期工作发现含磷脂酰胆碱超支化星形共聚物胶束具有优于PEG纳米微粒的长血液循环性能。本课题拟在此基础上设计并通过原子转移自由基聚合结合点击化学合成结构更加规整的(AB3)4型含磷脂酰胆碱超支化星形共聚物，以(AB)4和(AB2)4结构共聚物为对照，研究超支化星形共聚物结构结构对其自组装行为和自组装胶束表面物理化学性质的影响，同时通过研究自组装胶束与调理因子的相互作用阐明其从网状内皮系统逃逸并靶向肿瘤药物传递的机制，为设计长循环载药纳米微粒提供理论依据。

实现体内长效循环是纳米载体靶向药物投递的关键，本项目成功制备了三种长循环纳米载体，为实现药物的靶向投递提供了理论依据。主要研究内容分为以下三部分：.（1）合成了AB3、(AB3)2、(AB3)3三种结构的星形超支化聚乳酸-聚 2-甲基丙烯酰氧基乙基磷脂酰胆碱(PLA-PMPC)共聚物，实验结果表明，超支化星形聚合物胶束具有良好的生物相容性和体内稳定性；而且，随着表面 MPC 含量的增高，对血蛋白吸附的抑制作用越强，所包载疏水药物在体内的循环时间越长。.（2）合成了不同亲疏水链段长度的(AB)4型星形结构的聚苯乙烯-聚2-甲基丙烯酰氧基乙基磷酰胆碱（PS-PMPC）两亲性嵌段共聚物，研究结果表明PMPC链段长度的增加可以有效地改善双亲性纳米胶束的稳定性，并能提高其循环时间和药物靶向投递性能。.（3）以转铁蛋白标记超顺磁纳米微粒，分离红细胞分泌外泌体，与阿霉素孵化后形成具有体内磁靶向特性的载药纳米微粒，通过体内动物实验表明，该纳米微粒在外磁场条件下可靶向投递阿霉素到肿瘤。