靶向纳米级高分子囊泡作为口服胰岛素载体的研究

前期使用聚氧乙烯-聚氧丙烯-聚氧乙烯(PEO-PPO-PEO, Pluronic)和生物可降解聚乳酸[poly(lactic acid), PLA] 合成的纳米级高分子囊泡(PLA-Pluronic-PLA)为载体，制备成纳米级胰岛素囊泡后喂食糖尿病模型小鼠，显示了有效而持续的降血糖作用。现拟在此基础上，进一步合成含靶向基团叶酸(FA)的新型共聚物叶酸-Pluronic-聚乙丙交酯(FA-Pluronic-PLGA)。并研究该高分子材料自聚集形成纳米级囊泡的条件，以及该纳米囊泡包埋胰岛素后的释放行为、体内降血糖作用等。通过化学连接标记荧光探针罗丹明在FA-Pluronic-PLGA共聚物上，用Caco-2 细胞系作为实验模型探讨纳米囊泡的口服吸收机制和在细胞内的分布等。通过本项目的研究，期望能将纳米级高分子囊泡研发为新型口服胰岛素制剂的载体提供较全面的理论依据，给糖尿病的治疗带来新的希望。

Nano-sized polymeric vesicles composed of Pluronic 127 and poly(lactic acid) (PLA-F127-PLA) were used as oral carrier of insulin in our previous study. It was found in the diabetic mice that oral insulin-loaded PLA-F127-PLA vesicles showed the prolonged hypoglycemic effect. Based on these results, a novel block copolymer containing targeting folate group, Pluronic and Poly(lactide-co-glycolide) (FA-Pluronic-PLGA) will be synthesized. The condition of forming vesicular nanoparticles for FA-Pluronic-PLGA copolymer will be studied. The feasibility of nano-sized FA-Pluronic-PLGA vesicles as the oral insulin carrier will be further investigated in this project. The release behavior and hypoglycemic effect of insulin-loaded FA-Pluronic-PLGA vesicles will be studied. Fluorescence probe rhodamine will be grafted chemically on the end of FA-Pluronic-PLGA copolymer. Caco-2 cell line will be used to study the mechanism of oral absorption and intracellular distribution of insulin-loaded and rhodamine-labled vesicles. The goal of this project is to provide relatively comprehensive theoretical basis for nano-sized polymeric vesicles as oral insulin carriers so as to bring new hope for the therapy of diabetes.