基于可逆B-N键构筑糖响应聚合物载药胶束用于胰岛素的控制释放

Phenylboronic acid-based glucose-responsive materials have attracted great intention in recent years due to their potential application in insulin delivery. It is still a challenge to offer large capacity for drug loading because of the lack of strong interaction between the phenylboronic acid-based nanomaterials and insulin. Herein, we aim to develop a novel drug release system based on dynamic reversible B-N covalent bond formed by 2-formyl phenylboronic acid (FPBA) and amino group in insulin. The aldehydel group can form a five-membered heterocycle with the amino group, which significantly enhance the bonding energy of the B-N bond. Such B-N dynamic covalent bonds in the five-membered heterocycle have excellent sugar-responsiveness, which can be exploited to develop sugar-responsive on-off insulin release. Well-defined diblock copolymer of poly(2-methacryloyloxyethyl phosphorylcholine)-block-poly(2-formyl-5-acrylamido phenylboronic acid) (PMPC-b-PFAPBA) will be synthesized by reversible addition fragmentation chain transfer polymerization (RAFT). Polymeric micelles with hydrophilic PMPC as a shell and PFAPBA/insulin as a core could be formed with insulin acting as a cross-linker via the covalent bond between the amino groups of insulin and the phenylboronic acid, and the insulin drug would be loaded simultaneously by covalent bonding. This method has outstanding advantages that the load of insulin is realized by covalent bond which brings high load efficiency; the dynamic reversible B-N bonds in the five-membered heterocycle have excellent sugar-responsiveness, which can be exploited to develop on-off regulated sugar-responsive drug release; the hydrophilic PMPC shell can protect the polymeric micelles from the rapid elimination by the immune system leading to a prolonged blood circulation.

针对利用非共价键构筑的胰岛素智能载药体系存在胰岛素负载效率较低的问题，本项目以邻醛基苯硼酸衍生物为功能体，利用胰岛素胺基与其形成动态可逆、糖响应的B-N五元杂环，开发出键合胰岛素的载药体系，以期实现对胰岛素的高效负载和糖响应“开关”控制释放。设计合成嵌段聚合物聚（甲基丙烯酰氧乙基磷酸胆碱）-block -聚（5-丙烯酰胺-2-醛基苯硼酸）(PMPC-b-PFAPBA)，胰岛素加入到嵌段聚合物溶液中发生交联，形成以亲水链段PMPC为壳层、PFAPBA/胰岛素为核的聚合物载药胶束，实现胰岛素的键合负载。该方法的突出优点是：利用共价键负载胰岛素可有效提高胰岛素的负载效率；利用B-N五元杂环的动态可逆和糖响应性，实现胰岛素的糖响应“开关”控制释放；亲水的PMPC壳层可有效保护聚合物胶束不被免疫系统快速清除，延长胶束在血液中的循环时间。

针对当前胰岛素药物载体物理作用负载胰岛素效率较低、胰岛素不能在生理条件下(pH 7.4)糖响应控制释放、载药纳米粒子不能在生物体中长时间循环等问题，本项目将动态共价化学、糖响应性邻位乙羰基苯硼酸衍生物与嵌段聚合物材料相结合，探索构筑动态共价化学键合负载胰岛素的载药体系，实现胰岛素的生理条件下（pH 7.4）糖响应控制释放；基于聚（甲基丙烯酰氧乙基磷酸胆碱）（PMPC）优异的亲水性和不易被巨噬细胞识别，实现载药胶束在生物体血液中的长时间循环。.利用可逆加成裂解链转移自由基聚合（RAFT）方法合成结构可控、分子量窄分布的嵌段聚合物聚（甲基丙烯酰氧乙基磷酸胆碱）-block-聚（丙烯酰胺盐酸盐）（PMPC-b-PAH），酰化反应将功能性分子邻位乙羰基苯硼酸衍生物（APBA）链接于嵌段聚合物侧链，获得嵌段聚合物PMPC-b-(AH-co-APBA)；详细研究了嵌段聚合物对胰岛素的负载和糖响应控制释放性能，研究了载体的生物相容性和在生物体内的代谢和生物分布情况。结果表明：嵌段聚合物能够有效负载胰岛素，实现胰岛素的生理条件下（pH 7.4）葡萄糖响应控制释放，同时发现，载药胶束有很好的生物相容性，并且能够在生物体血液中长时间循环，为嵌段聚合物应用于临床实际应用提供良好的理论基础。.基于邻位乙羰基苯硼酸衍生物的嵌段聚合物为胰岛素的键合高效负载和糖响应控制释放提供了新途径，为新型的胰岛素载体的开发提供理论及实验基础。

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