葡萄糖响应性水凝胶-胶束复合载体协同释放胰岛素和二甲双胍

The combination of insulin and metformin is an effective method to treat type II diabetes. Co-delivery carrier system of the two drugs with glucose responsive under physiological conditions will be developed, which is expected to achieve collaborative release of insulin and metformin in response to physiological glucose level. Metformin will be loaded into glucose-responsive micelles self-assembled from phenylboronic acid (PBA)-contained block copolymer PEG-b-P(Asp-co-AspAPBA), and then, these drug-loaded micelles as well as insulin will be loaded together into hydrogel formed by glycopolymer P(Asp-co-AspAGal) and PBA-contained polymer P(Lys-co-LysFPBA). As increasing glucose content, the complexation between PBA and glycosyl will be destroyed and the insulin-loaded hydrogel will be swollen, following the relase of insulin. Then, metformin-loaded micelle will be broken up as the PBA group of micelle combining with glucose, following the relase of metformin. The collaborative release of insulin and metformin will be investigated. The studies will establish a novel hydrogel-micelle complex carrier collaborative releasing insulin and metformin for glucose-regulated, and provide scientific basis for the development and the design of the combination of insulin and metformin in diabetes treatment.

胰岛素和二甲双胍的联合用药是一种有效治疗II型糖尿病的方法，开发能够同时负载两种药物并具有葡萄糖响应性的载药体系，实现二者的协同释放，对于糖尿病的治疗具有重要的意义。本项目拟采用嵌段共聚物聚乙二醇-b-聚(天冬氨酸-co-天冬酰胺基苯硼酸) (PEG-b-P(Asp-co-AspAPBA))制备负载二甲双胍的葡萄糖响应性胶束载药体系，利用苯硼酸基团与半乳糖之间的可逆酯化平衡反应，采用可降解聚合物聚(天冬氨酸-co-天冬氨酰胺基半乳糖) P(Asp-co-AspAGal)和聚(赖氨酸-co-赖氨酰氨基氟苯硼酸) P(Lys-co-LysFPBA)，并负载胰岛素和载药胶束，构建葡萄糖响应性水凝胶-胶束复合载体，开展复合载药体系协同释放两种药物的研究，以期制备出能响应人体血糖变化、协同释放胰岛素和二甲双胍的新型水凝胶-胶束复合载药体系，为开发糖尿病治疗联合给药体系奠定基础。

胰岛素和二甲双胍的联合用药是一种有效治疗II型糖尿病的方法，开发能够同时负载两种药物并具有葡萄糖响应性的载药体系，实现二者的协同释放，对于糖尿病的治疗具有重要的意义。本项目采用开环聚合(ROP)方法制备含苯硼酸(PBA)的聚氨基酸嵌段共聚物，通过静电作用负载二甲双胍形成聚合物胶束药物载体；以含PBA的聚氨基酸和含半乳糖的聚氨基酸为基材，通过PBA和半乳糖的可逆相互作用，在生理条件下负载胰岛素和载药胶束，形成水凝胶-胶束复合载药体系。在葡萄糖浓度升高时，水凝胶中的苯硼酸酯交联点被破坏，体系发生溶胀，胰岛素扩散出凝胶体系进行释放，同时载药胶束也随葡萄糖浓度的升高发生溶胀，释放出二甲双胍，从而达到胰岛素和二甲双胍协同释放的目的。以此构建葡萄糖响应性水凝胶-胶束复合载体，开展了复合载药体系协同释放两种药物的研究，动物实验表明，这种载药体系能迅速降低II型糖尿病模型小鼠的高血糖，并使小鼠的血糖维持在正常水平长达48小时。