具有应用前景的葡萄糖响应性药物载体

In the Youth Science Foundation, we studied the glucose-responsiveness of phenylboronic acid-based block copolymer PEG-b-P(AA-co-AAPBA). It was firstly found that the self-assembled micelles could dissociate and release preloaded insulin in response to glucose at pH 7.4. The decrease of the pH value for the glucose-responsiveness was attributed to the coordination between carboxyl group and phenylboronic acid on the polymer chain based on Solid 11B NMR characterization of the micelles. Complexation between PEG-b-P(AA-co-AAPBA) and glycopolymer PAGA could substantially increase the sensitivity of the complex micelles to glucose. We also developed a reversible glucose-actuated nanocarrier with a P(Asp-co-AspAPBA) core and a mixed PEG/PNIPAM shell, which could repeatedly on-off release insulin in response to glucose. Until now, 3 papers have been published based on the youth science foundation, and 2 more papers are in review or writing.. This project is the expansion and deepening of the previous Youth Science Foundation. In vivo study of antidiabetic effect of insulin-loaded PEG-b-P(AA-co-AAPBA) micelles will be carried out on rats by both oral and intravenous administration. Chemical antidiabetic drugs will also be loaded in PEG-b-P(AA-co-AAPBA) micelles for the treatment of diabetes by oral administration. Different glycopolymers will be synthesized and used to form complex with PEG-b-P(AA-co-AAPBA). The glucose-responsiveness of the resulted complex micelles will be studied. Biocompatible polymers, such as PMEO2MA, will be synthesized and used to replace the non-biocompatible polymers and enhance the biosafety of drug carrier. We expect that this project can lay the foundation for the glucose-responsive drug carrier to practical application.

青年基金项目围绕含苯硼酸基团的聚合物，首次获得了在生理pH条件下具有葡萄糖响应性的嵌段共聚物胶束，实现了胰岛素的葡萄糖响应性控制释放。通过固体核磁等手段揭示了该胶束在pH 7.4具有葡萄糖响应性的机理。利用具有葡萄糖响应性内核和PEG/PNIPAM混合壳的复合胶束实现了葡萄糖浓度开关控制释放胰岛素。通过含苯硼酸基团的嵌段共聚物与糖基化聚合物复合，使所得胶束的葡萄糖敏感性大大提高。目前，已发表相关研究论文3篇（IF > 4），另有2篇论文在投稿或整理当中。.本项目是在青年基金项目基础上的扩展和深入，针对已有聚合物胶束，研究胰岛素载体的降血糖作用，负载化学降糖药物，研究其体外和体内释放行为。研究成不同结构的糖基化聚合物与含苯硼酸的聚合物的复合行为以及所得胶束的葡萄糖响应性。采用新的生物相容性聚合物替换原有材料中的非生物相容组分，改善载体的生物安全性。为葡萄糖响应性药物载体走向实用奠定基础。

对于I型糖尿病患者及部分II型糖尿病后期患者，摄入胰岛素是最有效的治疗手段。然而，当前常用的皮下注射给药或手术方法皮下埋植缓释载体仍存在使用不便或难以及时按需释放胰岛素的问题。因此，亟需开发能够模拟胰岛素生理分泌代谢模式，在较长时间内适时按需释放胰岛素的新剂型。具有葡萄糖响应性的高分子纳米载体或许是理想的选择。本项目主要利用苯硼酸与邻二醇或邻二酚类物质间的动态、可逆相互作用及其对葡萄糖浓度、pH值、谷光甘肽等刺激的响应性，主要开展了五个方面的研究工作：1）基于苯硼酸功能化聚合物与糖基化聚合物的自组装复合胶束在生理pH值对生理血糖浓度变化的响应性及对胰岛素的自调节释放；2）基于苯硼酸的新型葡萄糖响应性纳米药物载体的制备与应用；3）基于苯硼酸环酯动态共价键的多重响应性自组装体系作为亲水性药物载体的研究；4）基于苯硼酸与邻二酚相互的自组装复合胶束用于抗肿瘤药物的投递；5）具有环境响应性混合壳层表面的复合胶束用于小分子降糖药物格列苯脲和抗肿瘤药物阿霉素等投递。获得了在生理pH条件下对血糖浓度变化具有良好响应性的自组装复合胶束、囊泡等，从理论角度阐明了苯硼酸-糖基化聚合物自组装体系对生理血糖响应的机理，通过采用聚氨基酸类聚合物，有效改善了材料的生物相容性，实现了对包括胰岛素在内的多各种亲水性药物的负载和葡萄糖响应性自调节释放，取得了一系列重要的研究成果，为基于苯硼酸的葡萄糖响应性纳米药物载体走向实用化奠定了良好的基础。本项目研究内容及目标已经全部按计划完成，已发表相关SCI研究论文16篇，申请发明专利2项。