葡萄糖敏感纳米凝胶的制备及其在血糖调控中的应用

Presently, most of glucose-sensitive drug delivery systems based on phenylboronic acid, show glucose-sensitive properties only in the alkaline medium at a relatively higher glucose concentration (much larger than 2.0 mg/mL, the prandial blood glucose concentration for diabetics). In addition, most of matrixes used as the carriers are not biodegradable, which limited their clinical applications. The project will prepare a series of glucose-sensitive nanogels based on the biocompatible and biodegradable polypeptides combined with phenylboronic acid through ingenious design. The nanogels are used as carriers for loading insulin and co-loading insulin and cyclic adenosine monophosphate (cAMP). The nanogels have intelligent “on-off” drug release profiles that release drug rapidly and numerously under the diabetic blood glucose level but little under the healthy blood glucose level. Insulin, as exogenous hypoglycemic agent, can reduce blood glucose effectively, while cAMP can stimulate endogenous insulin secretion from pancreas beta cells. Insulin and cAMP co-loaded nanogels for the treatment of diabetes can low the blood glucose not only by the released exogenous insulin, but also by the endogenous insulin secreted through pancreas beta cells, which regulate the diabetic blood glucose fundamentally. The successful implementation of the project will provide new ideas and methods for glucose-sensitive drug delivery systems, and promote the clinical applications of the glucose-sensitive drug carriers.

目前，多数基于苯硼酸的葡萄糖敏感药物传递系统只有在碱性且高葡萄糖浓度（远大于糖尿病患者血糖水平2.0 mg/mL）下才具有葡萄糖敏感性能，且所用材料多不可降解，这限制了其临床应用。本项目拟将苯硼酸与生物相容性好且可生物降解的聚氨基酸结合，通过巧妙的设计制备一系列葡萄糖敏感纳米凝胶，用于担载胰岛素（INS）以及共担载INS和环腺苷酸（cAMP），使其在生理pH下，在糖尿病患者血糖水平下快速大量释放药物，而在正常血糖范围内较少释放药物，具有智能“开-关”式释放特性。INS为外源性降血糖药物，可有效降低血糖，cAMP能够促使胰腺β细胞分泌内源性INS。INS和cAMP的共担载用于糖尿病的治疗，不仅可以通过外源性INS的释放降低血糖浓度，更促进内源性胰岛素的分泌，从根本上调控血糖治疗糖尿病。本项目的成功实施将为葡萄糖敏感药物释放系统提供新的思路和方法，促进葡萄糖敏感药物载体的临床应用。

糖尿病患者急剧增加并呈现年轻化，创新性高效治疗手段的研发迫在眉睫。葡萄糖敏感自调式胰岛素传递系统有望取代常规注射给药途径而成为一种潜在的治疗方法。目前基于苯硼酸（PBA）的葡萄糖敏感体系并不理想，多采用不可降解的载体材料，且药物载体需在偏碱性的介质中才能体现葡萄糖敏感性能，不符合人体生理pH特性。此外，药物载体需在远高于糖尿病患者血糖浓度时才可实现葡萄糖敏感药物释放，不符合人体的生理需求。为了解决上述问题，本项目将苯硼酸与生物相容性好且可生物降解的聚氨基酸结合制备了葡萄糖敏感纳米凝胶。所制备的氯乙醇化聚氨基酸纳米凝胶和糖基化聚氨基酸纳米凝胶具有生理pH下的葡萄糖敏感性能，并具有在糖尿病患者血糖水平下快速大量释放药物，而在正常血糖范围内较少释放药物的智能“开–关”式药物释放特性。在本项目的资助下，我们共发表学术论文12篇，申请中国发明专利3项，其中已授权2项。本项目已完成了预定的研究目标。