胰岛素长效智能释放给药系统研究

Diabetic patients require long-term insulin therapy. Nowadays in clinic, subcutaneous injection is usually adopted in insulin treatment, but this thrice-a-day or more administration leads to dramatically bad compliance and makes diabetics suffer a lot. The newly developed insulin delivery systems mainly focus on pulmonary or rhinal routes of insulin administration which is neither intelligent nor long-acting, or subcutaneous insulin implant which is long-acting but not smart-releasing; and short-acting smart-releasing preparations of insulin also witness reports. Therefore, how to simultaneously realize the long circulation and the smart release of insulin delivery is a worldwide problem that is urgently to be solved. The current study here is to design a kind of long-acting smart-releasing insulin delivery system that will be sharply sensitive to blood glucose concentration changes and thus release an exact dose of insulin both timely and accurately. In this study, a kind of red blood cell (RBC)-coated polymeric nanoparticles with “core-shell” structure is designed to be engineered. pH-sensitive material was used to construct the “inner core” nanoparticles (NPs) loaded with insulin, and this “inner core” was built sharply glucose-sensitive property by co-loading glucose-response-associated enzymes. Additionally, NPs are planned to be skillfully loaded into live RBCs, which process nature long-circulation property and extremely good biocompatibility in blood; and this NPs’ “outer shell” will also provide a relatively closed microenvironment for enzymatic-oxidation scheme and create a stealth for the NPs in blood circulation. This novel type of drug delivery system is expected to intelligently release insulin sharply according to instantaneous blood glucose variation for as long as several weeks. The investigation insight of the project is certainly promising to provide scientific basis and application value for research and development of novel long-acting smart-releasing preparations for insulin.

糖尿病患者需要长期的胰岛素治疗，临床上普遍采用胰岛素皮下注射，一日三次或更多，患者顺应性差。已开发的新型胰岛素制剂多为肺部或鼻腔给药的非长效非智能制剂，或胰岛素储库皮下埋植剂等长效非智能制剂；短效的胰岛素智能释放制剂也有研究报道。同时实现胰岛素给药的长效和智能释放，是亟待解决的世界性难题。本课题拟设计一种可根据血糖浓度变化而及时确需释药的胰岛素长效智能释放给药系统。首先以pH敏感的高分子材料为载体，搭载胰岛素及葡萄糖响应相关酶系，构建具有葡萄糖响应性能的高载量胰岛素纳米内核（NPs）；再用特殊方法将NPs载入具有天然血液长循环特性和优良生物相容性的活性红细胞，以构建胰岛素长效智能释放给药系统；该递释系统有望依据血糖水平智能释放胰岛素长达数周。本课题的开展将为长效智能释放胰岛素新剂型的研发提供坚实的科学基础和应用价值。

糖尿病患者皆不同程度地依赖于长期胰岛素治疗，临床上普遍采用胰岛素皮下注射，一日三次或更多，患者顺应性差；研究开发胰岛素新型给药系统具有重要的科学价值和实用意义。本课题针对同时实现胰岛素给药的长效循环和智能释放这一难题，首次提出一类基于葡萄糖氧化酶酶促反应实现静脉注射给药的长效胰岛素智能递释系统，其可根据血糖水平变化而及时确需释药。. 为实现这一设想，本课题利用葡萄糖水平响应相关信号，如经葡萄糖氧化酶（GOx）催化生成的酸，选用生物相容性良好的葡聚糖、壳聚糖等为基础，设计合成缩醛化葡聚糖（Ace-Dex）、脱氧胆酸-乙酰半胱氨酸-壳聚糖（DCN）等pH响应载体材料，分别包载GOx-CAT酶系并搭载高剂量胰岛素以构建葡萄糖智能响应NPs这类“人工胰腺”。这些NPs在体外皆表现出敏锐的葡萄糖感应能力和良好的胰岛素释放自动“开-关”机制。在此基础上，利用红细胞的天然长循环特性及固有生物相容性，将NPs修饰覆盖上红细胞膜“外壳”（RBCm-Ace-Dex NPs）或使之寄乘于活性红细胞（DCN NPs@RBCs），构建长效胰岛素智能释放系统；两者皆在糖尿病模型小鼠体内表现出不低于96 h的长效智能血糖控制作用，从而成功实现智能释放胰岛素系统的长效循环。. 综上，本课题成功构建了葡萄糖敏感的胰岛素智能释放系统，并利用红细胞实现了其在血液循环中的长效血糖调节作用；为长效智能释放胰岛素新剂型的研发提供了科学基础。

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