基于葡萄糖敏感的多孔微球/聚合物复合凝胶的胰岛素高效负载和控释

The development of glucose-sensitive implantable hydrogels for delivery of insulin has important significance and application value for the treatment of diabetes. However, insulin has unique physic-chemical properties and administration methods, and thus the implantable delivery system for insulin should have the ability to efficiently load massive drug and can accurately control the long-acting release of insulin. Apparently, the polymeric hydrogels cannot meet the requirements of the implantable delivery of insulin. Based on glucose-sensitive phenyboronic acid (PBA), the advantages of polymeric hydrogels on locating and stimuli-response function and the properties of porous microspheres on efficient drug-loading were combined to develop a novel glucose-sensitive porous microspheres (GSM)/polymer hybrid hydrogel. The main functions of implantable hydrogels of insulin, including efficient loading, controlled release and stimuli-response, were creatively designated to the different unit of this new drug delivery system, which will facilitate to give full play to the function of porous microspheres, glucose-sensitive PBA polymers and polymeric hydrogels, respectively. And finally the glucose-sensitive implantable hydrogel of insulin with the similar functions of pancreas for the physiological self-regulated release characteristics was developed. Subsequently, the performance of the prepared GSM/polymer hybrid hydrogel on the glucose-sensitive property and on the physiological self-regulated delivery of insulin was deeply studied. This novel glucose-sensitive hybrid hydrogel may serve as a promising implantable platform for diabetes therapy. The research results would be helpful for the development of similar drug delivery system for other peptide and protein drugs.

开发胰岛素可植入凝胶给药系统具有重要意义。胰岛素具有独特理化属性和给药方式，单一高分子凝胶难以满足其高效大量负载、精确长效控释的要求。本项目拟利用苯基硼酸(PBA)的葡萄糖敏感性，结合凝胶载体的定位、刺激响应功能和多孔微球的高效负载特性，设计一种葡萄糖敏感多孔聚合物微球(GSM)/聚合物复合凝胶，创造性地将胰岛素负载、刺激响应、控制释放三个关键职能，划分到该复合凝胶的不同组成单元上，充分发挥多孔微球、PBA基团、高分子凝胶的各自功能和协同效应，开发胰岛素生理自调式可植入凝胶给药系统。并研究该系统各单元的组成和结构，在其体内、体外响应葡萄糖刺激与调控胰岛素释放中的协同作用和对应关系，建立协调发挥多孔微球、PBA单元、高分子凝胶三个单元职能的优化组合方案。上述新思路尚未见文献报道，该研究将为高效、便利的糖尿病治疗新剂型的开发提供新方案，对于开发研究其他多肽、蛋白质类给药系统也有很好的借鉴作用。

糖尿病是当前威胁人类健康的主要疾病之一。主要的治疗方式是皮下注射胰岛素，然而，长期频繁地注射胰岛素给病人带来了极大的痛苦。相对而言，在皮下或腹腔植入胰岛素给药系统具有明显的优势。因此, 开发胰岛素可植入凝胶给药系统具有重要意义。含苯硼酸的聚合物凝胶能够可逆、持续响应葡萄糖浓度变化，实现胰岛素智能释放，已经被用于模拟生理胰岛素分泌模式，展现出极为诱人的应用前景。尽管如此，现有基于苯硼酸聚合物凝胶体系难以满足胰岛素植入剂型对高效大量负载、精确长效控释等性能的需求。. 本项目利用苯硼酸的葡萄糖敏感性，结合凝胶载体的定位、刺激响应功能和多孔微球的高效负载特性，设计开发了一种葡萄糖敏感多孔聚合物微球/聚合物复合凝胶，创造性地将胰岛素负载、刺激响应、控制释放三个关键职能，划分到该复合凝胶的不同组成单元上，充分发挥多孔微球、苯基硼酸、高分子凝胶的各自功能和协同效应，开发胰岛素生理自调式可植入凝胶给药系统。研究方案主要是通过对PLGA多孔微球进行表面改性，引入苯硼酸基团。利用苯基硼酸与含顺式二羟基的聚合物（如聚乙烯醇（PVA）和多巴胺改性透明质酸（HA-DOPA））的结合作用形成PLGA多孔微球复合凝胶。深入系统研究复合凝胶的宏观及微观形态，葡萄糖敏感性，药物释放及细胞毒性。结果表明，PLGA多孔微球/HA-DOPA复合凝胶在生理条件下即可形成凝胶，并具有较好的生物粘附性和优异的生物相容性及可降解性。此外，凝胶具有剪切变稀的性能，可通过注射进入生物体内。注射进入糖尿病小鼠体内，实现长期降糖效果，展现出优异的应用前景，为胰岛素可植入凝胶制剂的开发提供了新思路，具有较高的应用前景和价值。此外，我们还对苯硼酸基团的敏感特性和相关硼酯基纳米材料开展了一系列基础研究，取得了丰硕成果。相关研究成果已经发表了各类论文30多篇，其中项目负责人以第一或通讯作者发表SCI论文17篇，包括SCI封面或封底文章4篇；申请发明专利4项，已授权3项；并培养了2名博士和8名研究生。