用于胰岛素精控释放的双响应双交联可注射水凝胶

This research intends to design dual responsive and cross-linked injectable hydrogel as fine controlled drug delivery system. Chitosan is used as starting materials for its biocompatibility and biodegradation, and phenylboronic acid group and bioactive molecules such as glucose oxidase are linked to the chitosan chains. Polymer with hydroxy and aldehyde groups such as oxide dextran is choosed as macromolecular crosslinking agent. pH/glucose dual responsive hydrogels are synthesized through imine and benzene boric acid ester, and glucose oxidase is immobilized in the gel matrix to form dual glucose responsive system. The double crosslinking network of the hydrogel can change greatly and release drugs due to the reversible reaction of the imine and benzene boric acid ester when phenylboronic acid and glucose oxidase sense the changes of glucose level in the environment simultaneously. Thus, the dual glucose responsive system can respond to the changes of glucose level sensitively and fastly, and accurately control the drug release kinetics due to the dual sense unit (phenylboronic acid and glucose oxidase) and dual accept unit (imine and benzene boric acid ester). The system can be used as insulin self-regulated release system for further development of long-acting insulin intelligent agents and diabetes treatment.

本项目拟选择具有良好生物相容性、生物降解性和抑菌性的壳聚糖衍生物为基础高分子，利用亚胺键和苯硼酸酯两种动态键制备pH/葡萄糖双敏感可注射水凝胶，同时将葡萄糖氧化酶通过二硫键引入到凝胶基质中，构筑双重葡萄糖响应体系。利用苯硼酸和葡萄糖氧化酶两种响应因素同时感应外界环境中的葡萄糖浓度变化，分别引起凝胶体系中亚胺键和苯硼酸酯的可逆反应，使水凝胶的双交联网络结构发生较大改变并释放出药物，通过双感应元（葡萄糖氧化酶和苯硼酸基）和双接受元（亚胺和苯硼酸酯）实现其对葡萄糖浓度变化响应的高灵敏性和快响应性。该体系采用双重葡萄糖响应因素精确控制药物释放动力学，可作为胰岛素自我调节药物释放载体，为今后进一步开发胰岛素长效智能化制剂和进行可注射凝胶用于糖尿病临床治疗的研究打下基础。

本项目以具有良好生物相容性、生物降解性和抑菌性的壳聚糖衍生物为基础高分子，利用亚胺键和苯硼酸酯两种动态键制备pH/葡萄糖双敏感可注射水凝胶。该水凝胶具有较高的模量和良好的弹性，其微结构可通过改变聚合物浓度和组成、pH和葡萄糖等环境参数进行调节。该体系具有良好的生物相容性，可原位同步包封阿霉素等小分子药物、胰岛素等大分子药物和活性细胞，并可实现药物的持续响应性释放和细胞的生长增殖。包封抗癌药物阿霉素的水凝胶可抑制细胞增殖，可用于发展抗肿瘤药物释放体系。同时包封胰岛素和L929细胞的双载水凝胶可作为生物活性敷料，用于糖尿病创伤的修复治疗，可有效控制高血糖大鼠的血糖水平，促进伤口处的血管新生和胶原积累，提高糖尿病创伤的愈合速度。