Development of self-regulated insulin delivery system based on novel glucose-responsive gel

近年来，随着外界刺激而改变其物理化学性质的聚合物凝胶因其作为化学阀门系统在药物控制释放、分析和制备分离以及传感器技术中的潜在应用而引起了人们极大的兴趣。事实上，在对热和光等物理刺激做出反应的凝胶的开发方面已经取得了显著的进展。然而，完全合成的凝胶对化学刺激(即环境中特定分子的浓度变化)做出反应的例子很少，无论它们如上所述的广泛适用性如何。更具体地说，糖响应性凝胶的开发可能会极大地推动构建自我调节的胰岛素递送系统，模仿胰腺中β细胞的功能，用于治疗糖尿病。在本研究项目中，首次制备了对外界葡萄糖浓度响应的全合成聚合物凝胶。该凝胶由具有较低临界溶解温度的聚合物链组成，如聚N-异丙基丙烯酰胺(PNIPAAm)，其中含有少量的苯基硼酸作为葡萄糖敏感部分。在配有视频监视器的显微镜下，凝胶在等温条件下发生了重复的体积相变，葡萄糖浓度的变化是由于苯基硼酸与葡萄糖络合使苯基硼酸的平衡从未解离(或未带电)到解离(或带电)的形式发生了变化。此外，根据外部葡萄糖浓度的变化，实现了对凝胶中胰岛素释放的开关调节，这表明这种新型的糖敏感凝胶在自我调节的胰岛素递送系统中具有潜在的用途。

Recently, polymeric gels which change their physicochemical properties with external stimuli have been the subject of great interest because of their potential utility as chemical valve system for controlled drug release, analytical and preparative separations, and sensor technologies. Indeed, remarkable progress has been made in the development of gels responding to physical stimuli such as heat and light. Yet, few examples are known of totally synthetic gels responding to chemical stimuli, i.e., a concentration change in particular molecules in the milieu, regardless of their wide applicability as described above. More specifically, development of sugar-responsive gels may give a great impetus to construct a self-regulating insulin-delivery system, mimicking the function of β-cells in pancreas, for the treatment of diabetes. In this research project, totally synthetic polymer gels responding to external glucose concentration was firstly prepared. The gel was composed of polymer strands showing lower critical solution temperature, such as poly (N-isopropylacrylamide) (PNIPAAm), with a small quantity of phenylboronic acid as glucose-sensing moieties. Repeated volume phase transition of the gel was demonstrated under microscopy equipped with a video monitor at isothermal condition with a change in glucose concentration due to the shift in the equilibrium of phenylboronic acid between the undissociated (or uncharged) and the dissociated (or charged) form through complexation with glucose. Further, on-off regulation of insulin release from the gel was achieved responding to a change in external glucose concentration, indicating a potential utility of this novel type of glyco-sensitive gel in self-regulated insulin delivery systems.