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由于其作为控制药物释放的化学阀系统、分析和制备分离以及传感器技术的潜在用途而受到极大关注。事实上，在响应物理刺激如热和光的凝胶的开发方面已经取得了显着的进展。然而，很少有完全合成的凝胶响应化学刺激的例子，即，环境中特定分子的浓度变化，而不管它们如上所述的广泛适用性。更具体地说，糖响应凝胶的开发可能会极大地推动构建一个自我调节的胰岛素递送系统，模拟胰腺中β细胞的功能，用于治疗糖尿病。本研究首次制备了对外界葡萄糖浓度响应的全合成高分子凝胶。该凝胶由具有较低临界溶解温度的聚合物链组成，例如聚（N-异丙基丙烯酰胺）（PNIPAAm），具有少量的苯基硼酸作为葡萄糖敏感部分。在配备有视频监视器的显微镜下，在等温条件下，由于苯硼酸的平衡在未解离的（或不带电的）和解离的（或带电的）形式之间的移动，通过与葡萄糖络合，在葡萄糖浓度的变化，证明了重复的体积相变的凝胶。此外，响应于外部葡萄糖浓度的变化实现了胰岛素从凝胶释放的开关调节，表明这种新型的糖敏感凝胶在自我调节胰岛素递送系统中的潜在用途。

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.