基于动态共价键的葡萄糖双响应性糖聚肽纳米载体用于胰岛素的自调节释放

The intelligent carrier system can regulate the release of insulin according to the blood sugar concentration. However, the on-off release in the process of self-regulated release of insulin is based on the fast glucose response mechanism. Therefore, it is of great theoretical significance and research value to develop the carrier system of fast sugar response. In this project, oxidizable phenylboronic acid functionalized polypeptides and glycopolymers will be mixed directly into biocompatible glycopolypeptide nanoparticles based on dynamic covalent bond between phenylboronic acid and diol, and then insulin and glucose oxidase (GOx) will be loaded into the nanoparticles. Glucose double responsive nanocarriers will be obtained quickly and efficiently by adjusting the mixing ratio of the two polymers. Under hyperglycemia, the combination of glucose and phenylboronic acid will result in the change of nanocarrier structure, which will lead to the release of insulin; meanwhile, glucose will react with GOx to produce hydrogen peroxide to degrade the nanocarriers, which can also cause insulin release. The fast glucose responsivity of the nanocarriers will be studied systematically. This project will lay the important theoretic and technical foundation for expanding the application of nanocarriers in insulin delivery.

智能响应性载体体系可根据血糖浓度自调节释放胰岛素，然而胰岛素自调节释放过程中开-关释放的转换是基于快速的糖响应机制，因此开发快速糖响应的载体系统具有重要的理论意义和研究价值。本项目利用苯硼酸和二醇之间的动态共价键，将可氧化苯硼酸修饰的聚氨基酸和含糖均聚物直接混合得到生物相容性良好的糖聚肽纳米粒子，并将之同时负载胰岛素和葡萄糖氧化酶（GOx）。通过调节两聚合物的混合比例，快速高效的筛选出葡萄糖双响应性纳米载体。在高血糖条件下，葡萄糖既与苯硼酸结合，引起纳米载体结构的改变，导致胰岛素的释放；又与GOx反应产生双氧水降解载体，同时引起胰岛素的释放。系统研究纳米载体的葡萄糖响应性，筛选出具有快速葡萄糖响应的新型纳米载体，为拓展其在胰岛素投递领域中的应用奠定重要的理论和技术基础。

智能响应性载体体系可根据血糖浓度自调节释放胰岛素，然而胰岛素自调节释放过程中开-关释放的转换正是基于快速的糖响应机制，因此开发快速糖响应的载体系统具有重要的理论意义和研究价值。本项目利用苯硼酸和二醇之间的动态共价键，将可氧化苯硼酸修饰的聚合物和含糖聚合物直接混合得到生物相容性良好的含糖纳米粒子，并将之同时负载胰岛素和葡萄糖氧化酶（GOx）。通过调节两聚合物的混合比例，快速高效的筛选出葡萄糖双响应性纳米载体。在高血糖条件下，葡萄糖既与苯硼酸结合，引起纳米载体结构的改变，导致胰岛素的释放；又与GOx反应产生双氧水降解载体，同时引起胰岛素的释放。通过DLS及体外释放试验证实，与仅负载胰岛素的纳米载体相比，同时负载胰岛素和GOx的纳米载体展示出快速的葡萄糖响应特性，证实其体内应用的可行性；进一步将该纳米载体应用于糖尿病小鼠体内，可实现将小鼠血糖维持在正常范围长达14小时，证实其良好的降糖效果；同时通过细胞毒性试验、溶血试验及H&E染色试验证实该类纳米载体具有优良的生物相容性。这些研究为该类纳米载体在胰岛素投递领域中的应用奠定重要的理论和技术基础。