聚肽参与的新型糖响应性纳米高分子药物递送体系的构建、组装及应用研究

Stability, biocompatibility, biodegradability and glucose-responsibility are currently common and key problems in the field of insulin delivery system. To these problems, this project would organically combine polypeptide with phenylborate and polycaprolactone, study and develop one class of novel green nanodrug delivery system to realize self-regulate insulin release. This project would thoroughly utilize polypeptide advantages including functional group diversity, hydrophilic-hydrophobic flexibility and polypeptide block adjusting glucose-responsibility of phenylborate unit to enhance the overall stability, glucose responsibility and practicability of the delivery system in physiological environment. Moreover, polypeptides' special self-assembly behavior without organic solvent assistant further supply one pave to develop green and safe nano drug delivery system. In addition, the introduction of polycaprolactone architecture into the glucose-responsive block as main backbone would increase the possibility of the whole delivery system degrading into low molecular weight polymer or small molecules after insulin releasing.

本申请项目在针对目前胰岛素递送体系在生理条件下普遍存在不能有效兼顾其生理环境稳定性、生物相容性、生物降解性和糖响应灵敏性的关键问题，巧妙将聚肽、苯硼酸酯和聚环己内酯三者有机结合，研究并发展一类通过聚肽片段调控聚苯硼酸酯糖响应能力，实现胰岛素自律性释放的新型绿色纳米药物递送体系。本项目充分发挥聚肽官能团多样性、亲疏水性易调节和良好的生物相容性等特点，利用聚肽极性官能团对苯硼酸酯单元的作用，提高整体递送体系在生理环境中的稳定性，糖响应功能以及生物相容性。通过聚肽无需有机溶剂辅助的独特自组装方式，发展一种绿色安全的纳米药物递送体系。另外，聚环己内酯主链结构引入到糖响应片段中进一步提高了递送体系整体生物降解能力。

本项目围绕目前研究胰岛素递送体系存在的耐盐稳定性、生物相容性、生物降解性和自律性胰岛素释放等关键科学问题，通过设计共聚单元化学结构和递送体系拓扑形态，系统探索符合需求，能有效调控苯硼酸酯结构糖响应能力的重要因素，研究了胰岛素自律性释放的新型闭环式纳米药物递送体系。通过温敏性或强疏水性单体与苯硼酸酯单体无规共聚的方式探索影响递送体系对糖浓度波动产生智能性释放行为的可能因素；将生物可降解性聚酯和Y型或刷状等聚合物拓扑结构相结合，利用不同拓扑结构的设计增大糖响应单元苯硼酸酯的局部密度，提高自律性糖响应行为以及生物相容性质；发挥聚肽-螺旋二级结构特点，通过共自组装方式构建聚肽为疏水性支架，维持在糖响应过程中递送体系整体框架，进而控制聚苯硼酸酯单元对糖浓度变化识别能力。而且，纳米递送体系中-螺旋二级结构极大的提高了整体耐盐性质。在此研究的基础上，构建了一种糖响应灵敏性强、耐盐稳定性高和生物相容性好的智能纳米递送体系，为进一步发展满足实际要求的自律性胰岛素递送体系提供了基础。