“药辅协同”响应型黄芩苷复合超分子水凝胶局部给药系统研究

The treatment of chronic osteomyelitis caused by pathogenic bacteria usually involves the implanted materials with antibiotics. However, the existing local drug delivery system has the defects of complex preparation and incomplete degradation. It not only cannot regulate the release rate, but also has no synergistic effect with drugs. In this project, we intend to fabricate of responsive puerarin/chitosan composite supramolecular hydrogel local delivery system base on “synergy of medicines and excipients” loading Chinese medicine effective component of baicalin. Using puerarin itself has antibacterial properties and bone inductivity, and chitosan with structure of amino groups, disulfide bond has responsiveness to pH and glutathione on inflammatory microenvironment, realize not only disassembly of composite supramolecular and release of puerarin, but also self-degradation of drug delivery system and drug controlled release. This project will study the relationship between the structure and property of supramolecular hydrogels, as well as the mechanism of self-degradation in the inflammatory microenvironment, drug controlled release and synergistic therapeutic effect. The innovation of this project lies in fabricating a new type of implantable supramolecular hydrogel local drug delivery system base on synergy of medicines and excipients utilizing of the supramolecular self-assembly properties of drug-induced puerarin as well as properties of chitosan with molecular enhancement and responsiveness to inflammatory microenvironment. It offers a new thinking for design and development of modernized forms of Chinese medicines.

由致病菌引起的慢性骨髓炎治疗通常是将含抗生素的药剂植入感染部位。针对传统给药系统制备方法繁琐、体内降解不完全、药物无法控释，且与药物无协同作用等不足，本项目构建负载中药有效成分黄芩苷的葛根素/壳聚糖复合超分子凝胶局部给药系统，利用葛根素的抗菌性和骨诱导性，及壳聚糖的氨基、二硫键等基团对炎症微环境的pH和谷胱甘肽的响应性，实现复合超分子的解组装、系统自降解和药物释控。研究该复合超分子凝胶结构与机械性能、响应性能的关系，以及在炎症微环境中的自降解和药物控释机理、协同治疗作用，揭示复合超分子凝胶局部给药系统的化学组成、相互作用等与炎症微环境的响应性、释药速率以及葛根素与黄岑苷对骨髓炎治疗的协同作用机理。本研究的创新点在于利用药源性葛根素的超分子自组装特性和壳聚糖的分子增强作用，以及对炎症微环境的响应性，构筑一种新型可植入“药辅协同”超分子凝胶局部给药系统，为中药剂型的设计和开发提出一条新思路。

用于慢性骨髓炎治疗的传统给药系统存在制备方法繁琐、药物无法控释，且与药物无协同治疗作用等不足。葛根素，是中药葛根的主要活性成分之一，它自组装形成的天然超分子水凝胶机械性能差，这限制了其在局部给药系统中的应用。本项目利用超分子自组装和双网络互穿原理，一步构筑壳聚糖/葛根素复合超分子水凝胶局部给药系统，实现可降解性、响应性、双重抗菌抗炎特性和药物控释。本项目已完成了壳聚糖/葛根素复合超分子水凝胶的构筑，通过流变、FTIR、HNMR、SEM、BET、MTT、Q-PCR、ELISA等对其进行了表征，结果表明复合超分子水凝胶具有良好的机械性能和触变性。葛根素自组装的纳米纤维与壳聚糖大分子相互缠绕导致复合超分子水凝胶的网络更致密，凝胶孔径为4.62 nm。降解实验和流变测试结果显示，复合超分子水凝胶具有pH响应性，其降解率随着降解介质pH值的增加而增加。抗菌实验结果表明复合超分子水凝胶对大肠杆菌和金黄色葡萄球菌具有良好的抗菌性能。以巨噬细胞RAW264.7细胞为研究对象，MTT实验和抗炎实验结果表明复合超分子水凝胶具有良好的细胞相容性，对TNF-α，IL-1β，IL-6和IL-10的表达具有一定的下调作用。以盐酸小檗碱作为模型药物，体外释药结果显示葛根素和盐酸小檗碱的释放表现为pH依赖性，其释放行为符合Weibull模型。抗菌实验表明载药复合超分子水凝胶对大肠杆菌具有明显的抑菌效果。本研究利用药源性葛根素的超分子自组装特性和壳聚糖的分子增强作用，构筑了一种“药辅协同”复合超分子水凝胶局部给药系统，为中药的现代化应用以及中药剂型的开发提供了新思路。