原位自组装缓控递释系统用于间质纤维化局部免疫治疗的研究

Fibrosis is a highly orchestrated pathological process, which is closely related to epithelium injury, activation of immune cells and myofibroblasts. With advances in the cellular and molecular mechanisms of fibrogenesis, immunotherapies hold great promise for the treatment of fibrosis-related diseases. To resolve delivery issues such as a lack of targetability and systemic adverse effects with present therapeutic strategies and to overcome the progression of interstitial fibrosis, this project aims to deliver small molecule drugs and biomacromoleucles locally to achieve controlled and prolonged release in vivo. Self-assembled three dimensional hydrogel networks are proposed to serve as a delivery platform for both poorly water soluble drugs and biomacromolecules: surface-modified polymeric micelles as hydrogel crosslinkers can encapsulate hydrophobic small molecules; the release of biomacromolecules can be well modulated via hydrogel network structure and the affinity with scaffold materials. To sum up, the platform material may help present chemical and biological cues in a controlled and prolonged manner to guide the repair and regeneration of interstitial healing process.

组织纤维化是一个多细胞、多因子参与的高度复杂过程，与上皮损伤、免疫细胞活化和成纤维细胞应激反应密切相关。随着对纤维化进程的细胞水平和分子水平研究的不断深入，免疫疗法有望突破抗纤维化病变治疗的瓶颈。针对现有疗法靶向递送效率差、全身毒副作用大等诸多问题，本课题提出以局部给药方式实现小分子药物和生物大分子的可控递释，这一策略将有助于抑制或逆转组织纤维化进程。选择自组装原位水凝胶为递释平台材料，采用带表面功能基的纳米胶束作为凝胶交联剂，同时实现难溶性小分子药物的载药和可控递释；大分子药物的控释可通过三维网状的水凝胶孔径和骨架亲和力进行调控。该平台材料的建立有望实现化学因素和生物学因素的可控传递，以引导间质组织的正常修复和再生。

本项目针对肾脏间质纤维化的病理生物学特点，构建了原位三维网状水凝胶实现局部给药的长效免疫治疗。通过选择高生物相容性的透明质酸为骨架材料，利用功能化纳米胶束为交联剂，实现脂溶性小分子载药、控释和凝胶交联的功能，同时利用水凝胶孔隙大小进行蛋白类药物的可控释放。同时，系统考察了骨架材料分子量、修饰度、交联度和组成比例对水凝胶理化性质、材料结构及释药行为的影响，阐明该材料体系对小分子及大分子药物释放行为的调控规律。构建单侧输尿管梗阻（UUO）的小鼠肾间质纤维化模型，合理选择小分子药物（雷公藤红素）和生物大分子药物（抗TGFβ抗体，miRNA29b），实现化学因素和生物学因素调控的局部长效可控递释，以引导肾间质组织的正常修复和再生，本研究为局部免疫疗法用于组织纤维化相关疾病的治疗提供了新方法和新思路。