双模式治疗肝纤维化的新型支化阳离子递送载体

Liver fibrosis is a scar recovery reaction that results from most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis and liver failure. A lot of researches have revealed that liver fibrosis in the early stage can be reversible. Taking active and effective anti-fibrosis therapy is the key of liver disease treatment. Nucleic acid delivery vectors could carry exogenous nucleic acid into cells to compensate gene defects or correct abnormal gene expressions to cure diseases. In this application, the branched cationic polymers will be synthesized by ring-opening polymerization of aminoglycosides and hydroxyethyl disulfide diglycidyl ether, then nitric oxide (NO) donor molecules (GSNO) and hepatic stellate cells (HSCs) targeted molecules (vitamin A) will be decorated on the polymers. Finally, a nucleic acid delivery system with multiple characteristics of targeting, dual-mode treatment and biodegradation will be constructed by combination of the cationic polymers with TGF-β1 siRNA to achieve efficient treatment of liver fibrosis. Through the research of this project, it is expected to reveal the composition-structure-property relationships and regulation mechanism between the nucleic acid delivery systems and the therapeutic nucleic acid or molecules, explore the feasibility of potential synergistic treatment, and lay a foundation for the development of novel multi-functional nucleic acid delivery vectors.

肝纤维化是慢性肝损伤后的瘢痕修复反应，可进一步发展成肝硬化及肝衰竭。早期的肝纤维化是一种可逆性病变，采取积极有效的抗肝纤维化治疗是当前慢性肝病治疗的关键。核酸递送载体可携带外源核酸进入细胞，补偿或纠正基因缺陷或表达异常，从而实现疾病治疗。本申请拟以胺基糖苷的胺基与连硫双环氧基团的开环反应构建富含可修饰基团的支化阳离子聚合物，并通过后修饰引入一氧化氮NO供体分子GSNO，肝星状细胞靶向分子维生素A，最终构建出携带转化生长因子TGF-β1 siRNA的靶向性、双模式治疗为一体的可降解核酸递送体系，实现肝纤维化的高效治疗。通过本项目的研究，有望揭示核酸递送体系与治疗核酸或治疗分子组成-结构-性能的关联性及其调控规律，探索潜在的协同治疗可行性，以及为新型多功能核酸递送载体的研制奠定基础。

肝纤维化是肝脏损伤后的一种疤痕修复反应，是肝脏疾病的一个重要节点。转化生长因子(TGFβ1)是已知最有效的促纤维化细胞因子之一，几乎参与了肝纤维化发展的所有关键方面。目前，减弱TGFβ1的促纤维化作用是一种很有前途的肝纤维化治疗方法。然而，该治疗方法应用的关键是找到一种安全、有效的靶向调控系统。本研究以肝星状细胞(HSC)靶向分子维生素A (VA)修饰的支化多氨基糖苷(SSHPT)为载体，构建了pshRNA-TGFβ1的靶向可降解核酸传递系统(SS-HPVA)。该纳米颗粒的物化性质及VA修饰使SS-HPVA具有较高的基因转染性能及对HSC细胞的特异性靶向特性。多光谱光声断层扫描和活体荧光成像证实，SS-HPVA/pshRNA-TGFβ1系统具有较好的肝靶向能力，特别是在肝纤维化模型中。在此基础上，通过无创检测和组织病理学分析证明，该体系通过下调TGFβ1的表达，对肝纤维化有较好的治疗作用。综上，该基因调控靶向传递系统有望为临床治疗肝纤维化提供一种新的策略。