活化HSCs靶向递药系统的构建和用于肝纤维化精准治疗的研究

Liver diseases are common in clinic, and targeted therapies represent one of the most important treatment options. Current targeted therapies, however, cannot distinguish normal liver cells from diseased liver cells thus resulting in poor therapeutic efficacy and specificity. Liver fibrosis has been proven a late-stage symptom induced by varieties of liver diseases, and hepatic stellate cells (HSCs) play critical roles in the formation, progression and regeneration of liver fibrosis, which represent a potential target for liver disease treatment. Based on the overexpression of CD44 receptors in activated HSCs and hepatic cancer cells in liver diseases, we proposed to use acidic mucopolysaccharides including chondroitin sulfate (CS) and hyaluronic acid (HA) as the targeting ligands that can specifically interact with CD44 receptors. CSs and HAs with varying molecular weights and modification ratios will be synthesized and screened to develop CS/HA-modified micellar delivery systems to specifically deliver therapeutics to activated HSCs. The study will systemically investigate the development, characterization, in vitro and in vivo targetability of the micellar delivery system. A mechanistic study will be performed in elucidating the cell-specific targeting of CS/HA-modified micellar delivery systems. Moreover, the safety and therapeutic efficacy will be evaluated using appropriate animal models. In sum, the study aims to develop a delivery system to specifically deliver therapeutics to activated hepatic stellate cells to achieve precision therapy with improved therapeutic efficacy and reduced systemic toxicity in the treatment of liver fibrosis.

肝脏疾病是常见病和多发病，肝纤维化是各种肝脏疾病发生发展的共同病理过程，而活化的肝星状细胞(HSCs)在肝纤维化的形成、发展和恢复过程中发挥极其重要的作用，是药物治疗的关键靶点。目前，已有报道的肝靶向药物递送系统虽然能实现肝脏器官水平的靶向分布，却不能有效区分肝实质细胞和病变肝星状细胞，故不具备细胞水平靶向特异性。本课题根据肝星状细胞在活化状态下细胞表面的CD44受体表达异常增高这一特点，采用可与CD44受体特异性结合的酸性黏多糖（硫酸软骨素、透明质酸）为靶头，筛选其合适的分子量、侧链修饰度，包裹在磷脂/胆盐胶束载体的表面上，制备特异性靶向活化肝星状细胞的递药系统。本课题将系统研究该递药系统的构建、表征、体内外靶向性及其靶向机理、对模型动物的疗效以及初步的安全性评价，期望研究出一种能精准靶向至活化肝星状细胞的新型递药系统用于肝纤维化治疗，以提高药物疗效及降低毒副作用。

肝脏疾病是常见病和多发病，肝纤维化是各种肝脏疾病发生发展的共同病理过程，而活化的肝星状细胞(HSCs)在肝纤维化的形成、发展和恢复过程中发挥极其重要的作用，是药物治疗的关键靶点。目前，已有报道的肝靶向药物递送系统虽然能实现肝脏器官水平的靶向分布，却不能有效区分肝实质细胞和病变肝星状细胞，故不具备细胞水平靶向特异性。本课题根据肝星状细胞在活化状态下细胞表面的CD44受体表达异常增高这一特点，采用可与CD44受体特异性结合的酸性黏多糖（硫酸软骨素、透明质酸）为靶头，筛选其合适的分子量、侧链修饰度，包裹在磷脂/胆盐胶束载体的表面上，制备特异性靶向活化肝星状细胞的递药系统。本课题系统研究了该递药系统的构建、表征、体内外靶向性及其靶向机理、对模型动物的疗效以及初步的安全性评价，研究开发出一种能精准靶向至活化肝星状细胞的新型递药系统用于肝纤维化治疗，显著提高了药物疗效，并降低了毒副作用。