靶向肝星状细胞的肝纤维化治疗研究进展

Hepatic stellate cell-targeted therapy for hepatic fibrosis

肝纤维化是各种形式慢性肝损伤进展的共同病理特征.目前临床尚无有效的肝纤维化治疗药物.肝星状细胞(hepatic stellate cells,HSCs)的活化和增生是肝纤维化进展的关键步骤,是肝纤维化治疗的靶细胞.将药物选择性递送于HSCs,能够有效降低其系统不良反应.甘露糖6-磷酸酯-人血清白蛋白偶合物、维生素A及透明质酸是最常用的靶向载体.将具有抗肝纤维化活性的血管紧张素1受体阻断剂、活化素样激酶5抑制剂、小干扰RNA、肝细胞生长因子基因、一氧化氮等与靶向载体偶联,能够特异性分布于HSCs,发挥抗肝纤维化作用.

Hepatic fibrosis is the ultimate pathological feature of all forms of chronic hepatic damage.There is currently no clinical cure for advanced liver fibrosis. Activation and proliferation of hepatic stellate cells（HSCs） is a key step in the development of l i ver fibrosis, and therefore, HSCs are target cells for hepatic fibrosis treatment. Targeted delivery of drugs to activated HSCs would increase the drug concentration in the liver at the sites of active fibrogenesis and avoid undesirable systemic effects. Mannose 6-phosphate modified human serum albumin, vitamin A, and hyaluronic acid are three kinds of the most investigated carriers that deliver drugs to the activated HSCs specifically. Conjugation of these carriers with molecules with anti-fibrosis activity such as angiotensin receptor blockers, activin-like kinase 5 inhibitors, Rho-kinase inhibitors, small inter fering RNAs, hepatocyte growth factor gene, or nitrogen monoxide can lead to specific distribution and effects in HSCs. This review will focus on these preclinical developments of HSCs-targeted drug conjugates for the treatment of liver fibrosis.