Du Shi-Lin, Pan Hong, Lu Wei-Yue, Wang Jian, Wu Jian, Wang Ji-Yao
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China.
J Pharmacol Exp Ther. 2007 Aug;322(2):560-8. doi: 10.1124/jpet.107.122481. Epub 2007 May 17.
Targeting hepatic stellate cells (HSCs) has been challenging due to the lack of specific receptors or motifs on the cells. The aim of the present study was to develop a HSC-specific system for improving drug delivery to HSCs. The affinity of a cyclic peptide containing Arg-Gly-Asp (cRGD) to collagen type VI receptor on HSCs was examined in both in vitro and in vivo experiments. Sterically stable liposomes (SSLs) were modified with this peptide to yield a new carrier, cRGD-SSL. The targeting efficiency of this carrier in delivering interferon (IFN)-alpha1b was investigated in a rat model of liver fibrosis induced by bile duct ligation (BDL). When incubating HSCs or hepatocytes with cyclic RGD peptide, the peptide was bound preferentially to activated HSCs. Biodistribution study showed that the accumulation of cRGD peptide-labeled liposomes in HSCs isolated from BDL rats was 10-fold more than unlabeled SSLs. BDL rats receiving injections of IFN-alpha1b entrapped in cRGD-SSL exhibited significantly reduced extent of liver fibrosis compared with BDL control rats or BDL rats treated with IFN-alpha1b entrapped in SSLs. Thus, cRGD-SSL is an efficient drug carrier, which selectively targets activated HSCs and improves drug therapy for liver fibrosis to a significant extent. This liposomal formulation represents a new means of targeting drug carrier for the treatment of liver fibrosis, and it may have potential clinical applications.
由于肝星状细胞（HSCs）缺乏特异性受体或基序，靶向这些细胞一直具有挑战性。本研究的目的是开发一种HSC特异性系统，以改善药物向HSCs的递送。在体外和体内实验中均检测了含精氨酸-甘氨酸-天冬氨酸（cRGD）的环肽与HSCs上VI型胶原受体的亲和力。用该肽修饰空间稳定脂质体（SSLs），以产生一种新的载体cRGD-SSL。在胆管结扎（BDL）诱导的肝纤维化大鼠模型中研究了该载体在递送干扰素（IFN）-α1b时的靶向效率。用环RGD肽孵育HSCs或肝细胞时，该肽优先与活化的HSCs结合。生物分布研究表明，从BDL大鼠分离的HSCs中，cRGD肽标记的脂质体的积累量比未标记的SSLs多10倍。与BDL对照大鼠或用SSLs包裹的IFN-α1b处理的BDL大鼠相比，接受cRGD-SSL包裹的IFN-α1b注射的BDL大鼠肝纤维化程度显著降低。因此，cRGD-SSL是一种有效的药物载体，它选择性地靶向活化的HSCs，并在很大程度上改善了肝纤维化的药物治疗。这种脂质体制剂代表了一种治疗肝纤维化的新型靶向药物载体，可能具有潜在的临床应用价值。
