Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
Nanotechnology. 2012 Jul 5;23(26):265101. doi: 10.1088/0957-4484/23/26/265101.
No satisfactory anti-fibrotic therapies have yet been applied clinically. One of the main reasons is the inability to specifically target the responsible cells to produce an available drug concentration and the side-effects. Exploiting the key role of the activated hepatic stellate cells (HSCs) in both hepatic fibrogenesis and over-expression of platelet-derived growth factor receptor- (PDGFR- ), we constructed targeted sterically stable liposomes (SSLs) modified by a cyclic peptide (pPB) with affinity for the PDGFR- to deliver interferon (IFN)- to HSCs. The pPB-SSL-IFN- showed satisfactory size distribution. In vitro pPB-SSL could be taken up by activated HSCs. The study of tissue distribution via living-body animal imaging showed that the pPB-SSL-IFN- mostly accumulated in the liver until 24 h. Furthermore, the pPB-SSL-IFN- showed more significant remission of hepatic fibrosis. In vivo the histological Ishak stage, the semiquantitative score for collagen in fibrotic liver and the serum levels of collagen type IV-C in fibrotic rats treated with pPB-SSL-IFN- were less than those treated with SSL-IFN- , IFN- and the control group. In vitro pPB-SSL-IFN- was also more effective in suppressing activated HSC proliferation and inducing apoptosis of activated HSCs. Thus the data suggest that pPB-SSL-IFN- might be a more effective anti-fibrotic agent and a new opportunity for clinical therapy of hepatic fibrosis.
目前尚无令人满意的抗纤维化疗法应用于临床。其中一个主要原因是无法特异性地靶向负责产生有效药物浓度的细胞，同时还存在副作用。我们利用激活的肝星状细胞（HSCs）在肝纤维化和血小板衍生生长因子受体-（PDGFR-）过度表达中的关键作用，构建了经具有 PDGFR-亲和力的环肽（pPB）修饰的靶向立体稳定脂质体（SSL）来递送干扰素（IFN）至 HSCs。pPB-SSL-IFN-具有满意的粒径分布。体外实验表明 pPB-SSL 可被激活的 HSCs 摄取。通过活体动物成像研究组织分布，结果表明 pPB-SSL-IFN-在 24 小时内主要积聚在肝脏中。此外，pPB-SSL-IFN-还能更显著地缓解肝纤维化。体内实验中，用 pPB-SSL-IFN-治疗的大鼠的组织学 Ishak 分期、纤维化肝脏中胶原的半定量评分以及纤维化大鼠血清中 IV-C 型胶原的水平均低于用 SSL-IFN-、IFN-和对照组治疗的大鼠。体外实验也表明 pPB-SSL-IFN-在抑制激活的 HSC 增殖和诱导激活的 HSC 凋亡方面更有效。因此，这些数据表明 pPB-SSL-IFN-可能是一种更有效的抗纤维化药物，为肝纤维化的临床治疗提供了新的机会。
