The improving effects on hepatic fibrosis of interferon-γ liposomes targeted to hepatic stellate cells.
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.
Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.
Qinghua
Q
Li
Zhiqiang
Z
Yan
Feng
F
Li
Weiyue
W
Lu
Jiyao
J
Wang
Chuanyong
C
Guo
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D006651:Histocytochemistry; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence; D014018:Tissue Distribution; D051598:Whole Body Imaging
D008081:Liposomes; D010456:Peptides, Cyclic; D007371:Interferon-gamma