Cyclic Arg-Gly-Asp peptide-labeled liposomes for targeting drug therapy of hepatic fibrosis in rats.
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.
Du
Shi-Lin
SL
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, 180 Fenglin Rd., Shanghai 200032, China.
Pan
Hong
H
Lu
Wei-Yue
WY
Wang
Jian
J
Wu
Jian
J
Wang
Ji-Yao
JY
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D001651:Cholestasis, Extrahepatic / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D024061:Collagen Type III / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods*; D004705:Endocytosis / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D053835:Unilamellar Liposomes / Q000737:chemistry
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D024042:Collagen Type I; D024061:Collagen Type III; D016898:Interferon-alpha; D008301:Maleimides; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010714:Phosphatidylethanolamines; D053835:Unilamellar Liposomes; C043592:maleimide; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D000410:Alanine Transaminase; D006909:Hydroxyproline