Abstract
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)-α1b 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-α1b entrapped in cRGD-SSL exhibited significantly reduced extent of liver fibrosis compared with BDL control rats or BDL rats treated with IFN-α1b 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.
Footnotes
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The study was supported in part by Grant 30270595 from the National Nature Science Foundation, People's Republic of China (to J.-Y.W.). J.Wu was supported by the National Institute of Diabetes, Digestive, and Kidney Diseases Grant DK069939.
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Part of this study was presented at the Annual Meeting of the American Gastroenterology Association; 2005 May 14–19; Chicago, IL, and it was published in an abstract form in Gastroenterology1284:A15, 2005.
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Both Drs. Ji-Yao Wang and Jian Wu share the equal authorship. Dr. Jian Wu's contact information: Department of Internal Medicine, Transplant Research Program, UC Davis Medical Center, 4635 2nd Ave., Suite 1001, Sacramento, CA 95817. E-mail: jdwu{at}ucdavis.edu.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.122481.
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ABBREVIATIONS: ECM, extracellular matrix; SEC, sinusoidal endothelial cell; HSC, hepatic stellate cell; HSA, human serum albumin; M6P, mannose-6-phosphate; IFN, interferon; RGD, Arg-Gly-Asp; EPC, egg phosphatidylcholine; Chol, cholesterol; PEG, polyethylene glycol; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; NHS, N-hydroxysulfosuccinimide; MAL, maleimide; SSL, sterically stable liposome; DMEM, Dulbecco's modified Eagle's medium; FITC, fluorescein isothiocyanate; PBS, phosphate-buffered saline; AGA, Arg-Gly-Arg; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium; DAPI, 4,6-diamidino-2-phenylindole; 99mTc, Technetium-99m; BDL, bile duct ligation/ligated; ALT, alanine aminotransferase; TB, total bilirubin; RT-PCR, reverse transcriptase-polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; DLPC, dilinoleoylphosphatidylcholine; cRGD, cyclic Arg-Gly-Asp.
- Received March 9, 2007.
- Accepted May 16, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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