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J Biol Chem, Vol. 275, Issue 17, 12743-12751, April 28, 2000
From the The key pathogenic event in liver fibrosis is the
activation of hepatic stellate cells (HSC). Consequently, new
antifibrotic therapies are directed toward an inhibition of HSC
activities. The aim of the present study was to develop a drug carrier
to HSC, which would allow cell-specific delivery of antifibrotic drugs
thus enhancing their effectiveness in vivo. We modified human serum albumin (HSA) with 10 cyclic peptide moieties recognizing collagen type VI receptors (C*GRGDSPC*, in which C* denotes the cyclizing cysteine residues) yielding pCVI-HSA. In vivo
experiments showed preferential distribution of pCVI-HSA to both
fibrotic and normal rat livers (respectively, 62 ± 6 and 75 ± 16% of the dose at 10 min after intravenous injection).
Immunohistochemical analysis demonstrated that pCVI-HSA predominantly
bound to HSC in fibrotic livers (73 ± 14%). In contrast,
endothelial cells contributed mostly to the total liver accumulation in
normal rats. In vitro studies showed that pCVI-HSA
specifically bound to rat HSC, in particular to the activated cells,
and showed internalization of pCVI-HSA by these cells. In conclusion,
pCVI-HSA may be applied as a carrier to deliver antifibrotic agents to
HSC, which may strongly enhance the effectiveness and tissue
selectivity of these drugs. This approach has the additional benefit
that such carriers may block receptors that play a putative role in the
pathogenesis of liver fibrosis.
Successful Targeting to Rat Hepatic Stellate Cells Using
Albumin Modified with Cyclic Peptides That Recognize the Collagen
Type VI Receptor*
§,,
,,,, and
Groningen University Institute for Drug
Exploration (GUIDE), Department of Pharmacokinetics and Drug Delivery,
University Centre for Pharmacy, 9713 AV Groningen, The Netherlands, the
¶ Med Klinik I, Unversität Erlangen-Nuernberg, 90154 Erlangen, Germany, and the Laboratory for Cell Biology and
Histology, Free University of Brussels, 1090 Brussels, Belgium
*
This work was supported by a grant from the Foundation of
Technical Sciences (STW), which is part of the Dutch Organization for
Scientific Research (NWO).The costs of publication of this article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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