Successful targeting to rat hepatic stellate cells using albumin modified with cyclic peptides that recognize the collagen type VI receptor

The key pathogenic event in liver fibrosis is the activation of hepatic ste llate cells (HSC). Consequently, new antifibrotic therapies are directed to ward an inhibition of HSC activities. The aim of the present study was to d evelop a drug carrier to HSC, which would allow cell-specific delivery of a ntifibrotic drugs thus enhancing their effectiveness in vivo. We modified h uman serum albumin (HSA) with 10 cyclic peptide moieties recognizing collag en type VI receptors (C*GRGDSPC*, in which C* denotes the cyclizing cystein e residues) yielding pCVI-HSA. In vivo experiments showed preferential dist ribution 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 boun d to HSC in fibrotic livers (73 +/- 14%). In contrast, endothelial cells co ntributed mostly to the total liver accumulation in normal rats. In vitro s tudies 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 antifibrot ic agents to HSC, which may strongly enhance the effectiveness and tissue s electivity of these drugs. This approach has the additional benefit that su ch carriers may block receptors that play a putative role in the pathogenes is of liver fibrosis.