title: The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissue.
abstract: Platelet derived growth factor (PDGF) is a key factor in the induction and progression of fibrotic diseases with the activated fibroblast as its target cell. Drug targeting to the PDGF-receptor is explored as a new approach to treat this disease. Therefore, we constructed a macromolecule with affinity for the PDGF-beta receptor by modification of albumin with a small peptide that recognises this PDGF-beta receptor. The binding of the peptide-modified albumin (pPB-HSA) to the PDGF-beta receptor was confirmed in competition studies with PDGF-BB using NIH/3T3-fibroblasts and activated hepatic stellate cells. Furthermore, pPB-HSA was able to reduce PDGF-BB-induced fibroblast proliferation in vitro, and proved to be devoid of proliferation-inducing activity itself. We assessed the distribution of pPB-HSA in vivo in two models of fibrosis and related the distribution of pPB-HSA to PDGF-beta receptor density. In rats with liver fibrosis (bile duct ligation model), pPB-HSA quickly accumulated in the liver in contrast to unmodified HSA (P<0.001). The major part of pPB-HSA in the fibrotic liver was localized in hepatic stellate cells. In rats with renal fibrosis (anti-Thy1.1 model), pPB-HSA also homed to the cells that expressed the PDGF-beta receptor, i.e. the mesangial cells in the glomeruli of the kidney. These results indicate that pPB-HSA may be applied as a macromolecular drug-carrier that accumulates specifically in cells expressing the PDGF-beta receptor, thus allowing a selective delivery of anti-fibrotic agents to these cells.
mesh_terms: D016475:3T3 Cells; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D008103:Liver Cirrhosis / Q000473:pathology*; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D012709:Serum Albumin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta