The preferential homing of a platelet derived growth factor receptor-recognizing macromolecule to fibroblast-like cells in fibrotic tissueBeljaars, L., Weert, B., Geerts, A., Meijer, D. K. F. & Poelstra, K., 1-Oct-2003, In : Biochem.Pharmacol.. 66, 7, p. 1307-1317 11 p.
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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-Thy 1.1 model), pPB-HSA also homed to the cells that expressed the PDGF-P 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. (C) 2003 Elsevier Inc. All rights reserved.
|Number of pages||11|
|Publication status||Published - 1-Oct-2003|
- PDGF, fibroblast, liver fibrosis, hepatic stellate cells (HSC), glomerulosclerosis, drug targeting, HEPATIC STELLATE CELLS, PROTEASE-ACTIVATED LIGAND, PDGF BETA-RECEPTOR, CYCLIC-PEPTIDES, KUPFFER CELLS, HUMAN LIVER, RAT, BINDING, GLOMERULONEPHRITIS, EXPRESSION