Local Inhibition of Liver Fibrosis by Specific Delivery of a Platelet-Derived Growth Factor Kinase Inhibitor to Hepatic Stellate Cells

• Published in: The Journal of pharmacology and experimental therapeutics 2007-06, Vol.321 (3), p.856-865
• Main Authors: Gonzalo, Teresa, Beljaars, Leonie, van de Bovenkamp, Marja, Temming, Kai, van Loenen, Anne-Miek, Reker-Smit, Catharina, Meijer, Dirk K F, Lacombe, Marie, Opdam, Frank, Kéri, György, Orfi, László, Poelstra, Klaas, Kok, Robbert J
• Format: Article
• Language: English
• Subjects: Actins - genetics; Actins - metabolism; Animals; Cell Survival - drug effects; Cells, Cultured; Collagen - metabolism; Collagen Type I - genetics; Drug Delivery Systems - methods; Gene Expression - drug effects; Humans; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - drug therapy; Liver Cirrhosis, Experimental - metabolism; Liver Cirrhosis, Experimental - pathology; Male; Mannosephosphates - chemistry; Organoplatinum Compounds - chemistry; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - therapeutic use; Rats; Rats, Wistar; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Serum Albumin - chemistry
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.106.114496

Liver fibrosis is characterized by excessive proliferation and activation of hepatic stellate cells (HSC), a process in which platelet-derived growth factor (PDGF) plays an important role. Inhibition of liver fibrosis via specific delivery of a PDGF kinase inhibitor to HSC might therefore be an attractive strategy. The HSC-selective carrier mannose-6-phosphate modified human serum albumin (M6PHSA) was equipped with a tyrosine kinase inhibitor, 4-chloro- N -[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (PAP19) (an imatinib derivative), by means of the platinum-based universal linkage system (ULS). The antifibrotic activity of PAP19-M6PHSA was evaluated in culture-activated rat HSC and precision-cut liver slices from fibrotic rats. After 24-h incubation, both free inhibitor PAP19 and PAP19-M6PHSA showed potent activity, as determined by quantitative reverse transcription-polymerase chain reaction analysis of α-smooth muscle actin (αSMA) and procollagen 1a1. Next, we examined the organ distribution and antifibrotic activity of PAP19-M6PHSA in bile duct-ligated (BDL) rats. Male Wistar rats at day 10 after BDL were administered a single dose of PAP19-M6PHSA and sacrificed at 2 h, 1 day, or 2 days afterward. The accumulation of PAP19-M6PHSA in the liver was quantified by high-performance liquid chromatography analysis (30% of the injected dose at 2 h) and detected in the liver by staining of the carrier. Liver drug levels were sustained at 24 and 48 h after the single dose. Furthermore, PAP19-M6PHSA reduced collagen deposition (Sirius red staining) and αSMA staining of activated HSC at these time points in comparison with saline-treated rats. We therefore conclude that delivery of a PDGF-kinase inhibitor to HSC is a promising technology to attenuate liver fibrogenesis.