Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells

Teresa Gonzalo, Leonie Beljaars, Marja Van De Bovenkamp, Kai Temming, Anne Miek Van Loenen, Catharina Reker-Smit, Dirk K.F. Meijer, Marie Lacombe, Frank Opdam, György Kéri, László Örfi, Klaas Poelstra, Robbert J. Kok

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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.

Original languageEnglish
Pages (from-to)856-865
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
Publication statusPublished - jún. 1 2007


ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Gonzalo, T., Beljaars, L., Van De Bovenkamp, M., Temming, K., Van Loenen, A. M., Reker-Smit, C., Meijer, D. K. F., Lacombe, M., Opdam, F., Kéri, G., Örfi, L., Poelstra, K., & Kok, R. J. (2007). Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. Journal of Pharmacology and Experimental Therapeutics, 321(3), 856-865. https://doi.org/10.1124/jpet.106.114496