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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

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

Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands (T.G., L.B., M.v.d.B., K.T., A.-M.v.L., C.R.-S., D.K.F.M., K.P., R.J.K.); Kreatech Biotechnology B.V., Amsterdam, The Netherlands (K.T., M.L., F.O.); Departments of Medical and Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary (G.K., L.Ö.); and Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, The Netherlands (R.J.K.)

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 -smooth muscle actin (SMA) 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 SMA 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.

Address correspondence to: Dr. Robbert J. Kok, Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands. E-mail: r.j.kok{at}pharm.uu.nl

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