title: Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells.
abstract: 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 alpha-smooth muscle actin (alphaSMA) 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 alphaSMA 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.
authors: Department of Pharmacokinetics and Drug Delivery, Groningen University Institute for Drug Exploration, University of Groningen, The Netherlands.
authors: Teresa
authors: T
authors: Gonzalo
authors: Leonie
authors: L
authors: Beljaars
authors: Marja
authors: M
authors: van de Bovenkamp
authors: Kai
authors: K
authors: Temming
authors: Anne-Miek
authors: AM
authors: van Loenen
authors: Catharina
authors: C
authors: Reker-Smit
authors: Dirk K F
authors: DK
authors: Meijer
authors: Marie
authors: M
authors: Lacombe
authors: Frank
authors: F
authors: Opdam
authors: György
authors: G
authors: Kéri
authors: László
authors: L
authors: Orfi
authors: Klaas
authors: K
authors: Poelstra
authors: Robbert J
authors: RJ
authors: Kok
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008360:Mannosephosphates / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D012709:Serum Albumin / Q000737:chemistry
chemical_list: D000199:Actins; D003094:Collagen; D024042:Collagen Type I; D008360:Mannosephosphates; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D017479:Receptors, Platelet-Derived Growth Factor; D012709:Serum Albumin; C498862:Acta2 protein, rat; C027693:mannose-6-phosphate