title: The antiproliferative drug doxorubicin inhibits liver fibrosis in bile duct-ligated rats and can be selectively delivered to hepatic stellate cells in vivo.
abstract: Hepatic stellate cell (HSC) proliferation is a key event in liver fibrosis; therefore, pharmacological intervention with antiproliferative drugs may result in antifibrotic effects. In this article, the antiproliferative effect of three cytostatic drugs was tested in cultured rat HSC. Subsequently, the antifibrotic potential of the most potent drug was evaluated in vivo. As a strategy to overcome drug-related toxicity, we additionally studied how to deliver this drug specifically to HSC by conjugating it to the HSC-selective drug carrier mannose-6-phosphate-modified human serum albumin (M6PHSA). We investigated the effect of cisplatin, chlorambucil, and doxorubicin (DOX) on 5-bromo-2'-deoxyuridine incorporation in cultured HSC and found DOX to be the most potent drug. Treatment of bile duct-ligated (BDL) rats with daily i.v. injections of 0.35 mg/kg DOX from day 3 to 10 after BDL reduced alpha-smooth muscle actin-stained area in liver sections from 8.5 +/- 0.8 to 5.1 +/- 0.9% (P < 0.01) and collagen-stained area from 13.1 +/- 1.3 to 8.9 +/- 1.5% (P < 0.05). DOX was coupled to M6PHSA, and the organ distribution of this construct (M6PHSA-DOX) was investigated. Twenty minutes after i.v. administration, 50 +/- 6% of the dose was present in the livers, and colocalization of M6PHSA-DOX with HSC markers was observed. In addition, in vitro studies showed selective binding of M6PHSA-DOX to activated HSC. Moreover, M6PHSA-DOX strongly attenuated HSC proliferation in vitro, indicating that active drug is released after uptake of the conjugate. DOX inhibits liver fibrosis in BDL rats, and HSC-selective targeting of this drug is possible. This may offer perspectives for the application of antiproliferative drugs for antifibrotic purposes.
authors.affiliation: Groningen University Institute for Drug Exploration (GUIDE), Department of Pharmacokinetics and Drug Delivery, University of Groningen, Groningen, The Netherlands. a.h.greupink@rug.nl
authors.forename: Rick
authors.initials: R
authors.lastname: Greupink
authors.forename: Hester I
authors.initials: HI
authors.lastname: Bakker
authors.forename: Wilma
authors.initials: W
authors.lastname: Bouma
authors.forename: Catharina
authors.initials: C
authors.lastname: Reker-Smit
authors.forename: Dirk K F
authors.initials: DK
authors.lastname: Meijer
authors.forename: Leonie
authors.initials: L
authors.lastname: Beljaars
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002779:Cholestasis / Q000150:complications*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004337:Drug Carriers / Q000493:pharmacokinetics; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000517:prevention & control*; D008297:Male; D008358:Mannose / Q000493:pharmacokinetics; D008360:Mannosephosphates / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D012709:Serum Albumin / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D008360:Mannosephosphates; D012709:Serum Albumin; C023840:mannose-bovine serum albumin conjugate; C027693:mannose-6-phosphate; D004317:Doxorubicin; D008358:Mannose