Hepatic stellate cell-targeted delivery of M6P-HSA-glycyrrhetinic acid attenuates hepatic fibrogenesis in a bile duct ligation rat model

Abstract

Background/Aims: Hepatic stellate cells (HSCs) play a key role in fibrogenesis. Here, we used mannose-6-phosphate-modified human serum albumin (M6P 26 -HSA) as a selective carrier to deliver antifibrotic drug 18β-glycyrrhetinic acid (18β-GA) in experimental fibrosis animals, and tested its effect in injured liver tissues. Methods: Bile duct ligation (BDL) was performed to induce liver damage in rats. Masson's stain and immunocytochemistry were used to assess hepatic collagen deposits and uptakes of M6P26-HSA-GA in HSCs in rat livers. Gene expression profiles of procollagen type I α2, smooth muscle actin (SMA), and transforming growth factor-β1 (TGF-β1) were analysed by TaqMan and quantitative polymerase chain reaction assays. The depositions of M6P26-HSA-GA in the HSC-T6 cell line and primary HSCs were assessed by immunofluorescent staining. Results: Treatment with M6P26-HSA-GA at 10 mg/kg (three times/week for 2 weeks), but not the equivalent doses of free 18β-GA and M6P26-HSA carrier alone, could significantly attenuate collagen deposits in BDL rat liver. Masson's stain and TaqMan assay revealed significant modulation of procollagen type I α2 in the BDL-injured liver. The depositions of M6P26-HSA-GA in HSCs were revealed by immunostaining with HSA and SMA markers. M6P26-HSA bound activated HSCs in vitro and the immunoreactivity of M6P26-HSA-GA was detected in the cytoplasm and cell surface of HSCs and HSC-T6 cells. The gene transcript levels of SMA and TGF-β1 were modulated in HSC-T6 cells treated with M6P26-HSA-GA. Conclusions: The M6P26-HSA holds promise as a targeting carrier for the liver or HSCs, which may be used to deliver 18β-GA as a therapeutic agent to treat liver fibrosis. © 2007 Blackwell Munksgaard.