title: Effectiveness of Losartan-Loaded Hyaluronic Acid (HA) Micelles for the Reduction of Advanced Hepatic Fibrosis in C3H/HeN Mice Model.
abstract: Advanced hepatic fibrosis therapy using drug-delivering nanoparticles is a relatively unexplored area. Angiotensin type 1 (AT1) receptor blockers such as losartan can be delivered to hepatic stellate cells (HSC), blocking their activation and thereby reducing fibrosis progression in the liver. In our study, we analyzed the possibility of utilizing drug-loaded vehicles such as hyaluronic acid (HA) micelles carrying losartan to attenuate HSC activation. Losartan, which exhibits inherent lipophilicity, was loaded into the hydrophobic core of HA micelles with a 19.5% drug loading efficiency. An advanced liver fibrosis model was developed using C3H/HeN mice subjected to 20 weeks of prolonged TAA/ethanol weight-adapted treatment. The cytocompatibility and cell uptake profile of losartan-HA micelles were studied in murine fibroblast cells (NIH3T3), human hepatic stellate cells (hHSC) and FL83B cells (hepatocyte cell line). The ability of these nanoparticles to attenuate HSC activation was studied in activated HSC cells based on alpha smooth muscle actin (α-sma) expression. Mice treated with oral losartan or losartan-HA micelles were analyzed for serum enzyme levels (ALT/AST, CK and LDH) and collagen deposition (hydroxyproline levels) in the liver. The accumulation of HA micelles was observed in fibrotic livers, which suggests increased delivery of losartan compared to normal livers and specific uptake by HSC. Active reduction of α-sma was observed in hHSC and the liver sections of losartan-HA micelle-treated mice. The serum enzyme levels and collagen deposition of losartan-HA micelle-treated mice was reduced significantly compared to the oral losartan group. Losartan-HA micelles demonstrated significant attenuation of hepatic fibrosis via an HSC-targeting mechanism in our in vitro and in vivo studies. These nanoparticles can be considered as an alternative therapy for liver fibrosis.
authors.affiliation: Department of Radiology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Reju George
authors.initials: RG
authors.lastname: Thomas
authors.affiliation: DKC Corporation (BioActs), Incheon, South Korea.
authors.forename: Myeong Ju
authors.initials: MJ
authors.lastname: Moon
authors.affiliation: Department of Pathology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Jo Heon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Jae Hyuk
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Radiology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Gwangju, Korea.
authors.forename: Yong Yeon
authors.initials: YY
authors.lastname: Jeong
mesh_terms: D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019808:Losartan / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D008823:Micelles
chemical_list: D004337:Drug Carriers; D008823:Micelles; D006820:Hyaluronic Acid; D003094:Collagen; D019808:Losartan