title: The use of nanoparticles to deliver nitric oxide to hepatic stellate cells for treating liver fibrosis and portal hypertension.
abstract: Polymeric nanoparticles are designed to transport and deliver nitric oxide (NO) into hepatic stellate cells (HSCs) for the potential treatment of both liver fibrosis and portal hypertension. The nanoparticles, incorporating NO donor molecules (S-nitrosoglutathione compound), are designed for liver delivery, minimizing systemic delivery of NO. The nanoparticles are decorated with vitamin A to specifically target HSCs. We demonstrate, using in vitro and in vivo experiments, that the targeted nanoparticles are taken up specifically by rat primary HSCs and the human HSC cell line accumulating in the liver. When nanoparticles, coated with vitamin A, release NO in liver cells, we find inhibition of collagen I and α-smooth muscle actin (α-SMA), fibrogenic genes associated with activated HSCs expression in primary rat liver and human activated HSCs without any obvious cytotoxic effects. Finally, NO-releasing nanoparticles targeted with vitamin A not only attenuate endothelin-1 (ET-1) which elicites HSC contraction but also acutely alleviates haemodynamic disorders in bile duct-ligated-induced portal hypertension evidenced by decreasing portal pressure (≈20%) and unchanging mean arterial pressure. This study clearly shows, for the first time, the potential for HSC targeted nanoparticle delivery of NO as a treatment for liver diseases with proven efficacy for alleviating both liver fibrosis and portal hypertension.
authors: Australian Centre for Nanomedicine and Centre for Advanced Macromolecular Design, School of Chemical Engineering, University of New South Wales, Sydney, 2052, Australia.
authors: Hien T T
authors: HT
authors: Duong
authors: Storr Liver Unit, Westmead Millenium Institute and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.|Shanghai First People's hospital, School of Medicine, Shanghai Jiaotong University, China.
authors: Zhixia
authors: Z
authors: Dong
authors: Storr Liver Unit, Westmead Millenium Institute and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
authors: Lin
authors: L
authors: Su
authors: Australian Centre for Nanomedicine and Centre for Advanced Macromolecular Design, School of Chemical Engineering, University of New South Wales, Sydney, 2052, Australia.
authors: Cyrille
authors: C
authors: Boyer
authors: Storr Liver Unit, Westmead Millenium Institute and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
authors: Jacob
authors: J
authors: George
authors: ARC Centre of Excellence in Convergent Bio-Nano Science & Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Melbourne, VIC, 3052, Australia.|Department of Chemistry, University of Warwick, Coventry, UK.
authors: Thomas P
authors: TP
authors: Davis
authors: Storr Liver Unit, Westmead Millenium Institute and Westmead Hospital, University of Sydney, Sydney, NSW, Australia.
authors: Jianhua
authors: J
authors: Wang
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006975:Hypertension, Portal / Q000188:drug therapy* / Q000503:physiopathology; D007275:Injections, Intravenous; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008856:Microscopy, Fluorescence; D053758:Nanoparticles / Q000737:chemistry*; D009569:Nitric Oxide / Q000494:pharmacology / Q000627:therapeutic use*; D010641:Phenotype; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution / Q000187:drug effects; D014801:Vitamin A / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D011108:Polymers; D014801:Vitamin A; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D003094:Collagen
keywords: drug delivery; medicine; nanoparticles; polymers