The Use of Nanoparticles to Deliver Nitric Oxide to Hepatic Stellate Cells for Treating Liver Fibrosis and Portal Hypertension |
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| Authors: | Hien T. T. Duong Zhixia Dong Lin Su Cyrille Boyer Jacob George Thomas P. Davis Jianhua Wang |
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| Affiliation: | 1. Australian Centre for Nanomedicine and Centre for Advanced Macromolecular Design, School of Chemical Engineering, University of New South Wales, Sydney, Australia;2. Storr Liver Unit, Westmead Millenium Institute and Westmead Hospital, University of Sydney, Sydney, NSW, Australia;3. Shanghai First People's hospital, School of Medicine, Shanghai Jiaotong University, China;4. ARC Centre of Excellence in Convergent Bio‐Nano Science & Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia;5. Department of Chemistry, University of Warwick, Coventry, UK |
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| 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. |
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| Keywords: | drug delivery medicine nanoparticles polymers |
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