The Use of Nanoparticles to Deliver Nitric Oxide to Hepatic Stellate Cells for Treating Liver Fibrosis and Portal Hypertension
The Use of Nanoparticles to Deliver Nitric Oxide to Hepatic Stellate Cells for Treating Liver Fibrosis and Portal Hypertension
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DOI：
10.1002/smll.201402870
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发表时间：
2015-05-20
期刊：
影响因子：
13.3
通讯作者：
Wang, Jianhua
中科院分区：
文献类型：
--
作者：
Duong, Hien T. T.;Dong, Zhixia;Wang, Jianhua
聚合物纳米颗粒被设计为将一氧化氮（NO）运输和递送到肝星状细胞（HSC）中，用于肝纤维化和门静脉高压的潜在治疗。纳米颗粒，结合NO供体分子（S-亚硝基谷胱甘肽化合物），被设计用于肝脏递送，最大限度地减少NO的全身递送。纳米颗粒用维生素A修饰，以特异性靶向HSC。我们使用体外和体内实验证明，靶向纳米颗粒被大鼠原代HSC和在肝脏中积累的人HSC细胞系特异性吸收。当纳米颗粒，涂有维生素A，释放NO在肝细胞中，我们发现抑制胶原蛋白I和平滑肌肌动蛋白（SMA），纤维化基因与激活的HSC表达在原代大鼠肝脏和人类激活的HSC没有任何明显的细胞毒性作用。最后，以维生素A为靶向的NO释放纳米颗粒不仅减弱了内皮素-1（ET-1），其引起HSC收缩，而且还急性加重了胆管结扎诱导的门静脉高压症中的血流动力学障碍，这通过降低门静脉压（约20%）和不变的平均动脉压来证明。这项研究首次清楚地表明，HSC靶向纳米颗粒递送NO作为肝脏疾病治疗的潜力，已证明其对减轻肝纤维化和门静脉高压具有疗效。
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 -smooth muscle actin (-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 (approximate to 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.