Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid
Amelioration of cirrhotic portal hypertension by targeted cyclooxygenase-1 siRNA delivery to liver sinusoidal endothelium with polyethylenimine grafted hyaluronic acid
复制标题
通过聚乙烯亚胺移植透明质酸将靶向 cyclooxygenase-1 siRNA 递送至肝窦内皮来改善肝硬化门静脉高压
DOI：
10.1016/j.nano.2017.06.019
复制
发表时间：
2017-10-01
影响因子：
5.4
通讯作者：
Zhu, Kangshun
中科院分区：
文献类型：
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作者：
Lin, Liteng;Cai, Mingyue;Zhu, Kangshun
门脉高压（PH）是肝硬化死亡的主要原因，缺乏有效的临床治疗策略。血栓素A(2) （TXA(2)）的增加，主要来源于肝硬化肝窦内皮细胞（LSECs）中环氧化酶-1 （COX-1）的上调，导致肝内皮功能障碍和ph。因此，阻断肝硬化LSECs中COX-1途径可能有利于ph的治疗。在本研究中，合成透明质酸盐-移植聚乙烯亚胺（HA-PEI），将COX-1 siRNA靶向递送到LSECs。与非靶向PEI相比，HA-PEI介导的siRNA传递效率更高，从而导致LSECs中有效的靶向基因沉默。在体内，HA-PEI显著增加了siRNA沿肝窦壁的积累，抑制了LSECs中COX-1/TXA(2)通路的过度激活，并成功降低了肝硬化小鼠的门脉压力。这些结果突出了HA-PEI复合siRNA作为lsecs特异性纳米医学系统的潜力，可用于有效的基因治疗。版权所有。
Portal hypertension (PH), a leading cause of mortality in cirrhosis, lacks effective clinical therapeutic strategies. The increased thromboxane A(2) (TXA(2)), derived primarily from the upregulation of cyclooxygenase-1 (COX-1) in cirrhotic liver sinusoidal endothelial cells (LSECs), is responsible for hepatic endothelial dysfunction and PH. Thus, blocking the COX-1 pathway in cirrhotic LSECs may benefit the treatment of PH. In this study, hyaluronate-graft-polyethylenimine (HA-PEI) was synthesized for the targeted delivery of COX-1 siRNA to LSECs. Compared to non-targeted PEI, HA-PEI mediated much more efficient siRNA delivery, which resulted in potent targeted gene silencing in LSECs. In vivo, HA-PEI notably increased the accumulation of siRNA along the sinusoidal lining of the liver, inhibited over-activation of the COX-1/TXA(2) pathway in LSECs, and successfully reduced portal pressure in cirrhotic mice. These results highlight the potential of HA-PEI complexed siRNA to serve as a LSECs-specific nanomedical system for effective gene therapy in PH. (C) 2017 Elsevier Inc. All rights reserved.