Targeted delivery of siRNA against hepatitis C virus by apolipoprotein A-I-bound cationic liposomes
Targeted delivery of siRNA against hepatitis C virus by apolipoprotein A-I-bound cationic liposomes
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DOI：
10.1016/j.jhep.2008.10.029
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发表时间：
2009-03-01
影响因子：
25.7
通讯作者：
Kim, Meehyein
中科院分区：
文献类型：
--
作者：
Kim, Soo In;Shin, Duckhyang;Kim, Meehyein
背景/目的：丙型肝炎病毒是人类主要的肝脏RNA病毒之一。最近，我们开发了一种由阳离子脂质体(DTC)和载脂蛋白A-I(apo A-I)组成的DTC-Apo肝脏特异性siRNA传递技术。在此，我们研究了DTC-Apo纳米粒子是否能够系统地将siRNA转移到表达丙型肝炎病毒蛋白的小鼠肝细胞中，并有效地抑制其表达。方法：通过流体动力注射在肝控制区和α1-抗胰蛋白酶启动子元件下表达病毒结构蛋白的质粒DNA，构建瞬时丙型肝炎病毒模型。结果：静脉注射DTC-Apo/丙型肝炎病毒特异性siRNA(2 mg siRNA/kg)后，病毒基因在肝脏中的表达在第2天被抑制65-75%。通过对其正义链上的两个U序列进行2‘-ome修饰，获得了无免疫毒性的活性(在第2天被击倒95%)。值得注意的是，修饰后的siRNA在第6天仍具有基因沉默作用，而未修饰的siRNA在第4天后失去了RNAi活性。结论：DTC-Apo脂质体是一种很有潜力的转导治疗性siRNA的载体，尤其是针对丙型肝炎病毒的siRNA。(C)2008年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background/Aims: Hepatitis C virus (HCV) is one of the major human hepatic RNA viruses. Recently, we developed a liver-specific siRNA delivery technology using DTC-Apo composed of cationic liposomes (DTC) and apolipoprotein A-I (apo A-I). Here, we investigated whether DTC-Apo nanoparticles can systemically deliver siRNA into mouse hepatocytes expressing HCV proteins and inhibit their expression efficiently.Methods: A transient HCV model was constructed by hydrodynamic injection of plasmid DNA expressing viral structural proteins under hepatic control region and alpha 1-antitrypsin promoter elements. Using this model, DTC-Apo containing HCV-core-specific siRNA was intravenously injected to assess antiviral activity as well as the duration of silencing.Results: Post-administration of DTC-Apo/HCV-specific siRNA at a dose of 2 mg siRNA/kg inhibited viral gene expression by 65-75% in the liver on day 2. Improved activity (95% knockdown on day 2) without immunotoxicity was obtained by 2'-OMe-modification at two U sequences on its sense strand. Notably, the gene silencing effect of the modified siRNA was still maintained at day 6, while the unmodified one lost RNAi activity after day 4.Conclusions: Our results suggest that DTC-Apo liposome is a highly potential delivery vehicle to transfer therapeutic siRNA especially targeting HCV to the liver. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.