Small interfering RNA delivery to the liver by intravenous administration of galactosylated cationic liposomes in mice
Small interfering RNA delivery to the liver by intravenous administration of galactosylated cationic liposomes in mice
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DOI：
10.1016/j.biomaterials.2006.11.010
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发表时间：
2007-03-01
期刊：
影响因子：
14
通讯作者：
Hashida, Mitsuru
中科院分区：
文献类型：
--
作者：
Sato, Ayumi;Takagi, Motoki;Hashida, Mitsuru
尽管小干扰RNA （siRNA）是一种潜在有用的治疗方法，可以沉默特定疾病的靶基因，但其在体内的稳定性限制了其使用。对于肝实质细胞（PC）选择性递送siRNA， siRNA与半乳糖化阳离子脂质体络合。半乳糖脂质体/siRNA复合物在血浆中表现出比裸siRNA更高的稳定性。在静脉注射半乳糖化脂质体/siRNA复合物后，siRNA不经过核酸酶消化和尿液排泄，并有效地递送到肝脏，并且在PC而不是肝脏非实质细胞（NPC）中检测到。当Ubc13- sirna与半乳糖化脂质体复合物以0.29 nmol/g的剂量给药小鼠时，内源性基因（Ubc13基因）在肝脏中的表达被抑制80%。相比之下，裸阳离子脂质体对Ubc13基因表达没有任何沉默作用。这些结果表明，半乳糖脂质体/siRNA复合物可以诱导内源性肝脏基因表达的基因沉默。半乳糖脂质体/siRNA复合物对干扰素的应答通过优化siRNA的序列来控制。此外，在任何测试条件下均未观察到半乳糖化脂质体/siRNA复合物引起的肝毒性。总之，我们证明了半乳糖脂质体在静脉给药后对肝细胞选择性基因的沉默作用。(c) 2006 Elsevier Ltd.版权所有。
Although small interfering RNA (siRNA) is a potentially useful therapeutic approach to silence the targeted gene of a particular disease, its use is limited by its stability in vivo. For the liver parenchymal cell (PC)-selective delivery of siRNA, siRNA was complexed with galactosylated cationic liposomes. Galactosylated liposomes/siRNA complex exhibited a higher stability than naked siRNA in plasma. After intravenous administration of a galactosylated liposomes/siRNA complex, the siRNA did not undergo nuclease digestion and urinary excretion and was delivered efficiently to the liver and was detected in PC rather than liver non-parenchymal cells (NPC). Endogenous gene (Ubc13 gene) expression in the liver was inhibited by 80% when Ubc13-siRNA complexed with galactosylated liposomes was administered to mice at a dose of 0.29 nmol/g. In contrast, the bare cationic liposornes did not induce any silencing effect on Ubc13 gene expression. These results indicated that galactosylated liposomes/siRNA complex could induce gene silencing of endogenous hepatic gene expression. The interferon responses by galactosylated liposomes/siRNA complex were controlled by optimization of the sequence of siRNA. Also no liver toxicity due to galactosylated liposomes/siRNA complex was observed under any of the conditions tested. In conclusion, we demonstrated the hepatocyte-selective gene silencing by galactosylated liposomes following intravenous administration. (c) 2006 Elsevier Ltd. All rights reserved.