Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA
Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA
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DOI：
10.1016/j.biomaterials.2011.04.047
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发表时间：
2011-08-01
期刊：
影响因子：
14
通讯作者：
Harashima, Hideyoshi
中科院分区：
文献类型：
--
作者：
Sakurai, Yu;Hatakeyama, Hiroto;Harashima, Hideyoshi
一种特异性沉默mRNA表达的siRNA是治疗包括癌症在内的许多疾病的潜在治疗剂。然而，siRNA的细胞摄取和生物利用度差仍然是临床发展的主要障碍。为了有效地递送到肿瘤组织，必须严格控制siRNA的药代动力学和细胞内运输。为了解决这一问题，我们开发了一种脂质体siRNA载体，一种多功能纳米器件（MEND）。我们在此描述了一种通过结合MEND系统和shGALA（一种促融合肽）将siRNA系统递送到肿瘤的方法。在培养细胞实验中，shgala修饰增强了封装在聚乙二醇修饰的MEND （PEG-MEND）中的siRNA的内体逃逸，导致82%的靶基因被敲除。体内系统给药澄清了shgala修饰的MEND （shGALA-MEND）在4 mg siRNA/kg体重的剂量下在肿瘤组织中显示58%的基因沉默。此外，仅观察到shGALA-MEND对肿瘤生长有显著抑制作用，未观察到躯体或肝脏毒性。鉴于上述数据，这种肽修饰的递送系统shGALA-MEND具有巨大的潜力，可以全身递送针对癌症治疗的治疗性siRNA。(C) 2011 Elsevier Ltd.版权所有。
An siRNA that specifically silences the expression of mRNA is a potential therapeutic agent for dealing with many diseases including cancer. However, the poor cellular uptake and bioavailability of siRNA remains a major obstacle to clinical development. For efficient delivery to tumor tissue, the pharmacokinetics and intracellular trafficking of siRNA must be rigorously controlled. To address this issue, we developed a liposomal siRNA carrier, a multi-functional nano device (MEND). We describe herein an approach for systemic siRNA delivery to tumors by combining the MEND system with shGALA, a fusogenic peptide. In cultured cell experiments, shGALA-modification enhanced the endosomal escape of siRNA encapsulated in a polyethylene glycol modified MEND (PEG-MEND), resulting in an 82% knockdown of the target gene. In vivo systemic administration clarified that the shGALA-modified MEND (shGALA-MEND) showed 58% gene silencing in tumor tissues at a dose of 4 mg of siRNA/kg body weight. In addition, a significant inhibition of tumor growth was observed only for the shGALA-MEND and no somatic or hepatic toxicity was observed. Given the above data, this peptide-modified delivery system, a shGALA-MEND has great potential for the systemic delivery of therapeutic siRNA aimed at cancer therapy. (C) 2011 Elsevier Ltd. All rights reserved.