A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth In vivo
A Nanoparticle System Specifically Designed to Deliver Short Interfering RNA Inhibits Tumor Growth In vivo
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DOI：
10.1158/0008-5472.can-08-3945
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Nagai, Ryozo
中科院分区：
文献类型：
--
作者：
Yagi, Nobuhiro;Manabe, Ichiro;Nagai, Ryozo
使用短干扰RNA （siRNA）是一种很有前途的新方法，被认为具有促进基因导向治疗快速发展的强大潜力。在这里，我们描述了一种新开发的，可全身注射的siRNA载体，“包裹体”（WS），它包含siRNA和一个阳离子脂肪感染复合物，其核心被中性脂质双分子层和亲水聚合物完全包裹。WS保护siRNA免受酶消化，在体循环中提供了较长的半衰期。此外，siRNA/WS从肿瘤内的血管渗漏到肿瘤组织中，在肿瘤组织中积累并随后转染到肿瘤细胞中。由于已知转录因子KLF5在肿瘤血管生成中起作用，我们设计了KLF5-siRNA来测试siRNA/WS的抗肿瘤活性。KLF5-siRNA/WS表现出显著的抗肿瘤活性，尽管含有对照的scramble - sirna的WS和含有KLF5-siRNA的盐水都不影响肿瘤的生长。Klf5 - sirna /WS在mRNA和蛋白水平上抑制肿瘤内Klf5的表达，显著减少血管生成，我们没有发现明显的急性或长期毒性。我们的发现支持了siRNA/WS可以用来敲除肿瘤内的特定基因，从而对癌症发挥治疗作用的观点。[癌症研究2009；69 (16): 6531 - 8]
Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the "wrapsome" (WS), which contains siRNA and a cationic lipofection complex in a core that is fully enveloped by a neutral lipid bilayer and hydrophilic polymers. WS protected siRNA from enzymatic digestion, providing a long half-life in the systemic circulation. Moreover, siRNA/WS leaked from blood vessels within tumors into the tumor tissue, where it accumulated and was subsequently transfected into the tumor cells. Because the transcription factor KLF5 is known to play a role in tumor angiogenesis, we designed KLF5-siRNA to test the antitumor activity of siRNA/WS. KLF5-siRNA/WS exhibited significant antitumor activity, although neither WS containing control scrambled-siRNA nor saline containing KLF5-siRNA affected tumor growth. KLF5-siRNA/WS inhibited Klf5 expression within tumors at both mRNA and protein levels, significantly reducing angiogenesis, and we detected no significant acute or long-term toxicity. Our findings support the idea that siRNA/WS can be used to knock down specific genes within tumors and thereby exert therapeutic effects against cancers. [Cancer Res 2009;69(16):6531-8]