Mirna Therapeutics, Inc, Austin, Texas 78744, USA.
Cancer Res. 2010 Jul 15;70(14):5923-30. doi: 10.1158/0008-5472.CAN-10-0655. Epub 2010 Jun 22.
Tumor suppressor microRNAs (miRNA) provide a new opportunity to treat cancer. This approach, "miRNA replacement therapy," is based on the concept that the reintroduction of miRNAs depleted in cancer cells reactivates cellular pathways that drive a therapeutic response. Here, we describe the development of a therapeutic formulation using chemically synthesized miR-34a and a lipid-based delivery vehicle that blocks tumor growth in mouse models of non-small-cell lung cancer. This formulation is effective when administered locally or systemically. The antioncogenic effects are accompanied by an accumulation of miR-34a in the tumor tissue and downregulation of direct miR-34a targets. Intravenous delivery of formulated miR-34a does not induce an elevation of cytokines or liver and kidney enzymes in serum, suggesting that the formulation is well tolerated and does not induce an immune response. The data provide proof of concept for the systemic delivery of a synthetic tumor suppressor mimic, obviating obstacles associated with viral-based miRNA delivery and facilitating a rapid route for miRNA replacement therapy into the clinic.
肿瘤抑制 microRNAs（miRNA）为癌症治疗提供了新的机会。这种方法，即“miRNA 替代疗法”，基于这样的概念：在癌细胞中耗尽的 miRNA 的重新引入可重新激活驱动治疗反应的细胞途径。在这里，我们描述了一种使用化学合成的 miR-34a 和基于脂质的递药载体开发的治疗制剂，该制剂可阻止非小细胞肺癌小鼠模型中的肿瘤生长。当局部或系统给药时，该制剂均具有疗效。抗肿瘤作用伴随着 miR-34a 在肿瘤组织中的积累和直接 miR-34a 靶标的下调。静脉内给予制剂化的 miR-34a 不会引起血清中细胞因子或肝、肾功能酶的升高，这表明该制剂具有良好的耐受性，并且不会引起免疫反应。这些数据为系统递送合成肿瘤抑制模拟物提供了概念验证，避免了与基于病毒的 miRNA 递送相关的障碍，并为 miRNA 替代疗法快速进入临床提供了途径。
