Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Laboratory of Experimental Therapy in Oncology, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
J Control Release. 2019 Aug 28;308:44-56. doi: 10.1016/j.jconrel.2019.07.006. Epub 2019 Jul 9.
Lung cancer is the leading cause of cancer-related deaths. Late diagnosis and inadequate therapies contribute to poor outcomes. MicroRNAs (miRNAs) are small non-coding RNAs and are involved in lung cancer development. Because miRNAs simultaneously regulate several cancer-related genes, they represent an interesting therapeutic approach for cancer treatment. We have developed Coated Cationic Lipid-nanoparticles entrapping miR-660 (CCL660) and intraperitoneally administered (1.5 mg/Kg) twice a week for four weeks into SCID mice carrying subcutaneously lung cancer Patients Derived Xenografts (PDXs). Obtained data demonstrated that miR-660 is down-regulated in lung cancer patients and that its replacement inhibited lung cancer growth by inhibiting the MDM2-P53 axis. Furthermore, systemic delivery of CCL660 increased miRNA levels in tumors and significantly reduced tumor growth in two different P53 wild-type PDXs without off-target effects. MiR-660 administration reduced cancer cells proliferation by inhibiting MDM2 and restoring P53 function and its downstream effectors such as p21. Interestingly, anti-tumoral effects of CCL660 also in P53 mutant PDXs but with a functional p21 pathway were observed. Stable miR-660 expression inhibited the capacity of H460 metastatic lung cancer cells to form lung nodules when injected intravenously into SCID mice suggesting a potential role of miR-660 in metastatic dissemination. To investigate the potential toxic effects of both miRNAs and delivery agents, an in vitro approach revealed that miR-660 replacement did not induce any changes in both mouse and human normal cells. Interestingly, lipid-nanoparticle delivery of synthetic miR-660 had no immunological off-target or acute/chronic toxic effects on immunocompetent mice. Altogether, our results highlight the potential role of coated cationic lipid-nanoparticles entrapping miR-660 in lung cancer treatment without inducing immune-related toxic effects.
肺癌是癌症相关死亡的主要原因。晚期诊断和治疗不足导致预后不良。微小 RNA（miRNA）是小的非编码 RNA，参与肺癌的发生发展。由于 miRNA 同时调节多个癌症相关基因，因此它们代表了癌症治疗的一种有趣的治疗方法。我们开发了包被阳离子脂质体纳米颗粒包封 miR-660（CCL660），并以 1.5mg/Kg 的剂量每周两次腹腔内给药，持续四周，用于携带皮下肺癌患者衍生异种移植（PDXs）的 SCID 小鼠。获得的数据表明，miR-660 在肺癌患者中下调，其替代物通过抑制 MDM2-P53 轴抑制肺癌生长。此外，CCL660 的系统给药增加了肿瘤中的 miRNA 水平，并在两种不同的 P53 野生型 PDX 中显著减少了肿瘤生长，而没有脱靶效应。miR-660 通过抑制 MDM2 和恢复 P53 功能及其下游效应物如 p21 来抑制癌细胞增殖。有趣的是，在 P53 突变型 PDX 中也观察到了 CCL660 的抗肿瘤作用，但 p21 途径具有功能。稳定的 miR-660 表达抑制了 H460 转移性肺癌细胞在静脉注射到 SCID 小鼠中形成肺结节的能力，这表明 miR-660 在转移扩散中可能发挥作用。为了研究 miRNA 和递药载体的潜在毒性作用，体外方法表明 miR-660 替代物不会引起小鼠和人正常细胞的任何变化。有趣的是，脂质纳米颗粒递送合成 miR-660 对免疫功能正常的小鼠没有免疫相关的脱靶或急性/慢性毒性作用。总之，我们的研究结果强调了包被阳离子脂质体纳米颗粒包封 miR-660 在肺癌治疗中的潜在作用，而不会引起免疫相关的毒性作用。
