Coated cationic lipid-nanoparticles entrapping miR-660 inhibit tumor growth in patient-derived xenografts lung cancer models

Abstract

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.