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

Massimo Moro, Daniela Di Paolo, Massimo Milione, Giovanni Centonze, Viviana Bornaghi, Cristina Borzi, Paolo Gandellini, Patrizia Perri, Ugo Pastorino, Mirco Ponzoni, Gabriella Sozzi, Orazio Fortunato

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)44-56
Number of pages13
JournalJournal of Controlled Release
Volume308
DOIs
Publication statusPublished - Aug 28 2019

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Keywords

  • Lipid-nanoparticles
  • Lung cancer
  • microRNA
  • P53
  • Patient-derived xenografts

ASJC Scopus subject areas

  • Pharmaceutical Science

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