A Combination RNAi-Chemotherapy Layer-by-Layer Nanoparticle for Systemic Targeting of KRAS/P53 with Cisplatin to Treat Non-Small Cell Lung Cancer.

Abstract

<b>Purpose:</b> Mutation of the Kirsten ras sarcoma viral oncogene homolog (KRAS) and loss of p53 function are commonly seen in patients with non-small cell lung cancer (NSCLC). Combining therapeutics targeting these tumor-defensive pathways with cisplatin in a single-nanoparticle platform are rarely developed in clinic.<b>Experimental Design:</b> Cisplatin was encapsulated in liposomes, which multiple polyelectrolyte layers, including siKRAS and miR-34a were built on to generate multifunctional layer-by-layer nanoparticle. Structure, size, and surface charge were characterized, in addition to <i>in vitro</i> toxicity studies. In vivo tumor targeting and therapy was investigated in an orthotopic lung cancer model by microCT, fluorescence imaging, and immunohistochemistry.<b>Results:</b> The singular nanoscale formulation, incorporating oncogene siKRAS, tumor-suppressor stimulating miR-34a, and cisplatin, has shown enhanced toxicity against lung cancer cell line, KP cell. <i>In vivo</i>, systemic delivery of the nanoparticles indicated a preferential uptake in lung of the tumor-bearing mice. Efficacy studies indicated prolonged survival of mice from the combination treatment.<b>Conclusions:</b> The combination RNA-chemotherapy in an LbL formulation provides an enhanced treatment efficacy against NSCLC, indicating promising potential in clinic. <i>Clin Cancer Res; 23(23); 7312-23. ©2017 AACR</i>.