Non-small cell lung cancer (NSCLC) is the main subtype of lung cancer, a leading cause of cell death. Adenocarcinoma, the most common subtype of NSCLC, is associated with mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS) and loss of p53 function. KRAS mutation is responsible for tumor formation and maintenance while loss of p53 is responsible with tumor cell proliferation, survival, drug resistance, and apoptosis. Due to the complex genetic mutation in tumor cells, cisplatin, the main chemotherapeutics for NSCLC, has limited success in clinical trials. Combination therapy comprising RNA-based therapeutics to target KRAS mutation and loss of p53 along with cisplatin is a promising approach to treat NSCLC. Herein, we report a nano-therapeutics based on layer-by-layer (LbL) approach, allowing packaging of both RNA therapeutics and cisplatin simultaneously. We showed a high loading of both therapeutics as well as a staged release <i>in vitro</i>. To demonstrate the treatment efficacy of the nano-therapeutics, we established an orthotopic lung adenocarcinoma model in nude mice. Biodistribution studies revealed that the nano-therapeutics accumulated in the lung tumor while no accumulation in lung was seen on healthy mice. Further efficacy studies demonstrated that the combination therapy approach prolonged the survival of mice significantly compared to either cisplatin or RNA therapeutics alone. Immunohistochemistry studies indicated that the synergistic effect of both cisplatin and RNAs lead to an enhanced killing effect of lung tumor thus providing an improved survival. Therefore, the combination nano-therapeutics from LbL can potentially be a targted approach for NSCLC treatment.

Kras/P53 targeted RNAi combination nano-therapeutics for treating non-small cell lung cancer

251st National Meeting (2016)

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