Abstract
MicroRNAs (miRNAs) and siRNAs have enormous potential as cancer therapeutics, but their effective delivery to most solid tumors has been difficult. Here, we show that a new lung-targeting nanoparticle is capable of delivering miRNA mimics and siRNAs to lung adenocarcinoma cells in vitro and to tumors in a genetically engineered mouse model of lung cancer based on activation of oncogenic Kirsten rat sarcoma viral oncogene homolog (Kras) and loss of p53 function. Therapeutic delivery of miR-34a, a p53-regulated tumor suppressor miRNA, restored miR-34a levels in lung tumors, specifically down-regulated miR-34a target genes, and slowed tumor growth. The delivery of siRNAs targeting Kras reduced Kras gene expression and MAPK signaling, increased apoptosis, and inhibited tumor growth. The combination of miR-34a and siRNA targeting Kras improved therapeutic responses over those observed with either small RNA alone, leading to tumor regression. Furthermore, nanoparticle-mediated small RNA delivery plus conventional, cisplatin-based chemotherapy prolonged survival in this model compared with chemotherapy alone. These findings demonstrate that RNA combination therapy is possible in an autochthonous model of lung cancer and provide preclinical support for the use of small RNA therapies in patients who have cancer.
Keywords:
miR-34; nanotechnology.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / therapy
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Animals
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Antineoplastic Agents / administration & dosage
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / therapy
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Cell Line, Tumor
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Cisplatin / administration & dosage
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Combined Modality Therapy
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Gene Expression
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Humans
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / therapy*
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MAP Kinase Signaling System
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Mice
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Mice, Knockout
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Mice, Transgenic
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MicroRNAs / administration & dosage
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MicroRNAs / genetics
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MicroRNAs / therapeutic use*
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Mutation
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Nanoparticles / administration & dosage
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Nanoparticles / therapeutic use
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Nanotechnology
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins p21(ras) / genetics
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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RNA, Small Interfering / administration & dosage
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RNA, Small Interfering / genetics
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RNA, Small Interfering / therapeutic use*
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / genetics
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ras Proteins / genetics
Substances
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Antineoplastic Agents
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KRAS protein, human
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MIRN34a microRNA, mouse
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MicroRNAs
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Proto-Oncogene Proteins
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RNA, Neoplasm
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RNA, Small Interfering
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Tumor Suppressor Protein p53
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)
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ras Proteins
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Cisplatin