Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles
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Mutations in KRAS and p53 signaling pathways contribute to loss of responsiveness to current therapies and a decreased survival in lung cancer. In this study, we have investigated the delivery and transfection of wild-type (wt-) p53 and microRNA-125b (miR-125b) expressing plasmid DNA, in SK-LU-1 human lung adenocarcinoma cells as well as in Kras(G12D)/p53(fl/fl) (KP) genetically engineered mouse model of lung cancer. Systemic plasmid DNA delivery with dual CD44/EGFR-targeted hyaluronic acid (HA)-based nanoparticles (NPs) resulted in a 2- to 20-fold increase in wt-p53 and miR-125b gene expression in SK-LU-1 cells. This resulted in enhanced apoptotic activity as seen with increased APAF-1 and caspase-3 gene expression. Similarly, in vivo evaluations in KP mouse model indicated successful CD44/EGFR-targeted delivery. Tumor growth inhibition and apoptotic induction were also observed with (wt-p53+miR125b) combination therapy in KP tumor model. Lastly, J774.A1 murine macrophages co-cultured with transfected SK-LU-1 cells showed a 14- to 35-fold increase in the iNOS-Arg-1 ratio, supportive of previous results demonstrating a role of miR-125b in macrophage repolarization. Overall, these results show tremendous promise of wt-p53 and miR-125b gene therapy using dual CD44/EGFR-targeting HA NP vector for effective treatment of lung cancer.
Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences
animals, apoptosis, cell line, tumor, cell survival, combined modality therapy, ERBB receptors, genetic engineering, genetic therapy, humans, hyaluronan receptors, hyaluronic acid, lung neoplasms, mice, micrornas, nanoparticles, neoplasms, experimental, plasmids, proto-oncogene proteins p21(RAS), transfection, tumor suppressor protein p53
Talekar, Meghna; Trivedi, Malav; Shah, Parin; Ouyang, Qiyun; Oka, Adwait; Gandham, Srujan; and Amiji, Mansoor M., "Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles" (2016). Faculty Articles. 179.