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
lung cancer, nanoparticles, therapy
MeSH Subject Heading
animals, apoptosis, genetic engineering, genetic therapy
Talekar, Meghna; Trivedi, Malav S.; 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. 55.