title: Combination wt-p53 and MicroRNA-125b Transfection in a Genetically Engineered Lung Cancer Model Using Dual CD44/EGFR-targeting Nanoparticles.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Meghna
authors.initials: M
authors.lastname: Talekar
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.|Current address: Department of Pharmaceutical Sciences, College of Pharmacy, Nova Southeastern University, Davie, Florida, USA.
authors.forename: Malav
authors.initials: M
authors.lastname: Trivedi
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Parin
authors.initials: P
authors.lastname: Shah
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Qijun
authors.initials: Q
authors.lastname: Ouyang
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Adwait
authors.initials: A
authors.lastname: Oka
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Srujan
authors.initials: S
authors.lastname: Gandham
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000378:metabolism; D005818:Genetic Engineering; D015316:Genetic Therapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000628:therapy*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D053758:Nanoparticles / Q000737:chemistry; D009374:Neoplasms, Experimental; D010957:Plasmids / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D018960:Hyaluronan Receptors; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006820:Hyaluronic Acid; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)