Suppression of lung cancer progression by biocompatible glycerol triacrylate– spermine-mediated delivery of shAkt1

Abstract

Seong-Ho Hong1,*, Ji-Eun Kim1,6,*, You-Kyoung Kim2, Arash Minai-Tehrani1, Ji-Young Shin1, Bitna Kang1, Hye-Joon Kim1, Chong-Su Cho2, Chanhee Chae3, Hu-Lin Jiang1, Myung-Haing Cho1,4–71Laboratory of Toxicology, 2Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, 3Laboratory of Pathology, College of Veterinary Medicine, 4Graduate Group of Tumor Biology, 5Center for Food and Toxicology, Seoul National University, Seoul, Korea; 6Department of Nano Fusion Technology, Graduate School of Convergence Science and Technology, 7Advanced Institute of Convergence Technology, Seoul National University, Suwon, Korea*These authors contributed equally to this workBackground: Polyethylenimine (PEI)-based nonviral gene-delivery systems are commonly employed because of their high transfection efficiency. However, the toxic nature of PEI is a significant obstacle in clinical gene therapy. In this study, we developed biocompatible glycerol triacrylate–spermine (GT–SPE) polyspermine as a nanosized gene carrier for potential lung cancer gene therapy.Methods: The GT–SPE was synthesized using the Michael addition reaction between GT and SPE. The molecular weight was characterized using gel permeability chromatography multiangle laser light scattering and the composition of the polymer was analyzed using proton nuclear magnetic resonance.Results: The GT–SPE successfully protected the DNA from nucleases. The average particle size of the GT–SPE was 121 nm with a zeta potential of +23.45 mV. The GT–SPE was found to be less toxic than PEI for various cell lines, as well as for a murine model. Finally, our results showed that the GT–SPE/small hairpin Akt1 (shAkt1) complex suppressed lung tumorigenesis in a K-rasLA1 lung cancer mice model by inducing apoptosis through the Akt signaling pathway and cell cycle arrest. Aerosol delivered GT–SPE/shAkt1, which reduced matrix metalloproteinase-9 activity and suppressed the expression levels of proliferating cell nuclear antigen, as well as vascular endothelial growth factors and CD31, which are known proliferation and angiogenesis markers, respectively.Conclusion: Our data suggest that GT–SPE may be a candidate for short hairpin-shaped RNA-based aerosol lung cancer gene therapy.Keywords: lung cancer, gene therapy, aerosol delivery, spermine