Inhibition of cell proliferation through an ATP-responsive co-delivery system of doxorubicin and Bcl-2 siRNA

Abstract

Jianxu Zhang,1,2,* Yudi Wang,2,* Jiawen Chen,2 Xiao Liang,2 Haobo Han,1,2 Yan Yang,2 Quanshun Li,1,2 Yanbo Wang1 1Department of Urology, First Hospital of Jilin University, 2Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, People’s Republic of China *These authors contributed equally to the work Abstract: Herein, DNA duplex was constructed through the hybridization of adenosine triphosphate (ATP)-responsive aptamer and its cDNA in which GC-rich motif could be used to load doxorubicin (DOX), and then, cationic polymer PEI25K was used as a carrier to simultaneously condense DOX-Duplex and Bcl-2 siRNA to prepare the ternary nanocomplex polyethylenimine (PEI)/DOX-Duplex/siRNA. The ATP concentration gradient between the cytosol and extracellular environment could achieve the stable loading of DOX in duplex and the rapid drug release in an ATP-responsive manner. Using human prostate tumor cell line PC-3 as a model, an obvious induction of cell proliferation could be detected with a cell viability of 53.3%, which was stronger than single cargo delivery, indicating the synergistic effect between these two components. The enhanced anti-proliferative effect of ternary nanocomplex could be attributed to the improved induction of cell apoptosis in a mitochondria-mediated pathway and cell-cycle arrest at the G2 phase. Overall, the ATP-responsive nanocarrier for co-delivering DOX and Bcl-2 siRNA has been demonstrated to be a smart delivery system with favorable anti-proliferative effect, especially for solving the multidrug resistance of tumors. Keywords: ATP response, aptamer, doxorubicin, Bcl-2 siRNA, anti-proliferation, synergistic effect

Keywords

• ATP response
• aptamer
• doxorubicin
• Bcl-2 siRNA
• anti-proliferation
• synergistic effect