Abstract 2139: RNA nanoparticles as a two-in-one siRNA delivery carrier synergistically suppress drug-resistance cancer via combination therapy with doxorubicin

Abstract

Abstract To overcome multi-drug resistance (MDR) caused by malfunction of genes in chemotherapy, we synthesize RNA nanoparticles (RNA NPs) as a “two-in-one” siRNA delivery system for MDR1 siRNA and BCL2 siRNA by using rolling circle transcription and base-pairing with folate-DNA-cholesterol fragments. The resulting RNA nanoparticles (Dsi RNPs), which contain multiple tandem copies of two siRNA sequences, form the self-assembled structure with about 100 nm of diameter, and simultaneously suppress pump and non-pump phenotypes in the same cancer cells. Using Dsi RNPs, we show that there exists an optimal time point within the window of time at which the synchronous silencing of MDR1 and BCL2 gene markedly enhances the chemosensitivity of MDR cancer cells to doxorubicin. Accordingly, a two-step sequential treatment of MDR cancer cells with Dsi RNPs and doxorubicin leads to the optimal synergistic cancer suppression. Finally, we demonstrate that such a synergism is attributed to the synchronous silencing of both genes, as well as to the precisely controlled timings of drugs and Dsi RNPs treatment. RNA NPs exhibit the folate receptor-specific cellular uptake, lowering the risk of severe adverse side effects. Also, RNA NPs do not induce innate immunostimulatory response and their highly condensed structure reveals the enhanced stability against nuclease attack in bloodstream. Therefore, RNA NPs delivery system provides an alternative tool as a two-in-one siRNA carrier that is suitable for the spatial-temporal synchronization of double gene silencing, and also, Dsi RNPs have great potential as combination chemotherapeutics with traditional anticancer drugs for suppression of MDR cancer. Citation Format: Hyung Jun Ahn. RNA nanoparticles as a two-in-one siRNA delivery carrier synergistically suppress drug-resistance cancer via combination therapy with doxorubicin. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2139.