RNAi-based therapeutics approaches holds a big promise for clinical translation. However, siRNAs are very weak and highly susceptible to degradation by nucleases. Nanoparticle delivery systems and chemical modifications of small interfering RNA (siRNA) can enhance efficient intracellular delivery and resistance to degradation for various siRNAs resulting in an increase in their clinical therapeutic potential. Here, we hypothesized that DOPC nanoparticles incorporated with a chemically fluoro phosphorodithioate (2`F-PS2) modified-PTGER3 siRNA will enhance the stability, prolong the silencing effect in vitro and increase the anti-tumoral effect when is combined with cisplatin in vivo. We screened 51 different chemically modified PTGER3-siRNAs which have 2'-F-PS2 or 2'-O-methyl modification on selectively protected nuclease-sensitive sites. We determined PTGER3 gene expression after siRNA-2'-F-PS2 or 2'-O-methyl modified mediated silencing, stability, time-response silencing effect and the therapeutic effect in xenograft OC in vivo model. We demonstrated that siRNA-2'-F-PS2 prolong the stability for more than 24 hours and enhance the silencing for more than 96 hours. Moreover, we found that PTGER3-silencing effect can control the expression of CFTR multidrug resistant pump by regulating ERK-ELK1-ETS1-CFTR axis, resulting in an increase of the cisplatin uptake, decreased the tumor-associated angiogenesis and tumor growth in xenograft OC in vivo model. SiRNA-PTGER3-2'-F-PS2 modification increase the stability and time-response silencing effect, leading to a synergistic anti-tumor in combination with cisplatin in ovarian cancer models.
Citation Format: Emine Bayraktar, Cristian Rodriguez-Aguayo, Zahid Siddik, Gabriel Lopez-Berestein. Delivery of 2`F-PS2 PTGER3 siRNA-DOPC enhances anti-tumoral activity in cisplatin resistant ovarian cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2066. doi:10.1158/1538-7445.AM2017-2066