Abstract 3668: Multistage delivery of RNA interfering nanotherapeutics targeting the PI3K/Akt/mTOR pathway

Abstract

Abstract An enhanced understanding of underlying processes governing tumorigenesis has led to the identification of several dysregulated pathways in cancer. As an example, the PI3K/Akt/mTOR pathway has recently emerged as one of the most aberrantly activated pathways in cancer, including breast cancer, making several molecular drivers along the cascade viable targets for therapy. However, important targets, such as translation initiation factor 4E (eIF4E), the rate-limiting factor for translation that is overexpressed upon activation of the PI3K/Akt/mTOR pathway, remain “undruggable.” Therefore, specifically targeting the pathway is not possible with chemotherapeutics or repositioned agents. Presently, RNA interference via small interfering RNAs (siRNAs) has proven effective at knocking down gene expression with immense specificity, but the lack of adequate delivery strategies hinders clinical translation. We have developed mesoporous silicon-based nanotherapeutic carriers, known as multistage vectors (MSVs), rationally designed to efficiently shuttle siRNAs to tumors. The carrier is designed to house siRNA-containing nanoparticles within nanostructured pores, providing enhanced stability and prolonged release at the site of action. We recently utilized this platform for the delivery of siRNA against eiF4E in triple negative breast cancer. Characterization of siRNA loading within nanoparticles, and subsequently within MSVs, was performed. Cellular uptake of MSVs and release of fluorescently-labeled siRNA was examined via confocal microscopy in SUM159 triple negative breast cancer cells. Growth proliferation following administration of siRNA against eIF4E in SUM159, MDA-MB-468, and MDA-MB-453 triple negative breast cancer cells was determined via MTT assays. Western blot analysis was conducted to examine extent of knockdown in these cells. MSVs containing siRNA against eIF4E were intravenously administered to murine models of triple negative breast cancer and in vivo knockdown in tumor extracts was determined via western blot analysis. siRNA-containing nanoparticles demonstrated efficient loading within pores of the MSVs, likely due to electrostatic interactions. MSVs were internalized within triple negative breast cancer cells, and release of siRNA from the pores was prolonged and sustained. MSVs were able to suppress proliferation of various triple negative breast cancer cell lines, showing efficient knockdown of eIF4E. Upon administration to mice, efficient knockdown of eIF4E was observed in vivo as well. Findings from this study open several avenues for the exploration of siRNA as a therapeutic modality in breast cancer, with the delivery strategy utilized also capable of accommodating several drugs for potential combination and synergistic therapies. Citation Format: Elvin Blanco, Suhong Wu, Francisca Cara, Victor Segura-Ibarra, Funda Meric-Bernstam, Mauro Ferrari. Multistage delivery of RNA interfering nanotherapeutics targeting the PI3K/Akt/mTOR pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3668. doi:10.1158/1538-7445.AM2015-3668