RNA interference offers the potential to treat disease at the earliest onset by selectively turning off intracellular oncogenes that drive cancer growth. However, the development of siRNA therapeutics has been limited due to the necessity to overcome numerous barriers including serum/lysosomal instability, membrane impermeability, and limited endosomal escape. While clinical successes with liver targeting have been achieved utilizing either lipid nanoparticle encapsulation or GalNAc targeting, attempts to deliver siRNA to extrahepatic targets have been largely unsuccessful. We hypothesized that siRNA delivery could be achieved in tumor cells using chemically stabilized siRNA that are conjugated to internalizing ligands. Ligands were selected based on their ability to bind receptors overexpressed on cancer cells and internalize as determined with imaging or cytotoxic drug delivery. Successful mRNA knockdown was shown in cells treated with highly stabilized siRNAs conjugated to various modalities, demonstrating that siRNA delivery was independent of modality. mRNA knockdown following treatment with siRNA conjugates required expression of targeting receptor and depended on the degree of internalization. Finally, both Centyrin- and antibody-siRNA conjugates were found to drive mRNA knockdown in tumor xenografts and anti-tumor efficacy in vivo. Overall, these data demonstrate the potential to identify groundbreaking therapeutics to silence oncogenes.

Enabling extrahepatic siRNA delivery with novel targeting ligands

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.