2’f-OMe-phosphorodithioate modified siRNAs show increased loading into the RISC complex and enhanced anti-tumour activity

Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2’- O -Methyl (2’-OMe) MePS2 on one nucleotide that significantly enhances potency and r...

Full description

Saved in:
Bibliographic Details
Published in:Nature communications 2014-03, Vol.5, p.3459-3459
Main Authors: Wu, Sherry Y., Yang, Xianbin, Gharpure, Kshipra M., Hatakeyama, Hiroto, Egli, Martin, McGuire, Michael H., Nagaraja, Archana S., Miyake, Takahito M., Rupaimoole, Rajesha, Pecot, Chad V., Taylor, Morgan, Pradeep, Sunila, Sierant, Malgorzata, Rodriguez-Aguayo, Cristian, Choi, Hyun J., Previs, Rebecca A., Armaiz-Pena, Guillermo N., Huang, Li, Martinez, Carlos, Hassell, Tom, Ivan, Cristina, Sehgal, Vasudha, Singhania, Richa, Han, Hee-Dong, Su, Chang, Kim, Ji Hoon, Dalton, Heather J., Kowali, Chandra, Keyomarsi, Khandan, McMillan, Nigel A.J., Overwijk, Willem W., Liu, Jinsong, Lee, Ju-Seog, Baggerly, Keith A., Lopez-Berestein, Gabriel, Ram, Prahlad T., Nawrot, Barbara, Sood, Anil K.
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of phosphorodithioate (PS2) and 2’- O -Methyl (2’-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2’-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM Domain Containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumors following MePS2-modified siRNA treatment, leading to a synergistic anti-tumor effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.
ISSN:2041-1723
DOI:10.1038/ncomms4459