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GalNAc Polyacrylate ACSCB article.pdf (2.2 MB)
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Triplex hybridization of siRNA with bifacial glycopolymer nucleic acid enables hepatocyte targeted silencing

preprint
revised on 15.01.2019 and posted on 15.01.2019 by Xin Xia, zhun zhou, chris desantis, John Rossi, Dennis Bong
In this manuscript, we demonstrate the utility of polyacrylates modified with both an artificial base-triple and a sugar (GalNAc) to serve as an siRNA packaging and delivery platform to hepatocytes in culture and in vivo (mice). This work is based upon our previously published finding that base-triple modified polyacrylates can triplex hybridize with oligo T/U DNA/RNA and deliver luciferase-targeted siRNA to HeLa cells engineered to express luciferase (JACS 2015). Herein, we expand on the scope of this work by employing a well-established liver-targeting ligand (GalNAc) to silence an endogenous human target, ApoB, the primary protein component of low density lipoprotein. Our platform was found to be effective in both hepatocyte (HepG2) cell culture as well as in an animal model of cardiac disease that features elevated ApoB levels. This manuscript thus validates the use of a synthetic platform that is designed to integrate both packaging via triplex hybridization with tissue-targeting ligand display. This enabling method could be useful as a new, convenient siRNA platform that accessible through scalable synthesis. Further, this platform would improve the efficiency of screening siRNA sequences for silencing efficacy using the identical glycopolymer carrier, thus alleviating the need for covalent ligand modification of each RNA substrate as typical for competing technologies.

Funding

GM111995-01A1

AI42554

AI29329

GRT00044810

DMR 1802432

History

Email Address of Submitting Author

bong.6@osu.edu

Institution

The Ohio State University

Country

USA

ORCID For Submitting Author

0000-0003-3778-9183

Declaration of Conflict of Interest

no conflict of interest noted

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