Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-12

AUTHORS

Bryan R Meade, Khirud Gogoi, Alexander S Hamil, Caroline Palm-Apergi, Arjen van den Berg, Jonathan C Hagopian, Aaron D Springer, Akiko Eguchi, Apollo D Kacsinta, Connor F Dowdy, Asaf Presente, Peter Lönn, Manuel Kaulich, Naohisa Yoshioka, Edwige Gros, Xian-Shu Cui, Steven F Dowdy

ABSTRACT

RNA interference (RNAi) has great potential to treat human disease. However, in vivo delivery of short interfering RNAs (siRNAs), which are negatively charged double-stranded RNA macromolecules, remains a major hurdle. Current siRNA delivery has begun to move away from large lipid and synthetic nanoparticles to more defined molecular conjugates. Here we address this issue by synthesis of short interfering ribonucleic neutrals (siRNNs) whose phosphate backbone contains neutral phosphotriester groups, allowing for delivery into cells. Once inside cells, siRNNs are converted by cytoplasmic thioesterases into native, charged phosphodiester-backbone siRNAs, which induce robust RNAi responses. siRNNs have favorable drug-like properties, including high synthetic yields, serum stability and absence of innate immune responses. Unlike siRNAs, siRNNs avidly bind serum albumin to positively influence pharmacokinetic properties. Systemic delivery of siRNNs conjugated to a hepatocyte-specific targeting domain induced extended dose-dependent in vivo RNAi responses in mice. We believe that siRNNs represent a technology that will open new avenues for development of RNAi therapeutics. More... »

PAGES

1256-1261

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nbt.3078

DOI

http://dx.doi.org/10.1038/nbt.3078

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1020084657

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25402614


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