Glycosylated Reversible Addition-Fragmentation Chain Transfer Polymers with Varying Polyethylene Glycol Linkers Produce Different Short Interfering RNA Uptake, Gene Silencing, and Toxicity Profiles

Elizabeth G.L. Williams, Oliver E. Hutt, Tracey M. Hinton, Sophie C. Larnaudie, Tam Le, James M. Macdonald, Pathiraja Gunatillake, San H. Thang, Peter J. Duggan

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Achieving efficient and targeted delivery of short interfering (siRNA) is an important research challenge to overcome to render highly promising siRNA therapies clinically successful. Challenges exist in designing synthetic carriers for these RNAi constructs that provide protection against serum degradation, extended blood retention times, effective cellular uptake through a variety of uptake mechanisms, endosomal escape, and efficient cargo release. These challenges have resulted in a significant body of research and led to many important findings about the chemical composition and structural layout of the delivery vector for optimal gene silencing. The challenge of targeted delivery vectors remains, and strategies to take advantage of nature's self-selective cellular uptake mechanisms for specific organ cells, such as the liver, have enabled researchers to step closer to achieving this goal. In this work, we report the design, synthesis, and biological evaluation of a novel polymeric delivery vector incorporating galactose moieties to target hepatic cells through clathrin-mediated endocytosis at asialoglycoprotein receptors. An investigation into the density of carbohydrate functionality and its distance from the polymer backbone is conducted using reversible addition-fragmentation chain transfer polymerization and postpolymerization modification.

Original languageEnglish
Pages (from-to)4099-4112
Number of pages14
JournalBiomacromolecules
Volume18
Issue number12
DOIs
Publication statusPublished - 11 Dec 2017
Externally publishedYes

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