Combining Fluorination and Bioreducibility for Improved siRNA Polyplex Delivery

Gang Chen, Kaikai Wang, Qi Hu, Ling Ding, Fei Yu, Zhanwei Zhou, Yiwen Zhou, Jing Li, Minjie Sun, David Oupický

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Polycations are promising vectors for the delivery of siRNA therapeutics but they often suffer from toxicity and low in vivo delivery efficacy. This study tests the hypothesis that combining fluorination and bioreducibility of polycations will overcome problems with both the toxicity and delivery efficacy. To test the hypothesis, we synthesized bioreducible (RHB) and nonreducible (NHB) poly(amido amine)s. The RHB were additionally fluorinated using reaction with heptafluorobutyric anhydride to obtain F-RHB. We found that both RHB and F-RHB showed significantly reduced cytotoxicity compared with NHB, which allowed their safe use in a wider range of doses than NHB. All three synthesized polycations formed polyplexes with siRNA. F-RHB achieved the best siRNA silencing efficacy in multiple cell lines in vitro, which was at least in part because of fluorination-induced enhancement of cellular uptake and improved endosomal escape. Lastly, F-RHB showed greatly improved Luc silencing efficacy in tumors in vivo when compared with polyplexes based on RHB, NHB, as well as control poly(ethylenimine) (PEI). This study suggests that combining fluorination with bioreducibility of polycations is a promising strategy to the design of siRNA delivery vectors with improved toxicity and in vivo activity profiles.

Original languageEnglish (US)
Pages (from-to)4457-4466
Number of pages10
JournalACS Applied Materials and Interfaces
Volume9
Issue number5
DOIs
StatePublished - Feb 8 2017

Keywords

  • cancer
  • fluorinated polymers
  • polyplexes
  • reducible polymers
  • siRNA delivery

ASJC Scopus subject areas

  • Materials Science(all)

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