Polymers modified with double-tailed fluorous compounds for efficient DNA and siRNA delivery

Significance Statement

The use of cationic polymers as non-viral vectors in gene delivery has been constrained by the compromise between the transfection efficacy and the toxicity on transfected cells. Researchers from East China Normal University, P.R. China reported a novel strategy to prepare polymers with both high transfection efficacy and minimal toxicity. The authors found that cationic polymers modified with a two-tailed fluorous ligand efficiently deliver both DNA and siRNA into cancer cells and show a lack of detectable cytotoxicity. In addition, the modified polymers exhibited high gene silencing efficacy in a tumor-bearing mice, which shows great promise in cancer gene therapy. This modification strategy works well on several cationic polymers including polyamidoamine dendrimers of different generations (generation 1, generation 2, and generation 5) and branched polyethylenimine with a low molecular weight of 1800 Da. These findings provide new insights for the design of polymeric gene vectors with excellent efficacy and safety.

About the author

Bingwei He is a postgraduate in the School of Life Sciences, East China Normal University, supervised by Professor Yiyun Cheng. She finished her undergraduate study in East China Normal University. Bingwei’s current research focused on gene and protein delivery system by using polymers.

About the author

Yiyun Cheng is a full professor of biomedical engineering at School of Life Sciences, East China Normal University. He received his PhD from University of Science and Technology of China and was a postdoctoral fellow at Washington University in St. Louis. Yiyun won the Excellent Young Scholars of NSF, and the New Century Excellent Talents in the Universities of Ministry of Education, China. He was the regional editor of Current Drug Discovery Technologies and the editorial board member of Letters in Drug Design & Discovery. Yiyun has published more than 80 peer-reviewed manuscripts on journals such as Nature Materials, Nature Communications, Chemical Reviews, Chemical Society Reviews, J. Am. Chem. Soc. and Angew. Chem. It. Ed. His research interests are focused on the biomedical applications of dendrimers and other dendritic polymers.

Journal Reference

Acta Biomater. 2015;22:111-9.

He B¹, Wang Y¹, Shao N¹, Chang H¹, Cheng Y².

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Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, PR China.
Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241, PR China. Electronic address: [email protected].

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Abstract

Cationic polymers are widely used as gene carriers, however, these polymers are usually associated with low transfection efficacy and non-negligible toxicity. Fluorination on polymers significantly improves their performances in gene delivery, but a high density of fluorous chains must be conjugated on a single polymer. Here we present a new strategy to construct fluorinated polymers with minimal fluorous chains for efficient DNA and siRNA delivery. A double-tailed fluorous compound 2-chloro-4,6-bis[(perfluorohexyl)propyloxy]-1,3,5-triazine (CBT) was conjugated on dendrimers of different generations and low molecular weight polyethylenimine via a facile synthesis. The yielding products with average numbers of 1-2 conjugated CBT moieties showed much improved EGFP and luciferase transfection efficacy compared to unmodified polymers. In addition, these polymers show high siRNA delivery efficacy on different cell lines. Among the synthesized polymers, generation 1 (G1) dendrimer modified with an average number of 1.9 CBT moieties (G1-CBT1.9) shows the highest efficacy when delivering both DNA and siRNA and its efficacy approaches that of Lipofectamine 2000. G1-CBT1.9 also shows efficient gene silencing in vivo. All of the CBT-modified polymers exhibit minimal toxicity on the cells at their optimal transfection conditions. This study provides a new strategy to design efficient fluorous polymers for DNA and siRNA delivery.

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Figure legend: Cationic polymers modified with a two-tailed fluorous ligand (a) efficiently deliver DNA (b) and siRNA (c) into cancer cells.