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PEI fluorination reduces toxicity and promotes liver-targeted siRNA delivery

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Abstract

Polyethyleneimine (PEI) has been extensively investigated as an efficient carrier for nucleic acid delivery. Yet, it suffers from a high toxicity profile that hinders clinical translation. Fluorination has proven to be a valid approach to reduce the cytotoxicity of PEI and improve the in vitro siRNA delivery potency. Hydrophobicity and lipophobicity can be controllably introduced into the side chains of PEI. However, the effect of fluorination on siRNA delivery in vivo, particularly the biodistribution of siRNA polyplex nanoparticles with fluorinated PEIs, has not been extensively explored. Here, we introduce two series of fluorinated PEIs via amidation with ethyl trifluoroacetate and perfluorobutyryl chloride. Fluorination substantially improved the performance of PEI for siRNA delivery by reducing the cytotoxicity to MDA-MB-231 cells. Importantly, fluorinated PEI enabled the major accumulation of siRNA polyplex nanoparticles in the liver while non-fluorinated PEI delivered siRNA nanoparticles mainly to the lungs after intravenous administration to mice. It is envisioned that fluorination may be an important general strategy for lowering toxicity of cationic polymers, and that the fluorination-induced alteration of biodistribution may be applicable for improved delivery to different organs.

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Funding

D.J.S. received financial support from the Cancer Prevention and Research Institute of Texas (CPRIT) (R1212), the Welch Foundation (I-1855), the American Cancer Society (RSG-17-012-01), and the Mary Kay Foundation (049-15). Y.Y. received financial support from Zhejiang Provincial Natural Science Foundation of China (LY19B040004).

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Author notes

  1. Lian Xue and Yunfeng Yan contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Lian Xue, Yunfeng Yan, Petra Kos & Daniel J. Siegwart

  2. College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, 310014, Zhejiang, China

    Yunfeng Yan & Xiaoping Chen

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  1. Lian Xue
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  2. Yunfeng Yan
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Correspondence to Daniel J. Siegwart.

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Xue, L., Yan, Y., Kos, P. et al. PEI fluorination reduces toxicity and promotes liver-targeted siRNA delivery. Drug Deliv. and Transl. Res. 11, 255–260 (2021). https://doi.org/10.1007/s13346-020-00790-9

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