writer：Lian Xue, Yunfeng Yan,* Petra Kos, Xiaoping Chen, and Daniel J. Siegwart*
keywords：Polyethyleneimine (PEI), siRNA, Nanoparticles, Gene silencing
source：期刊
specific source：Drug Delivery and Translational Research
Issue time：2020年

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.