title: Combining Fluorination and Bioreducibility for Improved siRNA Polyplex Delivery.
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.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
authors.forename: Kaikai
authors.initials: K
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Fei
authors.initials: F
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
authors.forename: Zhanwei
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.
authors.forename: Minjie
authors.initials: M
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing, 210009, China.|Center for Drug Delivery and Nanomedicine, Department of Pharmaceutical Sciences, University of Nebraska Medical Center , Omaha, Nebraska 68198, United States.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-4710-861X
authors.initials: D
authors.lastname: Oupický
mesh_terms: D002460:Cell Line; D011992:Endosomes; D054879:Halogenation; D034741:RNA, Small Interfering; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering
keywords: cancer; fluorinated polymers; polyplexes; reducible polymers; siRNA delivery