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Neutralization of negative charges of siRNA results in improved safety and efficient gene silencing activity of lipid nanoparticles loaded with high levels of siRNA

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Title: Neutralization of negative charges of siRNA results in improved safety and efficient gene silencing activity of lipid nanoparticles loaded with high levels of siRNA
Authors: Sato, Yusuke Browse this author →KAKEN DB
Matsui, Hideki Browse this author
Sato, Risa Browse this author
Harashima, Hideyoshi Browse this author →KAKEN DB
Keywords: Lipid nanoparticles
Short interfering RNA
Charge ratio
Therapeutic window
Issue Date: 28-Aug-2018
Publisher: Elsevier
Journal Title: Journal of controlled release
Volume: 284
Start Page: 179
End Page: 187
Publisher DOI: 10.1016/j.jconrel.2018.06.017
PMID: 29936118
Abstract: Lipid nanoparticles (LNPs) are one of the leading technologies for the in vivo delivery of short interfering RNA (siRNA). Cationic lipids are an important component for efficient endosomal escape via membrane fusion followed by release of siRNAs in cytosol where the site of action is located. A high cationic lipid/siRNA charge ratio is usually necessary for maximizing the gene silencing activity of the siRNA-loaded LNPs. However, high levels of cationic lipids are known to cause cytotoxicity through interactions with negatively charged biocomponents. A strategy for solving this dilemma is important, in terms of producing clinically applicable LNPs with a wide therapeutic window. We herein report on the development of LNPs with a high gene silencing activity and a low cationic lipid/siRNA charge ratio, which we refer to as low lipid core-nanoparticles (LLC-NPs). The negative charges of the siRNAs were neutralized by protamines, cationic proteins, to reduce the net dose of cationic lipid, YSK05, which was developed in our laboratory, for endosomal escape, resulting in preserved fusogenic activity and gene silencing activity, both in vitro and in vivo factor VII mouse model. In addition, the LLC-NPs showed an improved hepatotoxicity compared to conventional LNPs, which have a relatively higher cationic lipid/siRNA charge ratio. The concept of the LLC-NPs helps to realize clinically applicable LNPs with a wide therapeutic window and has the potential for use in various applications and for the delivery of different classes of nucleic acid.
Rights: ©2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
http://creativecommons.org/licenses/by-nc-nd/4.0/
Type: article (author version)
URI: http://hdl.handle.net/2115/75284
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 佐藤 悠介

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