論文 - 詳細
| RRC ID | 55978 |
|---|---|
| 著者 | Sato Y, Matsui H, Sato R, Harashima H. |
| タイトル | Neutralization of negative charges of siRNA results in improved safety and efficient gene silencing activity of lipid nanoparticles loaded with high levels of siRNA. |
| ジャーナル | J Control Release |
| 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. |
| 巻・号 | 284 |
| ページ | 179-187 |
| 公開日 | 2018-8-28 |
| DOI | 10.1016/j.jconrel.2018.06.017 |
| PII | S0168-3659(18)30363-8 |
| PMID | 29936118 |
| MeSH | Animals Drug Carriers / chemistry* Female HCT116 Cells HeLa Cells Humans Lipids / chemistry* Mice, Inbred ICR Nanoparticles / chemistry* RNA Interference* RNA, Small Interfering / administration & dosage* RNA, Small Interfering / genetics RNA, Small Interfering / pharmacokinetics |
| IF | 7.901 |
| 引用数 | 12 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 4 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HeLa |