Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo

被引：1016

作者：

Jayaraman, Muthusamy ^{[1
]}

Ansell, Steven M. ^{[2
]}

Mui, Barbara L. ^{[2
]}

Tam, Ying K. ^{[2
]}

Chen, Jianxin ^{[2
]}

Du, Xinyao ^{[2
]}

Butler, David ^{[1
]}

Eltepu, Laxman ^{[1
]}

Matsuda, Shigeo ^{[1
]}

Narayanannair, Jayaprakash K. ^{[1
]}

Rajeev, Kallanthottathil G. ^{[1
]}

Hafez, Ismail M. ^{[3
]}

Akinc, Akin ^{[1
]}

Maier, Martin A. ^{[1
]}

Tracy, Mark A. ^{[1
]}

Cullis, Pieter R. ^{[3
]}

Madden, Thomas D. ^{[2
]}

Manoharan, Muthiah ^{[1
]}

Hope, Michael J. ^{[2
]}

机构：

[1] Alnylam Pharmaceut, Cambridge, MA USA

[2] AlCana Technol, Vancouver, BC, Canada

[3] Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V5Z 1M9, Canada

来源：

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION | 2012年 / 51卷 / 34期

关键词：

drug delivery; gene silencing; ionizable amino lipids; liposomes; siRNA; INTRACELLULAR DELIVERY; CATIONIC LIPIDS; THERAPEUTICS; LIPOSOMES; MECHANISM; ACIDS;

D O I：

10.1002/anie.201203263

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Special (lipid) delivery: The role of the ionizable lipid pKa in the in?vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa?value and silencing of the mouse FVII gene (FVII ED50) was found, with an optimal pKa range of 6.2-6.5 (see graph). The most potent cationic lipid from this study has ED50 levels around 0.005?mg?kg?1 in mice and less than 0.03?mg?kg?1 in non-human primates.

引用

收藏

页码：8529 / 8533

页数：5

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