Rational design of cationic lipids for siRNA delivery

被引：1300

作者：

Semple, Sean C. ^{[1
]}

Akinc, Akin ^{[2
]}

Chen, Jianxin ^{[1
]}

Sandhu, Ammen P. ^{[1
]}

Mui, Barbara L. ^{[1
]}

Cho, Connie K. ^{[1
]}

Sah, Dinah W. Y. ^{[2
]}

Stebbing, Derrick ^{[1
]}

Crosley, Erin J. ^{[1
]}

Yaworski, Ed ^{[1
]}

Hafez, Ismail M. ^{[3
]}

Dorkin, J. Robert ^{[2
]}

Qin, June ^{[2
]}

Lam, Kieu ^{[1
]}

Rajeev, Kallanthottathil G. ^{[2
]}

Wong, Kim F. ^{[3
]}

Jeffs, Lloyd B. ^{[1
]}

Nechev, Lubomir ^{[2
]}

Eisenhardt, Merete L. ^{[1
]}

Jayaraman, Muthusamy ^{[2
]}

Kazem, Mikameh ^{[3
]}

Maier, Martin A. ^{[2
]}

Srinivasulu, Masuna ^{[4
]}

Weinstein, Michael J. ^{[2
]}

Chen, Qingmin ^{[2
]}

Alvarez, Rene ^{[2
]}

Barros, Scott A. ^{[2
]}

De, Soma ^{[2
]}

Klimuk, Sandra K. ^{[1
]}

Borland, Todd ^{[2
]}

Kosovrasti, Verbena ^{[2
]}

Cantley, William L. ^{[2
]}

Tam, Ying K. ^{[1
]}

Manoharan, Muthiah ^{[2
]}

Ciufolini, Marco A. ^{[4
]}

Tracy, Mark A. ^{[2
]}

de Fougerolles, Antonin ^{[2
]}

MacLachlan, Ian ^{[1
]}

Cullis, Pieter R. ^{[3
]}

Madden, Thomas D. ^{[1
]}

Hope, Michael J. ^{[1
]}

机构：

[1] Tekmira Pharmaceut, Burnaby, BC, Canada

[2] Alnylam Pharmaceut, Cambridge, MA USA

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

[4] Univ British Columbia, Dept Chem, Vancouver, BC, Canada

来源：

NATURE BIOTECHNOLOGY | 2010年 / 28卷 / 02期

关键词：

INTRACELLULAR DELIVERY; IN-VIVO; NONHUMAN-PRIMATES; MECHANISM; LIPOSOMES; DNA; ENCAPSULATION; THERAPEUTICS; BEHAVIOR; RELEASE;

D O I：

10.1038/nbt.1602

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

We adopted a rational approach to design cationic lipids for use in formulations to deliver small interfering RNA (siRNA). Starting with the ionizable cationic lipid 1,2-dilinoleyloxy-3-dimethylaminopropane (DLinDMA), a key lipid component of stable nucleic acid lipid particles (SNALP) as a benchmark, we used the proposed in vivo mechanism of action of ionizable cationic lipids to guide the design of DLinDMA-based lipids with superior delivery capacity. The best-performing lipid recovered after screening (DLin-KC2-DMA) was formulated and characterized in SNALP and demonstrated to have in vivo activity at siRNA doses as low as 0.01 mg/kg in rodents and 0.1 mg/kg in nonhuman primates. To our knowledge, this represents a substantial improvement over previous reports of in vivo endogenous hepatic gene silencing.

引用

页码：172 / U18

页数：7

共 23 条

[1] A combinatorial library of lipid-like materials for delivery of RNAi therapeutics [J].