A combinatorial library of lipid-like materials for delivery of RNAi therapeutics

被引：956

作者：

Akinc, Akin ^{[1
,5
]}

Zumbuehl, Andreas ^{[2
,5
]}

Goldberg, Michael ^{[3
]}

Leshchiner, Elizaveta S. ^{[5
]}

Busini, Valentina ^{[5
]}

Hossain, Naushad ^{[5
]}

Bacallado, Sergio A. ^{[5
]}

Nguyen, David N. ^{[5
]}

Fuller, Jason ^{[5
]}

Alvarez, Rene ^{[1
]}

Borodovsky, Anna ^{[1
]}

Borland, Todd ^{[1
]}

Constien, Rainer ^{[4
]}

de Fougerolles, Antonin ^{[1
]}

Dorkin, J. Robert ^{[1
]}

Jayaprakash, K. Narayanannair ^{[1
]}

Jayaraman, Muthusamy ^{[1
]}

John, Matthias ^{[4
]}

Koteliansky, Victor ^{[1
]}

Manoharan, Muthiah ^{[1
]}

Nechev, Lubomir ^{[1
]}

Qin, June ^{[1
]}

Racie, Timothy ^{[1
]}

Raitcheva, Denitza ^{[1
]}

Rajeev, Kallanthottathil G. ^{[1
]}

Sah, Dinah W. Y. ^{[1
]}

Soutschek, Juergen ^{[4
]}

Toudjarska, Ivanka ^{[1
]}

Vornlocher, Hans-Peter ^{[4
]}

Zimmermann, Tracy S. ^{[1
]}

Langer, Robert ^{[3
,5
]}

Anderson, Daniel G. ^{[5
]}

机构：

[1] Alnylam Pharmaceut Inc, Cambridge, MA 02142 USA

[2] Univ Geneva, Dept Organ Chem, CH-1211 Geneva 4, Switzerland

[3] MIT, Dept Chem, Cambridge, MA 02139 USA

[4] Alnylam Europe AG, D-95326 Kulmbach, Germany

[5] MIT, David H Koch Inst Integrat Canc Res, Dept Chem Engn, Cambridge, MA 02139 USA

来源：

NATURE BIOTECHNOLOGY | 2008年 / 26卷 / 05期

关键词：

D O I：

10.1038/nbt1402

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：

The safe and effective delivery of RNA interference (RNAi) therapeutics remains an important challenge for clinical development. The diversity of current delivery materials remains limited, in part because of their slow, multi-step syntheses. Here we describe a new class of lipid-like delivery molecules, termed lipidoids, as delivery agents for RNAi therapeutics. Chemical methods were developed to allow the rapid synthesis of a large library of over 1,200 structurally diverse lipidoids. From this library, we identified lipidoids that facilitate high levels of specific silencing of endogenous gene transcripts when formulated with either double-stranded small interfering RNA (siRNA) or single-stranded antisense 2'-O-methyl (2'-OMe) oligoribonucleotides targeting microRNA (miRNA). The safety and efficacy of lipidoids were evaluated in three animal models: mice, rats and nonhuman primates. The studies reported here suggest that these materials may have broad utility for both local and systemic delivery of RNA therapeutics.

引用

页码：561 / 569

页数：9

共 34 条

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