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

作者：Akinc Akin; Zumbuehl Andreas; Goldberg Michael; Leshchiner Elizaveta S; Busini Valentina; Hossain Naushad; Bacallado Sergio A; Nguyen David N; Fuller Jason; Alvarez Rene; Borodovsky Anna; Borland Todd; Constien Rainer; de Fougerolles Antonin; Dorkin J Robert; Jayaprakash K Narayanannair; Jayaraman Muthusamy; John Matthias; Koteliansky Victor; Manoharan Muthiah; Nechev Lubomir; Qin June; Racie Timothy; Raitcheva Denitza; Rajeev Kallanthottathil G; Sah Dinah W Y

来源：Nature Biotechnology, 2008, 26(5): 561-569.

DOI：10.1038/nbt1402

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.

• 出版日期2008-5