title: A combinatorial library of lipid-like materials for delivery of RNAi therapeutics.
abstract: 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.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.forename: Andreas
authors.initials: A
authors.lastname: Zumbuehl
authors.forename: Michael
authors.initials: M
authors.lastname: Goldberg
authors.forename: Elizaveta S
authors.initials: ES
authors.lastname: Leshchiner
authors.forename: Valentina
authors.initials: V
authors.lastname: Busini
authors.forename: Naushad
authors.initials: N
authors.lastname: Hossain
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Bacallado
authors.forename: David N
authors.initials: DN
authors.lastname: Nguyen
authors.forename: Jason
authors.initials: J
authors.lastname: Fuller
authors.forename: Rene
authors.initials: R
authors.lastname: Alvarez
authors.forename: Anna
authors.initials: A
authors.lastname: Borodovsky
authors.forename: Todd
authors.initials: T
authors.lastname: Borland
authors.forename: Rainer
authors.initials: R
authors.lastname: Constien
authors.forename: Antonin
authors.initials: A
authors.lastname: de Fougerolles
authors.forename: J Robert
authors.initials: JR
authors.lastname: Dorkin
authors.forename: K
authors.initials: K
authors.lastname: Narayanannair Jayaprakash
authors.forename: Muthusamy
authors.initials: M
authors.lastname: Jayaraman
authors.forename: Matthias
authors.initials: M
authors.lastname: John
authors.forename: Victor
authors.initials: V
authors.lastname: Koteliansky
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.forename: Lubomir
authors.initials: L
authors.lastname: Nechev
authors.forename: June
authors.initials: J
authors.lastname: Qin
authors.forename: Timothy
authors.initials: T
authors.lastname: Racie
authors.forename: Denitza
authors.initials: D
authors.lastname: Raitcheva
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.forename: Dinah W Y
authors.initials: DW
authors.lastname: Sah
authors.forename: Jürgen
authors.initials: J
authors.lastname: Soutschek
authors.forename: Ivanka
authors.initials: I
authors.lastname: Toudjarska
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Vornlocher
authors.forename: Tracy S
authors.initials: TS
authors.lastname: Zimmermann
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D008055:Lipids / Q000737:chemistry*; D012313:RNA / Q000008:administration & dosage* / Q000235:genetics*; D034622:RNA Interference
chemical_list: D004337:Drug Carriers; D008055:Lipids; D012313:RNA