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