Rational design of cationic lipids for siRNA delivery.
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.
Semple
Sean C
SC
Tekmira Pharmaceuticals, Burnaby, British Columbia, Canada. ssemple@tekmirapharm.com
Akinc
Akin
A
Chen
Jianxin
J
Sandhu
Ammen P
AP
Mui
Barbara L
BL
Cho
Connie K
CK
Sah
Dinah W Y
DW
Stebbing
Derrick
D
Crosley
Erin J
EJ
Yaworski
Ed
E
Hafez
Ismail M
IM
Dorkin
J Robert
JR
Qin
June
J
Lam
Kieu
K
Rajeev
Kallanthottathil G
KG
Wong
Kim F
KF
Jeffs
Lloyd B
LB
Nechev
Lubomir
L
Eisenhardt
Merete L
ML
Jayaraman
Muthusamy
M
Kazem
Mikameh
M
Maier
Martin A
MA
Srinivasulu
Masuna
M
Weinstein
Michael J
MJ
Chen
Qingmin
Q
Alvarez
Rene
R
Barros
Scott A
SA
De
Soma
S
Klimuk
Sandra K
SK
Borland
Todd
T
Kosovrasti
Verbena
V
Cantley
William L
WL
Tam
Ying K
YK
Manoharan
Muthiah
M
Ciufolini
Marco A
MA
Tracy
Mark A
MA
de Fougerolles
Antonin
A
MacLachlan
Ian
I
Cullis
Pieter R
PR
Madden
Thomas D
TD
Hope
Michael J
MJ
D002412:Cations; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding / Q000379:methods*; D015195:Drug Design; D008055:Lipids / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000737:chemistry*; D014162:Transfection / Q000379:methods*
D002412:Cations; D004337:Drug Carriers; D008055:Lipids; D034741:RNA, Small Interfering