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