title: An amino acid-based amphoteric liposomal delivery system for systemic administration of siRNA.
abstract: We demonstrate a systematic and rational approach to create a library of natural and modified, dialkylated amino acids based upon arginine for development of an efficient small interfering RNA (siRNA) delivery system. These amino acids, designated DiLA₂ compounds, in conjunction with other components, demonstrate unique properties for assembly into monodisperse, 100-nm small liposomal particles containing siRNA. We show that DiLA₂-based liposomes undergo a pH-dependent phase transition to an inverted hexagonal phase facilitating efficient siRNA release from endosomes to the cytosol. Using an arginine-based DiLA₂, cationic liposomes were prepared that provide high in vivo siRNA delivery efficiency and are well-tolerated in both cell and animal models. DiLA₂-based liposomes demonstrate a linear dose-response with an ED₅₀ of 0.1 mg/kg against liver-specific target genes in BALB/c mice.
authors.affiliation: Marina Biotech, Inc., Bothell, Washington, USA.
authors.forename: Roger C
authors.initials: RC
authors.lastname: Adami
authors.forename: Shaguna
authors.initials: S
authors.lastname: Seth
authors.forename: Pierrot
authors.initials: P
authors.lastname: Harvie
authors.forename: Rachel
authors.initials: R
authors.lastname: Johns
authors.forename: Renata
authors.initials: R
authors.lastname: Fam
authors.forename: Kathy
authors.initials: K
authors.lastname: Fosnaugh
authors.forename: Tianying
authors.initials: T
authors.lastname: Zhu
authors.forename: Ken
authors.initials: K
authors.lastname: Farber
authors.forename: Michael
authors.initials: M
authors.lastname: McCutcheon
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Goodman
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Erin
authors.initials: E
authors.lastname: Kwang
authors.forename: Michael V
authors.initials: MV
authors.lastname: Templin
authors.forename: Greg
authors.initials: G
authors.lastname: Severson
authors.forename: Tod
authors.initials: T
authors.lastname: Brown
authors.forename: Narendra
authors.initials: N
authors.lastname: Vaish
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.forename: Patrick
authors.initials: P
authors.lastname: Charmley
authors.forename: Barry
authors.initials: B
authors.lastname: Polisky
authors.forename: Michael E
authors.initials: ME
authors.lastname: Houston
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D034741:RNA, Small Interfering / Q000235:genetics*
chemical_list: D000596:Amino Acids; D008081:Liposomes; D034741:RNA, Small Interfering