title: Synergistic silencing: combinations of lipid-like materials for efficacious siRNA delivery.
abstract: Despite the promise of RNA interference (RNAi) therapeutics, progress toward the clinic has been slowed by the difficulty of delivering short interfering RNA (siRNA) into cellular targets within the body. Nearly all siRNA delivery vehicles developed to date employ a single cationic or ionizable material. In order to increase the material space available for development of siRNA delivery therapeutics, this study examined the possibility of using binary combinations of ionizable lipid-like materials to synergistically achieve gene silencing. Interestingly, it was found that ineffective single lipid-like materials could be formulated together in a single delivery vehicle to induce near-complete knockdown of firefly luciferase and factor VII in HeLa cells and in mice, respectively. Microscopy experiments suggested that synergistic action resulted when combining materials that respectively mediated cellular uptake and endosomal escape, two important steps in the delivery process. Together, the data indicate that formulating lipid-like materials in combination can significantly improve siRNA delivery outcomes while increasing the material space available for therapeutic development. It is anticipated that this binary formulation strategy could be applicable to any siRNA delivery material in any target cell population that utilizes the two-step endosomal delivery pathway.
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Whitehead
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sahay
authors.forename: George Z
authors.initials: GZ
authors.lastname: Li
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Love
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Alabi
authors.forename: Minglin
authors.initials: M
authors.lastname: Ma
authors.forename: Christopher
authors.initials: C
authors.lastname: Zurenko
authors.forename: William
authors.initials: W
authors.lastname: Querbes
authors.forename: Robert S
authors.initials: RS
authors.lastname: Langer
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods*; D004357:Drug Synergism; D005260:Female; D005453:Fluorescence; D006367:HeLa Cells; D006801:Humans; D008055:Lipids / Q000737:chemistry* / Q000493:pharmacokinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004337:Drug Carriers; D008055:Lipids; D034741:RNA, Small Interfering