title: Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity.
abstract: One of the most significant challenges in the development of clinically viable delivery systems for RNA interference therapeutics is to understand how molecular structures influence delivery efficacy. Here, we have synthesized 1,400 degradable lipidoids and evaluate their transfection ability and structure-function activity. We show that lipidoid nanoparticles mediate potent gene knockdown in hepatocytes and immune cell populations on IV administration to mice (siRNA EC50 values as low as 0.01 mg kg(-1)). We identify four necessary and sufficient structural and pKa criteria that robustly predict the ability of nanoparticles to mediate greater than 95% protein silencing in vivo. Because these efficacy criteria can be dictated through chemical design, this discovery could eliminate our dependence on time-consuming and expensive cell culture assays and animal testing. Herein, we identify promising degradable lipidoids and describe new design criteria that reliably predict in vivo siRNA delivery efficacy without any prior biological testing.
authors: 1] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2].
authors: Kathryn A
authors: KA
authors: Whitehead
authors: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: J Robert
authors: JR
authors: Dorkin
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Arturo J
authors: AJ
authors: Vegas
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Philip H
authors: PH
authors: Chang
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Omid
authors: O
authors: Veiseh
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Jonathan
authors: J
authors: Matthews
authors: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Owen S
authors: OS
authors: Fenton
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Yunlong
authors: Y
authors: Zhang
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Karsten T
authors: KT
authors: Olejnik
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Volkan
authors: V
authors: Yesilyurt
authors: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors: Delai
authors: D
authors: Chen
authors: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, USA.
authors: Scott
authors: S
authors: Barros
authors: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, USA.
authors: Boris
authors: B
authors: Klebanov
authors: Alnylam Pharmaceuticals, 300 Third Street, Cambridge, Massachusetts 02142, USA.
authors: Tatiana
authors: T
authors: Novobrantseva
authors: 1] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [3] The Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 USA.
authors: Robert
authors: R
authors: Langer
authors: 1] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [3] The Institute for Medical Engineering and Science, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139 USA.
authors: Daniel G
authors: DG
authors: Anderson
mesh_terms: D000818:Animals; D004337:Drug Carriers; D055785:Gene Knockdown Techniques / Q000379:methods*; D022781:Hepatocytes; D007962:Leukocytes; D008055:Lipids / Q000737:chemistry*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D014162:Transfection
chemical_list: D004337:Drug Carriers; D008055:Lipids; D034741:RNA, Small Interfering