title: In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight.
abstract: Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Dahlman
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Barnes
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Khan
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston 02115, USA.
authors.forename: Aude
authors.initials: A
authors.lastname: Thiriot
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Jhunjunwala
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Taylor E
authors.initials: TE
authors.lastname: Shaw
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Xing
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Sager
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sahay
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Speciner
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bader
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Roman L
authors.initials: RL
authors.lastname: Bogorad
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Yin
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Racie
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Dong
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: Seedorf
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Apeksha
authors.initials: A
authors.lastname: Dave
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Kamaljeet S
authors.initials: KS
authors.lastname: Sandu
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Webber
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Novobrantseva
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Ruda
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Abigail K R
authors.initials: AKR
authors.lastname: Lytton-Jean
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Levins
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, and Division of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston 02115, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Kalish
authors.affiliation: Vascular Biology Program, Children's Hospital Boston, and Division of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston 02115, USA.
authors.forename: Dayna K
authors.initials: DK
authors.lastname: Mudge
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Program, Department of Medicine, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Perez
authors.affiliation: Deparment of Biotechnology and Food Engineering, and The Russell Berrie Nanotechnology Institute, Technion Israel Institute of Technology, Haifa 3200, Israel.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Abezgauz
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Dutta
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Program, Department of Medicine, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Lynelle
authors.initials: L
authors.lastname: Smith
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Charisse
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston 02115, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Fitzgerald
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
authors.affiliation: Deparment of Biotechnology and Food Engineering, and The Russell Berrie Nanotechnology Institute, Technion Israel Institute of Technology, Haifa 3200, Israel.
authors.forename: Dganit
authors.initials: D
authors.lastname: Danino
authors.affiliation: Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Program, Department of Medicine, University of Colorado School of Medicine, Aurora, USA.
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston 02115, USA.
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.affiliation: Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
authors.forename: Akin
authors.initials: A
authors.lastname: Akinc
authors.affiliation: Department of Chemical Engineering, Technion Israel Institute of Technology, Haifa 32000, Israel.
authors.forename: Avi
authors.initials: A
authors.lastname: Schroeder
authors.affiliation: Department of Microbiology and Immunology, Harvard Medical School, Boston 02115, USA.
authors.forename: Dipak
authors.initials: D
authors.lastname: Panigrahy
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Victor
authors.initials: V
authors.lastname: Kotelianski
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
mesh_terms: D000818:Animals; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D011108:Polymers / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use
chemical_list: D011108:Polymers; D034741:RNA, Small Interfering