title: Lipopeptide nanoparticles for potent and selective siRNA delivery in rodents and nonhuman primates.
abstract: siRNA therapeutics have promise for the treatment of a wide range of genetic disorders. Motivated by lipoproteins, we report lipopeptide nanoparticles as potent and selective siRNA carriers with a wide therapeutic index. Lead material cKK-E12 showed potent silencing effects in mice (ED50 ∼ 0.002 mg/kg), rats (ED50 < 0.01 mg/kg), and nonhuman primates (over 95% silencing at 0.3 mg/kg). Apolipoprotein E plays a significant role in the potency of cKK-E12 both in vitro and in vivo. cKK-E12 was highly selective toward liver parenchymal cell in vivo, with orders of magnitude lower doses needed to silence in hepatocytes compared with endothelial cells and immune cells in different organs. Toxicity studies showed that cKK-E12 was well tolerated in rats at a dose of 1 mg/kg (over 100-fold higher than the ED50). To our knowledge, this is the most efficacious and selective nonviral siRNA delivery system for gene silencing in hepatocytes reported to date.
authors: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
authors: Yizhou
authors: Y
authors: Dong
authors: Kevin T
authors: KT
authors: Love
authors: J Robert
authors: JR
authors: Dorkin
authors: Sasilada
authors: S
authors: Sirirungruang
authors: Yunlong
authors: Y
authors: Zhang
authors: Delai
authors: D
authors: Chen
authors: Roman L
authors: RL
authors: Bogorad
authors: Hao
authors: H
authors: Yin
authors: Yi
authors: Y
authors: Chen
authors: Arturo J
authors: AJ
authors: Vegas
authors: Christopher A
authors: CA
authors: Alabi
authors: Gaurav
authors: G
authors: Sahay
authors: Karsten T
authors: KT
authors: Olejnik
authors: Weiheng
authors: W
authors: Wang
authors: Avi
authors: A
authors: Schroeder
authors: Abigail K R
authors: AK
authors: Lytton-Jean
authors: Daniel J
authors: DJ
authors: Siegwart
authors: Akin
authors: A
authors: Akinc
authors: Carmen
authors: C
authors: Barnes
authors: Scott A
authors: SA
authors: Barros
authors: Mary
authors: M
authors: Carioto
authors: Kevin
authors: K
authors: Fitzgerald
authors: Julia
authors: J
authors: Hettinger
authors: Varun
authors: V
authors: Kumar
authors: Tatiana I
authors: TI
authors: Novobrantseva
authors: June
authors: J
authors: Qin
authors: William
authors: W
authors: Querbes
authors: Victor
authors: V
authors: Koteliansky
authors: Robert
authors: R
authors: Langer
authors: Daniel G
authors: DG
authors: Anderson
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D020285:Cryoelectron Microscopy; D016503:Drug Delivery Systems / Q000379:methods*; D020868:Gene Silencing; D022781:Hepatocytes / Q000378:metabolism; D055666:Lipopeptides / Q000737:chemistry*; D008252:Macaca fascicularis; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000627:therapeutic use; D051381:Rats
chemical_list: D001057:Apolipoproteins E; D055666:Lipopeptides; D034741:RNA, Small Interfering
keywords: lipopeptide nanomaterials; liver genetic disorders; tissue and cell specificity; translational research