title: Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA.
abstract: Translation of siRNA technology into the clinic is limited by the need for improved delivery systems that target specific cell types. Macrophages are particularly attractive targets for RNAi therapy because they promote pathogenic inflammatory responses in a number of important human diseases. We previously demonstrated that a multicomponent formulation of β-1,3-d-glucan-encapsulated siRNA particles (GeRPs) can specifically and potently silence genes in mouse macrophages. A major advance would be to simplify the GeRP system by reducing the number of delivery components, thus enabling more facile manufacturing and future commercialization. Here we report the synthesis and evaluation of a simplified glucan-based particle (GP) capable of delivering siRNA in vivo to selectively silence macrophage genes. Covalent attachment of small-molecule amines and short peptides containing weak bases to GPs facilitated electrostatic interaction of the particles with siRNA and aided in the endosomal release of siRNA by the proton-sponge effect. Modified GPs were nontoxic and were efficiently internalized by macrophages in vitro. When injected intraperitoneally (i.p.), several of the new peptide-modified GPs were found to efficiently deliver siRNA to peritoneal macrophages in lean, healthy mice. In an animal model of obesity-induced inflammation, i.p. administration of one of the peptide-modified GPs (GP-EP14) bound to siRNA selectively reduced the expression of target inflammatory cytokines in the visceral adipose tissue macrophages. Decreasing adipose tissue inflammation resulted in an improvement of glucose metabolism in these metabolically challenged animals. Thus, modified GPs represent a promising new simplified system for the efficient delivery of therapeutic siRNAs specifically to phagocytic cells in vivo for modulation of inflammation responses.
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Cohen
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Yuefei
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Myriam
authors.initials: M
authors.lastname: Aouadi
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Pranitha
authors.initials: P
authors.lastname: Vangala
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Michaela
authors.initials: M
authors.lastname: Tencerova
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Shinya U
authors.initials: SU
authors.lastname: Amano
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Nicoloro
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Yawe
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
mesh_terms: D000588:Amines / Q000737:chemistry*; D000818:Animals; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D015316:Genetic Therapy; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000628:therapy; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000235:genetics / Q000628:therapy; D053495:Osteopontin / Q000037:antagonists & inhibitors* / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry*; D011509:Proteoglycans; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D047071:beta-Glucans / Q000737:chemistry*
chemical_list: D000588:Amines; D010446:Peptide Fragments; D011509:Proteoglycans; D034741:RNA, Small Interfering; C506896:Spp1 protein, mouse; D047071:beta-Glucans; D053495:Osteopontin; C010770:polysaccharide-K
keywords: RNA interference therapy; amphipathic peptide; glucan particle; inflammation; macrophage; siRNA delivery; small-molecule amine
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