Peptide- and Amine-Modified Glucan Particles for the Delivery of Therapeutic siRNA
Authors
Cohen, Jessica L.Shen, Yuefei
Aouadi, Myriam
Vangala, Pranitha
Tencerova, Michaela
Amano, Shinya U.
Nicoloro, Sarah M.
Yawe, Joseph
Czech, Michael P.
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2016-03-07Keywords
RNA interference therapyamphipathic peptide
glucan particle
inflammation
macrophage
siRNA delivery
small-molecule amine
Biochemistry
Medicinal and Pharmaceutical Chemistry
Medicinal Chemistry and Pharmaceutics
Molecular Biology
Metadata
Show full item recordAbstract
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 beta-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.Source
Mol Pharm. 2016 Mar 7;13(3):964-78. doi: 10.1021/acs.molpharmaceut.5b00831. Epub 2016 Feb 11. Link to article on publisher's siteDOI
10.1021/acs.molpharmaceut.5b00831Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28826PubMed ID
26815386Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1021/acs.molpharmaceut.5b00831