title: Fab'-bearing siRNA TNFα-loaded nanoparticles targeted to colonic macrophages offer an effective therapy for experimental colitis.
abstract: Patients suffering from inflammatory bowel disease (IBD) are currently treated by systemic drugs that can have significant side effects. Thus, it would be highly desirable to target TNFα siRNA (a therapeutic molecule) to the inflamed tissue. Here, we demonstrate that TNFα siRNA can be efficiently loaded into nanoparticles (NPs) made of poly (lactic acid) poly (ethylene glycol) block copolymer (PLA-PEG), and that grafting of the Fab' portion of the F4/80 Ab (Fab'-bearing) onto the NP surface via maleimide/thiol group-mediated covalent bonding improves the macrophage (MP)-targeting kinetics of the NPs to RAW264.7 cells in vitro. Direct binding was shown between MPs and the Fab'-bearing NPs. Next, we orally administered hydrogel (chitosan/alginate)-encapsulated Fab'-bearing TNFα-siRNA-loaded NPs to 3% dextran sodium sulfate (DSS)-treated mice and investigated the therapeutic effect on colitis. In vivo, the release of TNFα-siRNA-loaded NPs into the mouse colon attenuated colitis more efficiently when the NPs were covered with Fab'-bearing, compared to uncovered NPs. All DSS-induced parameters of colonic inflammation (e.g., weight loss, myeloperoxidase activity, and Iκbα accumulation) were more attenuated Fab'-bearing NPs loaded with TNFα siRNA than without the Fab'-bearing. Grafting the Fab'-bearing onto the NPs improved the kinetics of endocytosis as well as the MP-targeting ability, as indicated by flow cytometry. Collectively, our results show that Fab'-bearing PLA-PEG NPs are powerful and efficient nanosized tools for delivering siRNAs into colonic macrophages.
authors.affiliation: Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA. Electronic address: hlaroui@gsu.edu.
authors.forename: Hamed
authors.initials: H
authors.lastname: Laroui
authors.affiliation: Institute for Biomedical Sciences, USA; Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA; Veterans Affair Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Viennois
authors.affiliation: Institute for Biomedical Sciences, USA; Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA.
authors.forename: Brandon S B
authors.initials: BS
authors.lastname: Canup
authors.affiliation: Institute for Biomedical Sciences, USA; Center for Inflammation, Immunity, & Infection, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA.
authors.forename: Duke
authors.initials: D
authors.lastname: Geem
authors.affiliation: Institute for Biomedical Sciences, USA; Center for Inflammation, Immunity, & Infection, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Denning
authors.affiliation: Institute for Biomedical Sciences, USA; Department Chemistry and Biology, Center Diagnostics and Therapeutics, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA; Veterans Affair Medical Center, 1670 Clairmont Rd, Decatur, GA 30033, USA; Center for Inflammation, Immunity, & Infection, Georgia State University, 100 Piedmont Avenue, Atlanta, GA 30303, USA.
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D000906:Antibodies; D000943:Antigens, Differentiation; D007140:Immunoglobulin Fab Fragments; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C036763:monocyte-macrophage differentiation antigen; C542623:monomethoxypolyethyleneglycol-polylactide block copolymer; D011092:Polyethylene Glycols; D016264:Dextran Sulfate
keywords: DSS induced colitis; Ligand-mediated targeting; TNF secretion; Targeted siRNA release