title: Colonic gene silencing using siRNA-loaded calcium phosphate/PLGA nanoparticles ameliorates intestinal inflammation in vivo.
abstract: Cytokines and chemokines are predominant players in the progression of inflammatory bowel diseases. While systemic neutralization of these players with antibodies works well in some patients, serious contraindications and side effects have been reported. Therefore, the local interference of cytokine signaling mediated by siRNA-loaded nanoparticles might be a promising new therapeutic approach. In this study, we produced multi-shell nanoparticles consisting of a calcium phosphate (CaP) core coated with siRNA directed against pro-inflammatory mediators, encapsulated into poly(d,l-lactide-co-glycolide acid) (PLGA), and coated with a final outer layer of polyethyleneimine (PEI), for the local therapeutic treatment of colonic inflammation. In cell culture, siRNA-loaded CaP/PLGA nanoparticles exhibited a rapid cellular uptake, almost no toxicity, and an excellent in vitro gene silencing efficiency. Importantly, intrarectal application of these nanoparticles loaded with siRNA directed against TNF-α, KC or IP-10 to mice suffering from dextran sulfate sodium (DSS)-induced colonic inflammation led to a significant decrease of the target genes in colonic biopsies and mesenteric lymph nodes which was accompanied with a distinct amelioration of intestinal inflammation. Thus, this study provides evidence that the specific and local modulation of the inflammatory response by CaP/PLGA nanoparticle-mediated siRNA delivery could be a promising approach for the treatment of intestinal inflammation.
authors.affiliation: Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Germany; Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Annika
authors.initials: A
authors.lastname: Frede
authors.affiliation: Institute for Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University Duisburg-Essen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Neuhaus
authors.affiliation: Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Klopfleisch
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Walker
authors.affiliation: Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom.
authors.forename: Werner
authors.initials: W
authors.lastname: Müller
authors.affiliation: Institute for Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University Duisburg-Essen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Epple
authors.affiliation: Infection Immunology, Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Germany. Electronic address: astrid.westendorf@uk-essen.de.
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002130:Calcium Phosphates / Q000737:chemistry; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000235:genetics* / Q000276:immunology; D016264:Dextran Sulfate; D005260:Female; D020868:Gene Silencing; D007419:Intestinal Secretions / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D011094:Polyethyleneimine / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002130:Calcium Phosphates; D016207:Cytokines; D034741:RNA, Small Interfering; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011094:Polyethyleneimine; D016264:Dextran Sulfate; C020243:calcium phosphate
keywords: Delivery; Intestinal inflammation; Nanoparticles; siRNA