title: Mechanistic study of the adjuvant effect of biodegradable nanoparticles in mucosal vaccination.
abstract: For oral vaccination, incorporation of antigens into nanoparticles has been shown to protect the antigen from degradation, but may also increase its uptake through the intestinal epithelium via M-cells. The aim of this study was to understand the mechanisms by which oral administration of antigen-loaded nanoparticles induces an immune response and to analyze the effect of the nanoparticle composition on these mechanisms. Nanoparticles made from chitosan (CS) and its N-trimethylated derivative, TMC, loaded with a model antigen ovalbumin (OVA) were prepared by ionic gelation with tripolyphosphate. Intraduodenal vaccination with OVA-loaded nanoparticles led to significantly higher antibody responses than immunization with OVA alone. TMC nanoparticles induced anti-OVA antibodies after only a priming dose. To explain these results, the interaction of nanoparticles with the intestinal epithelium was explored, in vitro, using a follicle associated epithelium model and visualized, ex vivo, using confocal laser scanning microscopy. The transport of FITC-OVA-loaded TMC nanoparticles by Caco-2 cells or follicle associated epithelium model was higher than FITC-OVA-loaded CS or PLGA nanoparticles. The association of nanoparticles with human monocyte derived dendritic cells and their effect on their maturation were determined with flow cytometry. TMC nanoparticles but not CS or PLGA nanoparticles had intrinsic adjuvant effect on DCs. In conclusion, depending on their composition, nanoparticles can increase the M-cell dependent uptake and enhance the association of the antigen with DC. In this respect, TMC nanoparticles are a promising strategy for oral vaccination.
authors.affiliation: Leiden/Amsterdam Center for Drug Research, Division of Drug Delivery Technology, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: Slütter
authors.forename: Laurence
authors.initials: L
authors.lastname: Plapied
authors.forename: Virgine
authors.initials: V
authors.lastname: Fievez
authors.forename: Maria Alonso
authors.initials: MA
authors.lastname: Sande
authors.forename: Anne
authors.initials: A
authors.lastname: des Rieux
authors.forename: Yves-Jacques
authors.initials: YJ
authors.lastname: Schneider
authors.forename: Elly
authors.initials: E
authors.lastname: Van Riet
authors.forename: Wim
authors.initials: W
authors.lastname: Jiskoot
authors.forename: Véronique
authors.initials: V
authors.lastname: Préat
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry* / Q000633:toxicity; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D048271:Chitosan / Q000737:chemistry; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry* / Q000633:toxicity; D004339:Drug Compounding; D004386:Duodenum / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity; D010316:Particle Size; D010581:Peyer's Patches / Q000187:drug effects / Q000276:immunology; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics; D013499:Surface Properties; D014612:Vaccines / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics
chemical_list: D000276:Adjuvants, Immunologic; D001672:Biocompatible Materials; D004337:Drug Carriers; C118071:N-trimethyl chitosan chloride; D014612:Vaccines; D012710:Serum Albumin, Bovine; D048271:Chitosan