title: Nanogel vaccines targeting dendritic cells: contributions of the surface decoration and vaccine cargo on cell targeting and activation.
abstract: Dendritic cells (DCs) play crucial roles in initiating and promoting immune defences, providing a pivotal target for vaccines. Although nanoparticle/nanogel-based delivery vehicles are showing potential for delivering vaccines to the immune system, there is little information on their characteristics of interaction with DCs. While particle uptake by DCs has been shown, the mechanism of cell targeting has not been studied. Moreover, it is still unclear how particle surface decoration influences the handling of such vaccines by DCs. Accordingly, chitosan nanogels carrying a model antigen, ovalbumin (ova), were analysed for interaction with and processing by DCs. Nanogel surfaces decorated with alginate (alg) or mannosylated alginate (alg-man), were used for targeting particular DC receptors. DC uptake of particles was observed, being dependent on endosomal-based processes. Inhibiting PI3-kinase or lipid raft activities impaired the uptake, which was only reduced, indicating the involvement of more than one endocytic pathway; notably, this was observed with both nanogel-delivered or free ova. Importantly, surface decoration of particles was less influential on particle uptake, contrasting with the ova cargo which played the major role. Such influence of the vaccine cargo has to date been largely ignored. When receptors interacting directly with ova were blocked, this altered the uptake of alg-nanogels and alg-man-nanogels carrying ova. The nanogels did have an influential role, in that modulation of DC functional activity owed more to the nanogel structure. Using an in vitro restimulation assay with ova-specific lymphocytes, nanogel-delivered and free ova were similarly effective at inducing specific antibody. Nanogel-delivered ova with mannose surface decoration was superior to free ova for inducing interferon-γ production by T-lymphocytes. Together, the data demonstrates that particle-based vaccine delivery should consider the influences of both the surface decoration and the vaccine cargo; each can influence different aspects of the interaction with DCs. Such combined influences are likely to impinge on the characteristics of the immune response induced.
authors.affiliation: Institute of Virology and Immunoprophylaxis, 3147 Mittelhaeusern, Switzerland. Lisa.Harwood@ivi.admin.ch
authors.forename: L J
authors.initials: LJ
authors.lastname: Thomann-Harwood
authors.forename: P
authors.initials: P
authors.lastname: Kaeuper
authors.forename: N
authors.initials: N
authors.lastname: Rossi
authors.forename: P
authors.initials: P
authors.lastname: Milona
authors.forename: B
authors.initials: B
authors.lastname: Herrmann
authors.forename: K C
authors.initials: KC
authors.lastname: McCullough
mesh_terms: D000464:Alginates; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002626:Chemistry, Pharmaceutical; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D005079:Excipients; D007371:Interferon-gamma / Q000494:pharmacology; D008358:Mannose; D008856:Microscopy, Fluorescence; D000080385:Nanogels; D053758:Nanoparticles; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D013499:Surface Properties; D013552:Swine; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014612:Vaccines / Q000008:administration & dosage*; D014783:Viscosity
chemical_list: D000464:Alginates; D005079:Excipients; D000080385:Nanogels; D014612:Vaccines; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D007371:Interferon-gamma; D011094:Polyethyleneimine; D008358:Mannose