title: Shielding the cationic charge of nanoparticle-formulated dermal DNA vaccines is essential for antigen expression and immunogenicity.
abstract: Nanoparticle-formulated DNA vaccines hold promise for the design of in vivo vaccination platforms that target defined cell types in human skin. A variety of DNA formulations, mainly based on cationic liposomes or polymers, has been investigated to improve transfection efficiency in in vitro assays. Here we demonstrate that formulation of DNA into both liposomal and polymeric cationic nanoparticles completely blocks vaccination-induced antigen expression in mice and ex vivo human skin. Furthermore, this detrimental effect of cationic nanoparticle formulation is associated with an essentially complete block in vaccine immunogenicity. The blocking of DNA vaccine activity may be explained by immobilization of the nanoparticles in the extracellular matrix, caused by electrostatic interactions of the cationic nanoparticles with negatively charged extracellular matrix components. Shielding the surface charge of the nanoparticles by PEGylation improves in vivo antigen expression more than 55 fold. Furthermore, this shielding of cationic surface charge results in antigen-specific T cell responses that are similar as those induced by naked DNA for the two lipo- and polyplex DNA carrier systems. These observations suggest that charge shielding forms a generally applicable strategy for the development of dermally applied vaccine formulations. Furthermore, the nanoparticle formulations developed here form an attractive platform for the design of targeted nanoparticle formulations that can be utilized for in vivo transfection of defined cell types.
authors.affiliation: Department of Pharmacy & Pharmacology, Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands. joost.vandenberg@slz.nl
authors.forename: Joost H
authors.initials: JH
authors.lastname: van den Berg
authors.forename: Koen
authors.initials: K
authors.lastname: Oosterhuis
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Leonardus J
authors.initials: LJ
authors.lastname: van der Aa
authors.forename: Johan F J
authors.initials: JF
authors.lastname: Engbersen
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.forename: Bastiaan
authors.initials: B
authors.lastname: Nuijen
mesh_terms: D000328:Adult; D000818:Animals; D002412:Cations; D005260:Female; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D007271:Injections, Intradermal; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D053758:Nanoparticles; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011073:Polyamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D012867:Skin / Q000276:immunology* / Q000378:metabolism; D013499:Surface Properties; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014162:Transfection; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D014758:Viral Core Proteins / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D002412:Cations; D007252:Influenza Vaccines; D008055:Lipids; D008081:Liposomes; D010446:Peptide Fragments; C531249:Poly(amidoamine); D011073:Polyamines; D019444:Vaccines, DNA; D014758:Viral Core Proteins; C102366:nucleoprotein (366-374), influenza virus; D011092:Polyethylene Glycols