title: Nasal vaccination with N-trimethyl chitosan and PLGA based nanoparticles: nanoparticle characteristics determine quality and strength of the antibody response in mice against the encapsulated antigen.
abstract: Nasal vaccination is a promising, needle-free alternative to classical vaccination. Nanoparticulate delivery systems have been reported to overcome the poor immunogenicity of nasally administered soluble antigens, but the characteristics of the ideal particle are unknown. This study correlates differences in physicochemical characteristics of nanoparticles to their adjuvant effect, using ovalbumin (OVA)-loaded poly(lactic-co-glycolic acid) nanoparticles (PLGA NP), N-trimethyl chitosan (TMC) based NP (TMC NP) and TMC-coated PLGA NP (PLGA/TMC NP). PLGA NP and PLGA/TMC NP were prepared by emulsification/solvent extraction and TMC NP by ionic complexation. The NP were characterized physicochemically. Their toxicity and interaction with and stimulation of monocyte derived dendritic cells (DC) were tested in vitro. Furthermore, the residence time and the immunogenicity (serum IgG titers and secretory IgA levels in nasal washes) of the nasally applied OVA formulations were assessed in Balb/c mice. All NP were similar in size, whereas only PLGA NP carried a negative zeta potential. The NP were non-toxic to isolated nasal epithelium. Only TMC NP increased the nasal residence time of OVA compared to OVA administered in PBS and induced DC maturation. After i.m. administration all NP systems induced higher IgG titers than OVA alone, PLGA NP and TMC NP being superior to PLGA/TMC NP. Nasal immunization with the slow antigen releasing particles, PLGA NP and PLGA/TMC NP, did not induce detectable antibody titers. In contrast, nasal immunization with the positively charged, fast antigen releasing TMC NP led to high serum antibody titers and sIgA levels. In conclusion, particle charge and antigen release pattern of OVA-loaded NP has to be adapted to the intended route of administration. For nasal vaccination, TMC NP, releasing their content within several hours, being mucoadhesive and stimulating the maturation of DC, were superior to PLGA NP and PLGA/TMC NP which lacked some or all of these characteristics.
authors.affiliation: Division of Drug Delivery Technology, Leiden/Amsterdam Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2300 RA Leiden, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: Slütter
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bal
authors.forename: Chantal
authors.initials: C
authors.lastname: Keijzer
authors.forename: Roel
authors.initials: R
authors.lastname: Mallants
authors.forename: Niels
authors.initials: N
authors.lastname: Hagenaars
authors.forename: Ivo
authors.initials: I
authors.lastname: Que
authors.forename: Eric
authors.initials: E
authors.lastname: Kaijzel
authors.forename: Willem
authors.initials: W
authors.lastname: van Eden
authors.forename: Patrick
authors.initials: P
authors.lastname: Augustijns
authors.forename: Clemens
authors.initials: C
authors.lastname: Löwik
authors.forename: Joke
authors.initials: J
authors.lastname: Bouwstra
authors.forename: Femke
authors.initials: F
authors.lastname: Broere
authors.forename: Wim
authors.initials: W
authors.lastname: Jiskoot
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000917:Antibody Formation; D002478:Cells, Cultured; D048271:Chitosan / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D007071:Immunoglobulin A, Secretory / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D019344:Lactic Acid / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D010047:Ovalbumin / Q000276:immunology; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014611:Vaccination
chemical_list: D004337:Drug Carriers; D007071:Immunoglobulin A, Secretory; D007074:Immunoglobulin G; C118071:N-trimethyl chitosan chloride; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin; D048271:Chitosan