title: Poly-(lactic-co-glycolic-acid)-based particulate vaccines: particle uptake by dendritic cells is a key parameter for immune activation.
abstract: Poly(lactic-co-glycolic acid) (PLGA) particles have been extensively studied as biodegradable delivery system to improve the potency and safety of protein-based vaccines. In this study we analyzed how the size of PLGA particles, and hence their ability to be engulfed by dendritic cells (DC), affects the type and magnitude of the immune response in comparison to sustained release from a local depot. PLGA microparticles (MP, volume mean diameter≈112 μm) and nanoparticles (NP, Z-average diameter≈350 nm) co-encapsulating ovalbumin (OVA) and poly(I:C), with comparable antigen (Ag) release characteristics, were prepared and characterized. The immunogenicity of these two distinct particulate vaccines was evaluated in vitro and in vivo. NP were efficiently taken up by DC and greatly facilitated MHC I Ag presentation in vitro, whereas DC cultured in the presence of MP failed to internalize significant amounts of Ag and hardly showed MHC I Ag presentation. Vaccination of mice with NP resulted in significantly better priming of Ag-specific CD8(+) T cells compared to MP and OVA emulsified with incomplete Freund's adjuvant (IFA). Moreover, NP induced a balanced TH1/TH2-type antibody response, compared to vaccinations with IFA which stimulated a predominant TH2-type response, whereas MP failed to increase antibody titers. In conclusion, we postulate that particle internalization is of crucial importance and therefore particulate vaccines should be formulated in the nano- but not micro-size range to achieve efficient uptake, significant MHC class I cross-presentation and effective T and B cell responses.
authors.affiliation: Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: A L
authors.initials: AL
authors.lastname: Silva
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands; Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: Rosalia
authors.affiliation: Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Varypataki
authors.affiliation: Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Sibuea
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Ossendorp
authors.affiliation: Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands. Electronic address: w.jiskoot@lacdr.leidenuniv.nl.
authors.forename: W
authors.initials: W
authors.lastname: Jiskoot
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D010047:Ovalbumin / Q000276:immunology; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014612:Vaccines / Q000276:immunology*
chemical_list: D014612:Vaccines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D010047:Ovalbumin
keywords: Adjuvants; Cellular immune response; Immunotherapy; Microparticles; Nanoparticles; PLGA; Protein antigen