title: Directed antigen presentation using polymeric microparticulate carriers degradable at lysosomal pH for controlled immune responses.
abstract: The types of the immune responses generated against an antigen are determined by the intracellular fate of the antigen. Endogenous antigens are processed in the cytoplasm and initiate cytotoxic T lymphocyte (CTL) activation. In contrast, exogenous antigens are degraded in the lysosome (or phagolysosome) of antigen presenting cells (APCs), and induce antibody-mediated immune responses and assist CTL activation. Therefore, maximizing a desired response by controlling delivery pathways is indispensable in vaccine development and immunotherapy. New cleavable microparticles have been prepared for use as protein-based vaccine carriers by polymerizing water soluble monomers including a newly developed aliphatic monomer with a pendant primary amine group and a cleavable acetal linkage with a wholly aliphatic cleavable acetal cross-linker. Incorporation of the cleavable amine monomer in the polymerization mixture increased the encapsulation efficiency of a model antigen, ovalbumin. Ex vivo assays showed that the composition of the particles greatly affected the magnitude and the pathway of antigen presentations, which determine the type of immune responses. The degradable particles synthesized with the new cross-linker enhanced MHC I antigen presentation 2-3-fold over nondegradable particles. It was also found that, by adding 10% cationic cleavable monomers to the microparticles, MHC I restricted antigen presentation was enhanced ca. 75 times over that achieved with nondegradable particles. The microparticles introduced in this study can be further used for targeting and gene delivery due to functionalizable and cleavable cationic monomers in addition to degradability.
authors.affiliation: Center for New Directions in Organic Synthesis, Department of Chemistry, University of California-Berkeley, Berkeley, CA 94720-1460, USA.
authors.forename: Young Jik
authors.initials: YJ
authors.lastname: Kwon
authors.forename: Stephany M
authors.initials: SM
authors.lastname: Standley
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Goodwin
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Gillies
authors.forename: Jean M J
authors.initials: JM
authors.lastname: Fréchet
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000378:metabolism; D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D016503:Drug Delivery Systems; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008213:Lymphocyte Activation; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D015394:Molecular Structure; D010316:Particle Size; D011108:Polymers / Q000737:chemistry / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014612:Vaccines
chemical_list: D003432:Cross-Linking Reagents; D015395:Histocompatibility Antigens Class I; D011108:Polymers; D014612:Vaccines