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Size of the polymeric particulate antigen delivery system and its interactions with antigen-presenting cells (APCs) influence the immune response both qualitatively and quantitatively. In this paper, we report that antigen-loaded polymeric microparticles elicit antibody titers without being phagocytosed by macrophages; and size of the antigen-loaded particles modulates immune response from single-point immunization. Antibody titers varied significantly from single-point immunization with different sized polylactide (PLA) particles entrapping hepatitis B surface antigen. Nanoparticles (200–600nm) were efficiently taken up by macrophages and elicited lower antibody titers in comparison to microparticles (2–8μm). PLA microparticles that elicited highest and long-lasting antibody titers from single-point immunization were not taken up by the macrophages and found attached to the surface of the macrophages …