(156b) Functionalization of Novel Polyanhydride Nanoparticle Adjuvants to Promote Pathogen-Mimicking Characteristics

An imminent need exists to design improved adjuvants and vaccines to control emerging and re-emerging diseases. An ideal vaccine will mimic the way in which a naturally occurring infection induces a robust immune response yet avoids the undesirable effects of disease. To accomplish this, new adjuvants must engage pattern recognition receptors on antigen presenting cells (APCs). In this work, we employ novel strategies to enhance the adjuvanticity of polyanhydride nanoparticles composed of sebacic acid (SA) and 1,6-bis(p-carboxyphenoxy) hexane (CPH) by functionalizing their surface with glycolic acid linker or the pathogen associated molecular pattern di-mannose (diM) to confer “pathogen-like” properties. Co-incubation of linker functionalized nanoparticles with APCs elicited significant increases in surface expression of antigen presentation and co-stimulatory molecules and secretion of proinflammatory cytokines. An 800% increase in uptake of linker and diM-nanoparticles was also observed. Microscopic analysis revealed that majority of the linker particles trafficked to LAMP-1+ vesicles implicated in MHC II presentation pathway. A small proportion of linker nanoparticles trafficked to ER and a subsequent increase in MHC I MFI was observed suggesting that encapsulated antigen could be presented to CD8⁺ T cells via MHC I in vivo. Together, our data show that APCs incubated with linker functionalized nanoparticles demonstrated similar patterns of uptake, intracellular fate, persistence and activation as did APCs exposed to live, pathogenic Y. pestis or E. coli. The innovative combination of polyanhydride nanoparticles and their surface modification provides mechanistic insight into the properties required for next-generation adjuvants to safely mimic the immune stimulating activities of bacterial pathogens.