Abstract
Abstract Improving efficacy of subunit-based immunization protocols without eliciting adverse reactions continues to be a hurdle in vaccine design. Vaccination of mice in our laboratory with surface eroding polyanhydride nanoparticles (NPs) prepared from 1,6-bis(p-carboxyphenoxy)hexane (CPH) and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) administered as a single intranasal dose provided high-titer and high-avidity humoral responses and protection against a live Yersinia pestis challenge at 23 weeks post-vaccination. The goal of the current study was to elucidate the immune-enhancing properties of the NPs by functionalizing them with TLR3 ligands (i.e., poly I:C) via either surface modification or encapsulation into the particle in order to activate macrophages. We also tested the hypothesis that the protective responses observed following intranasal NP vaccinations was due to particles undergoing endocytic processing by targeting TLR3 located on the endosomal membrane. Our results demonstrated that stimulation of primary macrophages (bone marrow-derived) with poly I:C modified particles increased surface expression of MHC II and CD80/86 as well as enhanced secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α as compared to stimulation with non-functionalized NPs. Encapsulation of TLR ligands in polyanhydride NPs enhanced the activation status of macrophages and targeted functionalization may improve the efficacy of this novel vaccine platform.
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