Thursday, November 11, 2010: 4:45 PM
Grand Ballroom F (Salt Palace Convention Center)
While vaccines have proven to be the most effective method of eliminating infectious diseases, many issues associated with vaccine protection (i.e., multi-dose administration, poor immunogenicity of vaccine antigens, and undesirable side effects) still persist. These problems could be overcome by designing better administration methods using biocompatible adjuvants (i.e., polymer nanoparticles) capable of providing a depot for sustained antigen release and enhancing the immune response. Polyanhydrides are a class of biodegradable polymers with excellent biocompatibility and have shown much promise as drug/vaccine delivery vehicles. They are capable of providing a sustained antigen release, tunable by polymer chemistry, and have demonstrated protein stabilization properties. Additionally, they have been shown to have adjuvant capabilities to enhance the immune response. To most effectively design polanhydrides for use as vaccine adjuvants, a broad array of polymer chemistries must be investigated for optimization of antigen release rate, antigen stability, cellular compatibility, and immune cell activation. This can be achieved with the use of a high-throughput combinatorial approach which has been developed for studying antigen-biomaterial and cell-biomaterial interactions. This platform was implemented to rapidly assess the effect of polyanhydride nanoparticle chemistry on cellular toxicity, uptake, and immune activation of murine C3H/OuJ bone marrow derived dendritic cells (DCs) by copolymers based on sebacic acid (SA), 1,6-bis(p-carboxyphenoxy)hexane (CPH), and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG). Nanoparticle libraries of twelve varying CPH:SA and CPTEG:CPH chemistries were investigated in parallel for their effect on cell viability, immune activation (intracellular and extracellular cytokine production and cell surface marker expression), and uptake by DCs. Flow cytometry was used to assess both uptake and immune activation by staining with fluorescent antibodies for cell markers and internal cytokines and by encapsulating a fluorescent marker into the particles to monitor cellular uptake. The results indicate that all nanoparticle chemistries proved to be biocompatible except for SA-rich chemistries at high doses which resulted in a slight decrease in cell viability. Nanoparticle chemistry demonstrated a strong influence on particle uptake and immune activation of the DCs. Expression of the cell surface markers, MHC II, CD86, CD40, and CD209, were most stimulated by CPTEG-rich and SA-rich chemistries. Conversely, the CPH-rich and CPTEG-rich chemistries were the most effective at promoting the secretion of the cytokines, IL-6 and IL-12p40, from the DCs. The uptake studies revealed high levels of particle uptake for SA-rich polymer chemistries which suggests that the activation of DCs treated with the SA-rich nanoparticles may be related to the high level of particle internalization. The enhanced adjuvant effect demonstrated by the SA-rich and CPTEG-rich nanoparticles combined with their tunable release kinetics makes them promising biomaterials as vaccine delivery adjuvants. This rapid investigation of cell-biomaterial interactions with a combinatorial-based platform paves the way for rational design and optimization of biomaterial adjuvants for drug/vaccine delivery.