(235d) Nanoparticle Vaccines for Biodefense Pathogens

Polyanhydrides are a class of hydrophobic biomaterials that degrade by hydrolytic cleavage of the anhydride bond. Our overall objective is to engineer polyanhydrides with tailored chemistry and nanostructure to regulate drug/protein distribution and to design delivery systems with physiologically meaningful functionality and release profiles. The underlying hypothesis is that polymer chemistry and nanostructure not only regulates drug/protein distribution and release, but also conveys immune functionality and material fate. To systematically investigate this hypothesis, a system based on the anhydride monomers, 1,6-bis(p-carboxyphenoxy)hexane), 1,8-bis(p-carboxyphenoxy)3,6-dioxaoctane, and sebacic anhydride has been chosen. Two examples of controlled delivery systems based on these polyanhydrides will be discussed. First, proteins can be stabilized within and released from polyanhydride particles. Several examples of therapeutic proteins that have been stabilized within polyanhydride micro- and nano-particles will be discussed. Studies have been performed that examine the hierarchical structure of the protein during fabrication, storage, and release that demonstrate important principles to preserve structural integrity and functionality of the released protein. Second, vaccines based on polyanhydride nano-adjuvants have been designed that have the unique capability to modulate immune response mechanisms. We have studied the in vitro activation of dendritic cells by polyanhydride nanoparticles and discovered that the chemistry and size of the particles play a major role in up-regulating dendritic cell activation. This is the first step in the evaluation of an in vivo immune response that may be governed by a combination of adjuvant chemistry, antigen release kinetics, and the migration of dendritic cells from the injection site to the draining lymph nodes. These studies are complemented with in vivo work that demonstrates the protective capability of nanoparticle-based biodefense vaccines against anthrax and pneumonic plague. The fundamental treatment of the mechanistic aspects of release and immune response will ultimately facilitate rational means of designing single-dose vaccines.