Acetal-modified Dextran: An Acid-sensitive, Biodegradable Material for Effective Microparticulate Antigen Delivery (41.53)

Abstract Polymer-based microparticle systems capable of delivering proteins to antigen-presenting cells (APCs) of the immune system have been investigated for the enhancement of vaccines and immunotherapy. The size of the particles in these systems can be controlled to passively target APCs , without being taken up by other cells in the body. We have developed a new concept in acid-sensitive microparticles based on the use of a water-soluble polysaccharide, dextran, that can be rendered insoluble in aqueous solutions by protecting the hydroxyl groups with acid-sensitive acetals. The resulting polymer is soluble in organic solvents used to generate protein loaded particles by a variety of methods in which the modified polymer is condensed around the encapsulated antigen. Once administered, the acetals rapidly hydrolyze under the acidic conditions present in the phagosomes of APCs to provide a solubility switch that enables particle degradation and release of encapsulated antigen in a controlled manner. We have recently demonstrated the ability to control the rate of particle degradation over a range of minutes to several hours at pH 5, with interesting results observed in how degradation rate affects the presentation of model antigens by APCs to T cells in vitro, as well as how degradation rate may affect the processing mechanism of the released antigen within APCs.