UC Berkeley

Vaccination represents one of the most cost-effective methods for the treatment and prevention of disease. Due to safety concerns surrounding the use of live attenuated and killed/inactivated pathogens, there has been significant interest in the development of subunit vaccines, which are composed of discrete antigenic proteins or polysaccharides. Unfortunately, protein-based vaccines are poorly immunogenic and typically require the use of adjuvants for the induction of protective immunity. Because of their tunability and synthetic addressability, polymeric particulate carriers represent a promising approach for enhancing the efficacy of protein-based vaccines, and are the subject of this dissertation. In particular, we report on the development of acid-degradable materials, which are capable of releasing encapsulated protein antigens and immunostimulatory molecules following uptake by cells of the immune system and subsequent trafficking to acidic endosomal vesicles. Specific emphasis is placed on the development, functionalization and immunological evaluation of biodegradable acid-sensitive particle systems.

Chapter 1 introduces various delivery strategies for enhancing the potency of subunit vaccines and discusses the basics of vaccine immunology. Additionally, the field of polymeric particulate antigen carriers is reviewed, with a focus on relevant design criteria for materials intended to interact with the immune system.

In Chapter 2, the synthesis of acid-sensitive acrylamide-based microparticles containing an immunomodulatory agent is discussed. The optimal conjugation strategy for an immunostimulatory DNA sequence is investigated and particles containing a model protein antigen are studied in several models, including a cancer immunotherapy study, to ascertain in vivo the importance of co-delivering antigen and maturation signals to cells of the adaptive immune system.

Chapter 3 discusses the synthesis of a second generation acid-sensitive polyurethane particle system which is designed to degrade entirely into biocompatible small molecule byproducts. The ability of these particles to elicit an immune response to a model antigen is studied and a method to monitor the production of polymer degradation byproducts in cells is presented.

Chapters 4 and 5 investigate the synthesis, characterization, and a method for the functionalization of a third generation acid-sensitive particle system. The preparation of these particles from acetal-modified dextran and their pH-dependent degradation behavior is described. Additionally, a facile method for the surface functionalization of these particles using alkoxyamine reagents is presented.