Novel amphiphilic polyanhydrides for vaccine delivery

Abstract

<p>The rapid development of biopharmaceuticals suggests that many future vaccines will involve the delivery of peptide or protein sub units. The overall goal of this work is to design novel vaccine adjuvants based on biodegradable polymers that protect, stabilize, and enhance the immunogenicity of these protein antigens. Polyanhydrides, which are surface erodible polymers, have shown excellent performance as drug carriers. Their hydrophobic nature prevents water penetration into the bulk, thus eliminating water-induced covalent aggregation of proteins. Unfortunately, protein inactivation by non-covalent aggregation may still persist. It has been suggested that the use of carriers containing both hydrophobic and hydrophilic entities may provide a gentler environment for proteins. Hence, the synthesis and characterization of a novel amphiphilic polyanhydride system based on the anhydride monomers 1,6-bis(p-carboxyphenoxy)hexane (CPH) and 1,8-bis(p-carboxyphenoxy)-3,6-dioxaoctane (CPTEG) was carried out. Subsequently, as most vaccines involve the delivery of peptides or protein subunits, protein stabilization in the CPTEG:CPH environment was analyzed. It was demonstrated that CPTEG:CPH system provides a gentle environment for proteins and sustained release from copolymer microspheres is attained. In order to evaluate the adjuvant characteristics of the CPTEG:CPH system, the activation of immune cells incubated with CPTEG:CPH microspheres and the implications for vaccine design were addressed. The promising adjuvant capabilities of CPTEG-content microspheres were evidenced by enhanced maturation of dendritic cells, the most potent antigen presenting cells of the immune system. Altogether, the studies presented in this thesis provide an excellent foundation for testing the viability of this system as an effective adjuvant for the development of vaccines. Development and application of this technology will facilitate the rational design of vaccines and the ability to appropriately redirect the immune response to develop protective immunity.</p>