Engineering bioerodible polymers with tailored micro/nanostructure for vaccine delivery

摘要

This work describes the investigation of bioerodible polyanhydrides as controlled drug delivery vehicles. The polymers studied are based on the 1,6-bis(p-carboxyphenoxy)hexane (CPH) and sebacic acid (SA) monomers. These two materials erode at vastly different rates and can be combined in random copolymers or blends to achieve tailored erosion kinetics. The hydrophobic nature of these materials offers the potential to stabilize proteins, and their mutual incompatibility and semicrystallinity provide an interesting phase behavior, which can be exploited to aid in tailoring the release kinetics. Theoretical and experimental description of the microstructure of polyanhydride copolymers reveals the details of the microstructure, which are essential to understanding the erosion and drug release kinetics. Injectable drug delivery systems based on polyanhydride microspheres are developed and tested in vitro and in vivo to ascertain drug release kinetics and immune responses to a model antigen, tetanus toxoid (TT). Tailored release profiles of small molecular weight drugs are demonstrated by combining microspheres with different erosion kinetics in \u22cocktails.\u22 This concept is extended to vaccine formulations, where it is demonstrated that the in vivo immune response mechanism can be tuned by altering the drug release kinetics. To achieve control of the immune response mechanism, TT-loaded microspheres providing a controlled release are combined with unencapsulated antigen or delivered without the addition of unencapsulated antigen. Hypotheses regarding the phenomena controlling the immune response are discussed. Finally, accurate erosion and drug release kinetics models are developed that incorporate details of the polymer microstructure and offer molecular level descriptions of the complex process of erosion to aid future developments of polyanhydride systems for biomedical applications.