Design and activation of small organic molecules for localized immunosuppression.
Since the implementation of the Edmonton Protocol in the early 2000s, many efforts have been made to further improve the long-term viability of transplanted islets in recipients with type 1 diabetes mellitus. These efforts have included suppression of both the innate and adaptive immune responses as well as the masking of pancreatic islets via encapsulation technologies. This dissertation details the synthesis and characterization of various prodrugs of small molecules designed to locally inhibit the immune system – either the innate or the adaptive response. Following successful synthesis and characterization, the prodrugs were then investigated for catalyzed activation using either exogenous nitroreductase (from e. coli) or palladium resins in aqueous buffer. These molecules were also looked at for biological relevance through the use of various in vitro studies. The experiments performed on the final prodrugs successfully demonstrated the safety and effectiveness of these prodrug strategies in vitro and have generated interest in further consideration for in vivo application.