Introduction of new immunosuppressive drugs has transformed liver transplantation from an experimental procedure to a successful solution for patients who are otherwise doomed to death. However, the use of these drugs has resulted in significant morbidity and mortality due to their toxicity. Recent data indicates that local immunosuppression at the site of transplanted graft will increase graft survival and reduce the toxicity of immunosuppressive agents in other organs. However, current methods of local immunosuppression have several limitations, which seriously hamper their clinical use. We propose here to use macromolecular prodrugs of immunosuppressants, which preferentially accumulate in the liver, for the purpose of local immunosuppression in liver transplantation. Specifically, we will investigate the tissue accumulation and immunosuppressive profile of a dextran prodrug of methylprednisolone (MP) in rats. Our hypothesis is that the dextran prodrug of MP will preferentially accumulate in the liver, where it gradually regenerates the active drug, resulting in sustained local immunosuppression in liver transplantation. Prodrugs will be synthesized by attaching dextran to MP via various linkers, and an optimum linker will be selected. The pharmacokinetics of the selected prodrug will then be tested in rats with respect to the dose and frequency of prodrug administration. Further, the effects of the prodrug on the systemic and local immune response will be compared with those of the parent drug. Finally, the effectiveness of the prodrug in prevention of allograft rejection will be compared with those of the parent drug in an orthotopic rat liver transplantation model. It is our expectation that this approach will substantially reduce the drug dose needed for effective immunosuppression of transplanted livers in rats. These studies are significant because they will eventually lead to a substantial reduction in morbidity and mortality associated with the current immunosuppressive protocols used in liver transplantation.
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