The long-term objective of the applicant is to use dextran polymers as macromolecular prodrugs for targeted and/or sustained delivery of pharmacotherapeutic agents. The specific purpose of this application is to study the feasibility of dextran prodrugs for targeted delivery of immunosuppressants to the liver, using methylprednisolone (MP) as a model drug. It is hypothesized that the dextran prodrug of MP would accumulate in the liver, where it releases free MP gradually, resulting in a sustained, local immunosuppression which would be beneficial in liver transplantation. To test this hypothesis, first, dextran-methylprednisolone succinate (DEX-MPS) will be prepared by conjugation of methylprednisolone succinate (MPS) with a 70 kD dextran. Second, the preferential accumulation of DEX-MPS and subsequent release of MP in the liver will be tested by in vitro studies in rat blood, serum, and liver lysosomes, and by in vivo experiments in rats after single doses (equivalent to 5 mg/kg MP) of DEX-MPS. Third, the effects of DEX-MPS on the systemic and local immune systems will be tested after in vivo administration of a similar dose of the prodrug. For systemic effects, the time course of immunosuppression will be quantitated by using the spleen lymphocyte proliferation test. For local effects, the time course of the release of cytokines (interleukin-1 and interleukin-6) from lipopolysaccharide-challenged isolated perfused rat livers will be determined. For comparison, similar disposition and pharmacologic data will be collected after the administration of equivalent doses of free MP. The concentrations of MP, NOS, and DEX-MPS in biological samples will be determined using specific chromatographic methods, and appropriate pharmacokinetic and pharmacodynamic parameters will be estimated. The results of these studies will be used to assess the potential role of dextran-immunosuppressant conjugates in local immunosuppression of the liver.
