Systematic development of targeting systams for prevention of tissue damages in organ transplantation

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The purpose of the present study was to develop novel drug delivery systems for prevention of the tissue damages in organ transplantation. A macromolecuar prodrug of tacrolimus (FK506), a powerful immunosuppressant agent, and several derivatives of superoxide dismutase (SOD), an antioxidant enzyme, were developed. Macromolecular prodrug of FK506, FK506-dextran conjugate.was synthesized and the coupling molar ratio was approximately 1 : 1(dextram : FK506). FK506 was released from the conjugate by a chemical hydrolysis with a half-life of 150hr in phosphate buffer. In vitro immunosuppressive activity of the conjugate assessed by rat lymphocyte stimulation test was almost comparable to that of free FK506, suggesting biologically active FK506 could be liberated from the conjugate. In vivo biodistribution studies demonstrated that conjugation with the dextran derivative dramatically changed the pharmacokinetic properties of FK506 after intravenous injection in rats. AUC of the FK506-dextran … More conjugate was almost 2000 times higher than that of free FK506 and organ uptake clearances of the conjugate were significantly smaller than those of free drug. These results suggest that the FK506-dextran conjugate behaves as a prodrug of FK506 with an extended blood circulating time and can be expected to have an improved therapeutic potency. On the other hand, chemical modification was carried out on SOD without significant loss of its enzymatic activity. Among them, glycosylated SOD derivatives, galactosylated and mannosylated SOD,were successfully delivered to the liver parenchmal and non-parenchymal cells, respectively, via receptor-mediated endocytosis. The therapeutic effects of the SOD derivatives wereevaluated in rat models. The SOD derivatives showed superior preventive effects in hepatic ischemia/reperfusion injury compared with unmodified SOD.Thus, the present study has demonstrated that the FK506-dextran conjugate and SOD derivatives would be useful delivery systems for the prevention of organ damages in organ transplantation. Less