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T Fujita, M Nishikawa, C Tamaki, Y Takakura, M Hashida and H Sezaki
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Four types of superoxide dismutase (SOD) derivatives such as SOD- carboxymethyl dextran conjugate, SOD-diethylaminoethyl dextran conjugate, galactosylated SOD and mannosylated SOD were synthesized and their potential for selective targeting to organs or cells was evaluated in mice by pharmacokinetic analysis. All SOD derivatives retained 50 to 80% of the original enzymatic activity and were stable during incubation with mouse serum retaining enzymatic activity greater than 80% for 3 hr. After intravenous injection, native SOD was rapidly excreted into urine and no significant accumulation was observed in the organs except the kidney. SOD-carboxymethyl dextran conjugate gave a long plasma half-life because of impaired glomerular filtration and tissue interaction. By contrast, galactosylated-SOD and mannosylated- SOD were very rapidly eliminated from the circulation and taken up by parenchymal and nonparenchymal cells of the liver, respectively, via receptor-mediated endocytosis. These uptake processes were nonlinear and hepatic uptake clearance decreased as the dose increased, although almost complete extraction was obtained at a dose of 0.1 mg/kg. Furthermore, the accumulation in kidney of both glycosylated SODs was drastically decreased due to reduced renal proximal tubular reabsorption and also enhanced hepatic clearance. SOD-diethylaminoethyl dextran conjugate also rapidly disappeared from plasma and distributed into liver, but its accumulation occurred due to electrostatic interaction and was nonspecific in cellular distribution. These results suggest the possibility of controlling the in vivo fate of SOD at a cellular level by chemical modification utilizing sugar moieties with varied physicochemical and/or biological characteristics.
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