Fujita T, Nishikawa M, Tamaki C, Takakura Y, Hashida M, Sezaki H
Department of Basic Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
J Pharmacol Exp Ther. 1992 Dec;263(3):971-8.
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.
合成了四种超氧化物歧化酶（SOD）衍生物，即SOD-羧甲基葡聚糖缀合物、SOD-二乙氨基乙基葡聚糖缀合物、半乳糖基化SOD和甘露糖基化SOD，并通过药代动力学分析评估了它们在小鼠体内选择性靶向器官或细胞的潜力。所有SOD衍生物保留了原始酶活性的50%至80%，并且在与小鼠血清孵育期间保持稳定，3小时内酶活性保留大于80%。静脉注射后，天然SOD迅速排泄到尿液中，除肾脏外，在其他器官中未观察到明显蓄积。由于肾小球滤过受损和组织相互作用，SOD-羧甲基葡聚糖缀合物具有较长的血浆半衰期。相比之下，半乳糖基化SOD和甘露糖基化SOD从循环中非常迅速地被清除，分别通过受体介导的内吞作用被肝脏的实质细胞和非实质细胞摄取。这些摄取过程是非线性的，随着剂量增加，肝脏摄取清除率降低，尽管在剂量为0.1mg/kg时几乎完全被摄取。此外，由于肾近端小管重吸收减少以及肝脏清除增强，两种糖基化SOD在肾脏中的蓄积均显著降低。SOD-二乙氨基乙基葡聚糖缀合物也迅速从血浆中消失并分布到肝脏中，但其蓄积是由于静电相互作用，在细胞分布上是非特异性的。这些结果表明，利用具有不同物理化学和/或生物学特性的糖基进行化学修饰，有可能在细胞水平上控制SOD在体内的命运。
