Evaluation of cationized rat albumin as a potential blood-brain barrier drug transport vector.
Evaluation of cationized rat albumin as a potential blood-brain barrier drug transport vector.
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发表时间：
1990-11
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通讯作者：
W. Pardridge;D. Triguero;J. Buciak;Jing Yang
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作者：
W. Pardridge;D. Triguero;J. Buciak;Jing Yang
目前的研究评估了在 8 周内重复施用阳离子化大鼠白蛋白对大鼠的影响，未来的目标是使用这种修饰蛋白作为载体，将药物转运穿过脑毛细血管内皮壁，即血脑屏障。大鼠白蛋白在 pH = 7.8 下用六亚甲基二胺阳离子化，蛋白质的等电点从 5.5 升高至约 8。基于十二烷基硫酸钠聚丙烯酰胺凝胶电泳期间的迁移率，阳离子化蛋白质是单体。放射性标记后，阳离子化大鼠血清白蛋白 (RSA) 被分离的大鼠或牛脑微血管吸收，而放射性标记的天然 RSA 在体外不被毛细血管吸收。静脉注射同位素后，3H-阳离子化RSA的脑分布体积在5小时内线性增加，并在5小时内达到46+/-3微升/克（平均值+/-S.E.）的值，而125I-天然RSA的脑分布体积在5小时内保持恒定（9.3+/-0.7微升/克，等于脑血）量）。每天（周一至周五）向各组大鼠皮下注射阳离子化和天然 RSA，剂量为 1 mg/kg，持续 4 周和 8 周。根据正常体重增加、正常组织组织学和正常血清化学的结果，该剂量方案没有产生明显的毒性。因此，阳离子化大鼠白蛋白可用于未来的研究，通过重复施用阳离子化大鼠白蛋白嵌合肽来评估这些物质在体内通过血脑屏障的转运。
The present investigations evaluated the effects in rats of repetitive administration of cationized rat albumin over an 8-week period with the future aim of using this modified protein as a vector to transport drugs across the brain capillary endothelial wall, i.e., the blood-brain barrier. Rat albumin was cationized at pH = 7.8 with hexamethylenediamine, and the isoelectric point of the protein was raised from 5.5 to approximately 8. The cationized protein was monomeric based on mobility during sodium dodecylsulfate polyacrylamide gel electrophoresis. After radiolabeling, the cationized rat serum albumin (RSA) was taken up by isolated rat or bovine brain microvessels, whereas radio-labeled native RSA was not taken up by the capillaries in vitro. The brain volume of distribution of the 3H-cationized RSA increased linearly over a 5-hr period after an intravenous injection of the isotope and reached a value of 46 +/- 3 microliter/g (mean +/- S.E.) by 5 hr, whereas the brain volume of distribution of the 125I-native RSA was constant during the 5-hr time period (9.3 +/- 0.7 microliter/g, which is equal to the brain blood volume). The cationized and native RSAs were administered daily (Monday through Friday) at a dose of 1 mg/kg subcutaneously to groups of rats for 4- and 8-week periods. This dosage regimen resulted in no discernible toxicity, based on the findings of normal weight gain, normal tissue histology and normal serum chemistry. Therefore, cationized rat albumin may be used in future studies that use the repetitive administration of cationized rat albumin chimeric peptides for the evaluation of the transport of these substances through the blood-brain barrier in vivo.