ANTITRANSFERRIN RECEPTOR ANTIBODY AND ANTIBODY-DRUG CONJUGATES CROSS THE BLOOD-BRAIN-BARRIER
ANTITRANSFERRIN RECEPTOR ANTIBODY AND ANTIBODY-DRUG CONJUGATES CROSS THE BLOOD-BRAIN-BARRIER
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DOI：
10.1073/pnas.88.11.4771
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发表时间：
1991-06-01
影响因子：
11.1
通讯作者：
STARZYK, RM
中科院分区：
文献类型：
--
作者：
FRIDEN, PM;WALUS, LR;STARZYK, RM
非亲脂性药物向脑的递送受到构成血脑屏障的紧密贴壁的毛细血管内皮细胞的阻碍。 我们已经研究了单克隆抗体（OX-26）的能力，它识别大鼠转铁蛋白受体，作为一个载体的药物传递通过血脑屏障。 这种抗体先前显示在静脉内施用后优先结合脑中的毛细血管内皮细胞（Jefferies，W.一、布兰登，M. R.，Hunt，S.五、威廉姆斯，A. F.、Gatter，K. C. & Mason，D. Y.（1984）Nature（伦敦）312，162-163）以剂量依赖性方式标记整个脑血管床。 最初均匀标记的脑毛细血管变得非常点状几乎等于注射后4小时，表明时间依赖性螯合的抗体。 毛细血管耗竭实验，其中脑被分离成毛细血管和脑实质部分，显示放射性标记的抗体从毛细血管到脑实质的时间依赖性迁移，这与化合物穿过血脑屏障的转胞吞作用一致。 在体内测试抗体-甲氨蝶呤缀合物以评估该抗体的载体能力。 免疫组化染色的OX-26-甲氨蝶呤共轭物的任何一个组成部分显示脑血管标记的模式与未改变的抗体所观察到的相同。 当药物与OX-26偶联时，放射性标记的甲氨蝶呤在脑实质中的蓄积大大增强。
Delivery of nonlipophilic drugs to the brain is hindered by the tightly apposed capillary endothelial cells that make up the blood-brain barrier. We have examined the ability of a monoclonal antibody (OX-26), which recognizes the rat transferrin receptor, to function as a carrier for the delivery of drugs across the blood-brain barrier. This antibody, which was previously shown to bind preferentially to capillary endothelial cells in the brain after intravenous administration (Jefferies, W. A., Brandon, M. R., Hunt, S. V., Williams, A. F., Gatter, K. C. & Mason, D. Y. (1984) Nature (London) 312, 162-163), labels the entire cerebrovascular bed in a dose-dependent manner. The initially uniform labeling of brain capillaries becomes extremely punctate almost-equal-to 4 hr after injection, suggesting a time-dependent sequestering of the antibody. Capillary-depletion experiments, in which the brain is separated into capillary and parenchymal fractions, show a time-dependent migration of radiolabeled antibody from the capillaries into the brain parenchyma, which is consistent with the transcytosis of compounds across the blood-brain barrier. Antibody-methotrexate conjugates were tested in vivo to assess the carrier ability of this antibody. Immunohistochemical staining for either component of an OX-26-methotrexate conjugate revealed patterns of cerebrovascular labeling identical to those observed with the unaltered antibody. Accumulation of radiolabeled methotrexate in the brain parenchyma is greatly enhanced when the drug is conjugated to OX-26.