Claudin-5-Binders Enhance Permeation of Solutes across the Blood-Brain Barrier in a Mammalian Model
Claudin-5-Binders Enhance Permeation of Solutes across the Blood-Brain Barrier in a Mammalian Model
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DOI：
10.1124/jpet.117.243014
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发表时间：
2017-11-01
影响因子：
3.5
通讯作者：
Kondoh, Masuo
中科院分区：
文献类型：
--
作者：
Hashimoto, Yosuke;Shirakura, Keisuke;Kondoh, Masuo
目前中枢神经系统（CNS）药物开发的瓶颈是缺乏针对CNS的药物递送系统。血脑屏障 (BBB) 内皮细胞之间的细胞间隙由称为紧密连接 (TJ) 的复杂蛋白质结构密封。 Claudin-5 (CLDN-5) 是一种四跨膜蛋白，是 TJ 密封的关键成分，可防止药物细胞旁扩散进入 CNS。在本研究中，为了研究 CLDN-5 结合剂是否可用于将药物递送至 CNS，我们生成了针对 CLDN-5 胞外结构域的单克隆抗体 (mAb)。在 BBB 体外模型中，抗 CLDN-5 mAb 减弱了跨上皮/内皮电阻并增强了溶质渗透。这些抗 CLDN-5 mAb 是开发针对 CNS 的新型药物递送系统的潜在先导。
A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood-brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin-5 (CLDN-5), a tetra-transmembrane protein is a key component of the TJ seal that prevents the paracellular diffusion of drugs into the CNS. In the present study, to investigate whether CLDN-5 binders can be used for delivery of drugs to the CNS, we generated monoclonal antibodies (mAbs) specific to the extracellular domains of CLDN-5. In an in vitro model of the BBB, the anti-CLDN-5 mAbs attenuated trans-epithelial/endothelial electrical resistance and enhanced solute permeation. These anti-CLDN-5 mAbs are potential leads for the development of novel drug delivery systems targeting the CNS.