Department of Biological Engineering, Inha University, Incheon, South Korea.
Biotechnol Bioeng. 2018 Oct;115(10):2624-2631. doi: 10.1002/bit.26742. Epub 2018 Jul 16.
Globally, approximately a billion patients are estimated to suffer from neurological disorders. Although there are many therapeutic candidates for the central nervous system, treatment of brain disorders is restricted by the blood-brain barrier (BBB), which is a highly selective membrane that protects the brain from exogenous substances. This study was undertaken to develop a novel strategy to overcome the BBB and improve the efficiency of drug delivery to the brain by mechanical load increase using hypergravity. Human cerebral microvascular endothelial cells were exposed three times to 20 min hypergravity (10g), with a 20-min rest period between each exposure. The applied hypergravity reversibly decreased the cellular metabolic activity and increased the permeation rate of fluorescein sodium salt, fluorescein isothiocyanate-labeled dextran (FD-4), and fluorescein-labeled jacalin. Following the exposure to hypergravity, we also observed structural changes of the cytoskeleton and tight junctions, and an alteration in the expression levels of related genes. These results indicate that increased mechanical load due to the applied hypergravity affects the cytoskeletal arrangement and tight junctions, thereby weakening the cell barrier function and enhancing the permeability of the paracellular pathway. Thus, the mechanical load increase by hypergravity has the potential of being used as a novel strategy to overcome the BBB for brain drug delivery.
据估计，全球有大约 10 亿患者患有神经疾病。尽管中枢神经系统有许多治疗候选药物，但由于血脑屏障 (BBB) 的存在，治疗脑部疾病受到限制，血脑屏障是一种高度选择性的膜，可保护大脑免受外源性物质的侵害。本研究旨在开发一种新策略，通过使用超重增加机械负荷来克服 BBB，提高药物向大脑的递送效率。将人脑血管内皮细胞三次暴露于 20 分钟的超重（10g）中，每次暴露之间有 20 分钟的休息时间。施加的超重会可逆地降低细胞代谢活性并增加荧光素钠盐、异硫氰酸荧光素标记的葡聚糖（FD-4）和荧光素标记的 jacalin 的渗透速率。在超重暴露后，我们还观察到细胞骨架和紧密连接的结构变化，以及相关基因表达水平的改变。这些结果表明，施加的超重引起的机械负荷会影响细胞骨架排列和紧密连接，从而削弱细胞屏障功能并增强细胞旁途径的通透性。因此，超重引起的机械负荷增加有可能被用作克服 BBB 以实现脑部药物递送的新策略。
