基于 perfluoroarene 的宏循环可增强通过血脑屏障的透能力
Colin M Fadzen1, Justin M Wolfe1, Choi-Fong Cho2
1Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
Journal of the American Chemical Society
|October 10, 2017
概括
使用 perfluoroaryl-cysteine SNAr 化学反应进行化,可以增强血脑屏障 (BBB) 的透. 这种新的方法改善了临床前模型中的 transportan-10 和 BIM BH3 的传递.
科学领域:
- 医学化学
- 神经科学
- 生物化学
背景情况:
- 血脑屏障 (BBB) 限制了大多数治疗分子,包括,进入中枢神经系统.
- 基于的疗法具有很大的潜力,但由于稳定性差和BBB透性有限,因此面临重大交付挑战.
- 在治疗神经系统疾病方面,制定增强分泌的策略至关重要.
研究的目的:
- 通过 perfluoroaryl-cysteine SNAr 化学来改善血脑屏障 (BBB) 透的可用性.
- 评估这种宏循环化策略对稳定性和细胞吸收的影响.
- 在临床前模型中评估宏环在体内进入大脑的情况.
主要方法:
- 使用 perfluoroaryl-cysteine SNAr 化学方法合成转运-10 (TP10) 的宏环类型.
- 在不同细胞系中评估细胞吸收和蛋白质溶解稳定性.
- 使用细胞球形模型对BBB透的评估.
- 在静脉注射宏环后对小鼠大脑的体外成像.
- 合成和评估BIM蛋白BH3域的宏循环类型.
主要成果:
- 与原始相比,TP10的宏环类别显示细胞吸收增加和蛋白质溶解稳定性提高.
- 一种类型的M13显著改善了BBB的细胞球形模型的传递.
- 在静脉注射后,ex vivo成像证实了宏环TP10类似物进入小鼠脑膜的增加.
- 一种BIM BH3域的宏环类型也表现出透到小鼠大脑组织的增加.
结论:
- 通过 perfluoroaryl-cysteine SNAr介导的大环化是一种可行的策略,可以增强 BBB 透.
- 这种方法提高了在BBB的稳定性和传递性.
- 该方法适用于具有治疗意义的,如BIM BH3域,为新的神经治疗提供了潜力.
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