The improved blood-brain barrier permeability of endomorphin-1 using the cell-penetrating peptide synB3 with three different linkages
The improved blood-brain barrier permeability of endomorphin-1 using the cell-penetrating peptide synB3 with three different linkages
复制标题
使用具有三种不同连接的细胞穿透肽 synB3 改善内吗啡肽 1 的血脑屏障通透性。
DOI：
10.1016/j.ijpharm.2014.08.045
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发表时间：
2014-12-10
影响因子：
5.8
通讯作者：
Wang, Rui
中科院分区：
文献类型：
--
作者：
Liu, Hui;Zhang, Wei;Wang, Rui
尽管内吗啡具有很高的止痛活性和很少的不良副作用，但由于血脑屏障(BBB)，它们没有在临床上使用。一种有希望的解决方案是使用细胞穿透肽(CPPs)。CPP具有移位细胞膜的能力，已成功地应用于跨血脑屏障的治疗分子输送。然而，关于货物和CPP之间不同共轭策略的运输效率知之甚少。在本研究中，内吗啡素-1(EM-1)通过酰胺、马来酰亚胺和二硫键与高效的CPP载体SynB3偶联。从药效学和体外代谢稳定性两个方面比较了三种连接物的给药效率。应用近红外荧光和荧光显微镜实验，定性和定量检测CPP在脑内的摄取和分布。在筛选出最成功的连锁后，对进一步的连锁机理进行了讨论。我们的结论是，与其他两个键相比，二硫键是通过血脑屏障传递EM-1的最有效的键，并证实在大脑中的生理条件下，它可以被还原并释放其活性形式。这些发现表明，对于那些需要在大脑中释放游离药物并保持活动的人来说，二硫键可能是跨越血脑屏障的最有效的联系。(C)2014爱思唯尔B.V.保留所有权利。
Endomorphins, although they have high analgesic activity and few undesirable side effects, are not in clinical use because of the blood-brain barrier (BBB). One promising solution is to use cell-penetrating peptides (CPPs). CPPs have the ability to translocate cell membranes and have been successfully applied for delivery of therapeutic molecules across the BBB. However, little is known about the transport efficiency of different conjugation strategies between cargo and CPPs. In this study, endomorphin-1 (EM-1) was conjugated with SynB3, an efficient CPP-carrier, via amide, maleimide and disulfide linkages. The delivery efficiency of three linkers was compared in terms of pharmacodynamics and in vitro metabolic stability. Near-infrared fluorescent and fluorescent microscopy experiments were applied to detect the brain uptake and distribution of CPP delivery qualitatively and quantitatively. After the most successful linkage was screened out, the further mechanisms were discussed. We concluded that compared with the other two linkages, the disulfide bond was the most efficient linkage to deliver EM-1 across the BBB and confirmed that it could be reduced at physiological conditions in the brain and release its active form. These findings indicate that for those who need to release a free drug in the brain and maintain activity, a disulfide bond might be the most efficient linkage across the BBB. (C) 2014 Elsevier B.V. All rights reserved.