GLUT1-mediated venlafaxine-thiamine disulfide system-glucose conjugates with "lock-in" function for central nervous system delivery
GLUT1-mediated venlafaxine-thiamine disulfide system-glucose conjugates with "lock-in" function for central nervous system delivery
复制标题
GLUT(1)介导的文拉法辛-二硫化硫胺素系统-具有“锁定”功能的葡萄糖缀合物用于中枢神经系统递送
DOI：
10.1111/cbdd.13128
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发表时间：
2018-03-01
影响因子：
3
通讯作者：
Wu, Yong
中科院分区：
文献类型：
--
作者：
Zhao, Yi;Zhang, Li;Wu, Yong
文拉法辛是一种新型的第三代抗抑郁药物，由于其抑制去甲肾上腺素和血清素神经元再摄取的能力，以及轻微抑制多巴胺再摄取的能力，被描述为重度抑郁症的参考治疗。然而，它的临床应用受到大脑分布有限的阻碍。糖基化是增强药物脑靶向能力的有效途径，但葡萄糖转运蛋白1 （GLUT(1)）的双向转运可能会在母体药物文拉法辛释放前降低脑内文拉法辛-葡萄糖（V-G）的浓度。为了克服GLUT(1)的这一缺点，引入了锁相硫胺素二硫化体系（TDS）来修饰V-G共轭物。两种偶联物与各种缓冲液、小鼠血浆和脑匀浆孵育时均能释放文拉法辛。体内评价表明，文拉法辛- tds -葡萄糖（V-TDS-G）与裸文拉法辛和V-G相比，具有更好的靶向能力，显著提高了文拉法辛在脑内的水平。相对吸收效率（RE）和浓度效率（CE）分别是纯文拉法辛的5.69倍和5.70倍。本研究结果表明，基于葡萄糖- tds （G-TDS）的缀合策略可增强中枢神经系统（CNS）药物进入大脑的传递。
Venlafaxine, a novel third-generation antidepressant drug, has been described as a reference treatment for major depression, owing to its ability of inhibiting both noradrenalin and serotonin neuronal reuptake, and inhibiting dopamine reuptake slightly. However, its clinical application is hampered by a limited brain distribution. Glucosylation is an effective way to enhance the brain targeting ability of drugs, but the bidirectional transport of glucose transporter 1 (GLUT(1)) might decrease the concentrations of venlafaxine-glucose (V-G) in brain before the release of parent drug venlafaxine. To conquer this drawback of GLUT(1), lock-in thiamine disulfide system (TDS) was introduced to modify the V-G conjugate. Both conjugates could release venlafaxine when incubated with the various buffers, mice plasma, and brain homogenate. The evaluation in vivo demonstrated that venlafaxine-TDS-glucose (V-TDS-G) had an improved targeting ability and significantly increased the level of venlafaxine in brain compared to the naked venlafaxine and V-G. The relative uptake efficiency (RE) and concentration efficiency (CE) were enhanced to 5.69 and 5.70 times higher than that of naked venlafaxine, respectively. The results of this study suggest that the conjugate strategy based on the glucose-TDS (G-TDS) is available to enhance the delivery of central nervous system (CNS) drugs into brain.