A Cyclodextrin-Stabilized Spermine-Tagged Drug Triplex that Targets Theophylline to the Lungs Selectively in Respiratory Emergency.
A Cyclodextrin-Stabilized Spermine-Tagged Drug Triplex that Targets Theophylline to the Lungs Selectively in Respiratory Emergency.
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DOI：
10.1002/adtp.202000153
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发表时间：
2020-12
影响因子：
4.6
通讯作者：
Jones SA
中科院分区：
文献类型：
--
作者：
Sofian ZM;Benaouda F;Wang JT;Lu Y;Barlow DJ;Royall PG;Farag DB;Rahman KM;Al-Jamal KT;Forbes B;Jones SA
将茶碱等救生药物与靶向部分进行离子配对可能会对哮喘持续状态或COVID-19诱导的肺气肿等医疗紧急情况产生重大影响。然而，为了在体内实现快速药物靶向，必须保护离子对在进入靶组织之前免受破坏。本研究旨在研究当茶碱与多胺转运蛋白底物精胺离子配对时，将其插入环糊精（CD）中形成三链体，是否可以在静脉给药后选择性地将支气管扩张剂引导至肺部。NMR表明，在形成三链体精胺后，精胺从CD腔中突出，这导致A549细胞中的能量依赖性摄取（1.8倍增强），持续超过20分钟。在体内，在大鼠和小鼠中注射后20分钟，三链体分别使肺中的茶碱增加2.4倍和2.2倍（p < 0.05）。肺靶向是选择性的，不会增加脑或心脏的摄取，其中茶碱的副作用是治疗限制性的。选择性地将肺部的茶碱浓度增加一倍可以改善这种窄治疗指数药物的获益风险比，这在重症监护中仍然很重要。这篇文章证明了离子配对茶碱，一种用于哮喘持续状态或COVID-19诱导的肺气肿等医疗紧急情况的药物，与多胺一起，可以直接输送到肺部。当离子对被环糊精稳定为三链体时，这种方法是有效的，这增加了体内离子对的寿命，以促进肺中的活性积累。
Ion‐pairing a lifesaving drug such as theophylline with a targeting moiety could have a significant impact on medical emergencies such as status asthmaticus or COVID‐19 induced pneumomediastinum. However, to achieve rapid drug targeting in vivo the ion‐pair must be protected against breakdown before the entry into the target tissue. This study aims to investigate if inserting theophylline, when ion‐paired to the polyamine transporter substrate spermine, into a cyclodextrin (CD), to form a triplex, could direct the bronchodilator to the lungs selectively after intravenous administration. NMR demonstrates that upon the formation of the triplex spermine protruded from the CD cavity and this results in energy‐dependent uptake in A549 cells (1.8‐fold enhancement), which persists for more than 20 min. In vivo, the triplex produces a 2.4‐fold and 2.2‐fold increase in theophylline in the lungs 20 min after injection in rats and mice, respectively (p < 0.05). The lung targeting is selective with no increase in uptake into the brain or the heart where the side‐effects of theophylline are treatment‐limiting. Selectively doubling the concentration of theophylline in the lungs could improve the benefit‐risk ratio of this narrow therapeutic index medicine, which continues to be important in critical care. This article demonstrates that ion‐pairing theophylline, a drug used in medical emergencies such as status asthmaticus or COVID‐19 induced pneumomediastinum, with a polyamine, can direct delivery to the lung. Such an approach is effective when the ion‐pair is stabilized as a triplex with cyclodextrin, which increases the in vivo ion‐pair life‐time to facilitate active accumulation in the lung.
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