Development of nitroxide-based theranostic compounds that act both as anti-inflammatory drugs and brain redox imaging probes in MRI
Development of nitroxide-based theranostic compounds that act both as anti-inflammatory drugs and brain redox imaging probes in MRI
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DOI：
10.1002/mrc.4431
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发表时间：
2016-09-01
影响因子：
2
通讯作者：
Fujii, Hirotada G.
中科院分区：
文献类型：
--
作者：
Emoto, Miho C.;Sato, Shingo;Fujii, Hirotada G.
治疗探针在一个分子中提供治疗和诊断成像能力，并在磁共振成像（MRI）检查中显示出重要的前景。本研究首次描述了具有非甾体抗炎作用的氮基造影剂的合成和应用。在二氯甲烷中，以双环己基碳二亚胺和4-二甲氨基吡啶存在的情况下，通过缩合反应将布洛芬或酮洛芬的羧基与3-羟甲基-2,2,5,5-四甲基脯氨酸-1-氧的羟基连接，制备了靶向治疗探针。给药后的小鼠头部MRI显示，探针通过血脑屏障（BBB）进入大脑，导致小鼠大脑T1对比增强。这种增强持续了大约40分钟的半衰期，这比大多数硝基吡咯烷分子获得的半衰期要长。使用脂多糖（LPS）诱导的脑炎症模型检测这些治疗探针的治疗能力。一氧化氮是由LPS诱导的脓毒症小鼠脑内的炎症标志物，添加两种合成探针可显著抑制一氧化氮的产生，表明它们也具有抗炎药的作用。目前的研究结果表明，基于氮氧化物的治疗探针在败血症小鼠脑中既可以作为血脑屏障渗透的氧化还原敏感造影剂，也可以作为抗炎药物。版权所有：John Wiley & Sons， Ltd。
Theranostic probes provide both therapeutic and diagnostic imaging capabilities in one molecule and show significant promise for use inmagnetic resonance imaging (MRI) examinations. The present study describes for the first time the synthesis and utility of nitroxide-based contrast agents exhibiting a nonsteroidal anti-inflammatory drug effect. The target theranostic probes were prepared by connecting the carboxyl group of ibuprofen or ketoprofen to the hydroxyl group of 3-hydroxymethyl-2,2,5,5- tetramethylprrolidine-1-oxyl by a condensation reaction in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine in dichloromethane. MRI of mouse heads after administration of either synthesized theranostic probe indicated that the probes enter the brain by passing through the blood-brain barrier (BBB), resulting in T1 contrast enhancement in mouse brain. This enhancement persisted for the duration of the half-life of about 40 min, which is longer than that obtained by most of pyrrolidine nitroxide molecules. The therapeutic capacities of these theranostic probes were examined using a lipopolysaccharide (LPS)-induced brain inflammation model. The production of nitric oxide, an inflammation marker in septic mouse brain induced by LPS, was remarkably inhibited by the addition of either synthesized probe, indicating that they also act as anti-inflammatory drugs. The present results indicate that nitroxide-based theranostic probes act as both BBB-permeable redox-sensitive contrast agents and as an anti-inflammatory drug in septicmouse brain. Copyright (C) 2016 John Wiley & Sons, Ltd.