Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive contrast agents
Probing the intracellular redox status of tumors with magnetic resonance imaging and redox-sensitive contrast agents
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DOI：
10.1158/0008-5472.can-06-0879
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Krishna, Murali C.
中科院分区：
文献类型：
--
作者：
Hyodo, Fuminori;Matsumoto, Ken-ichiro;Krishna, Murali C.
氮氧自由基是磁共振成像（MRI）中使用的顺磁性造影剂，也具有抗氧化作用。它们参与细胞氧化还原反应，在给药后随着时间的推移而失去提供对比度的能力。在这项研究中，对比度损失率与组织的还原能力或“氧化还原状态”相关。“通过MRI观察到，与正常组织相比，肿瘤中的氮氧化物优先减少。Mill使用两种细胞可渗透的氮氧化物4-羟基-2，2，6，6-四甲基-1-哌啶氧基（Tempol）和3-氨基甲酰基-2，2，5，5-四甲基吡咯烷-1-氧基（3CP）和一种细胞不可渗透的氮氧化物3-羧基-2，2，5，5，5-四甲基吡咯烷-1-氧基（3CxP）研究了氮氧化物结构对还原速率的影响。使用MRI同时获得这些氮氧自由基在小鼠正常组织、肿瘤、肾脏和动脉区域中的药代动力学图像。肿瘤组织中Tempol和3CP的衰减明显快于正常组织。从组织提取物中未观察到总氮氧化物（氧化+还原形式）的显著变化，表明作为时间函数的对比度损失是细胞内生物还原的结果。然而，在3CxP（膜不可渗透）的情况下，正常组织和肿瘤组织之间的减少率没有差异。T的时程、3CxP的增强和股骨区域3CxP的总量（氧化+还原）显示出相似的药代动力学。这些结果表明，肿瘤和正常组织中的细胞渗透性氮氧化物的差异生物还原是由细胞内过程支持的，并且还原速率是可以非侵入性地评估细胞内氧化还原状态的手段。
Nitroxide radicals are paramagnetic contrast agents, used in magnetic resonance imaging (MRI), that also exert antioxidant effects. Participating in cellular redox reactions, they lose their ability to provide contrast as a function of time after administration. In this study, the rate of contrast loss was correlated to the reducing power of the tissue or the "redox status." The preferential reduction of nitroxides in tumors compared with normal tissue was observed by MRI. The influence of the structure of the nitroxide on the reduction rate was investigated by Mill using two cell-permeable nitroxides, 4-hydroxy-2,2,6,6,-tetramethyl-1-piperidynyloxyl (Tempol) and 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (3CP), and one cell-impermeable nitroxide, 3-carboxy-2, 2,5,5,5-tetramethylpyrrolidine-1-oxyl (3CxP). Pharmacokinetic images of these nitroxides in normal tissue, tumor, kidney, and artery regions in mice were simultaneously obtained using MRI. The decay of Tempol and 3CP in tumor tissue was significantly faster than in normal tissue. No significant change in the total nitroxide (oxidized + reduced forms) was noted from tissue extracts, suggesting that the loss in contrast as a function of time is a result of intracellular bioreduction. However, in the case of 3CxP (membrane impermeable), there was no difference in the reduction rates between normal and tumor tissue. The time course of T, enhancement by 3CxP and the total amount of 3CxP (oxidized + reduced) in the femoral region showed similar pharmacokinetics. These results show that the differential bioreduction of cell-permeable nitroxides in tumor and normal tissue is supported by intracellular processes and the reduction rates are a means by which the intracellular redox status can be assessed noninvasively.