Zhelev Zhivko, Gadjeva Veselina, Aoki Ichio, Bakalova Rumiana, Saga Tsuneo
Diagnostic Imaging Program, Molecular Imaging Center, NIRS-Chiba, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Mol Biosyst. 2012 Oct;8(10):2733-40. doi: 10.1039/c2mb25128k.
The present study shows that hydrophobic and cell-penetrating piperidine-type nitroxide radicals SLENU and TEMPOL, but not hydrophilic and partially penetrating or non-penetrating pyrrolidine-type nitroxides carbamoyl-PROXYL and carboxy-PROXYL, are appropriate contrast agents for magnetic resonance imaging (MRI) of cancer, based on its functionality - tissue redox activity. The experiments were conducted on anesthetized mice: healthy and neuroblastoma-bearing in a moderate stage of cancer development. The method is based on the nitroxide redox cycle, coupled with appearance or disappearance of the MRI signal. The half-life (τ(1/2)) of a nitroxide-enhanced MRI signal in the respective tissue was used as a marker to assess tissue redox activity to the nitroxide radical. In the case of SLENU and TEMPOL, there were large differences in the histograms between control and cancer-bearing mice. All tissues (cancer and non-cancer) of cancer-bearing organisms were characterized by a long-lived MRI signal (τ(1/2) > 14 min), indicating a high oxidative activity. The tissues of healthy organisms were characterized by a short-lived MRI signal (τ(1/2) = 1-3 min), indicating a high reducing activity. In the case of carbamoyl-PROXYL and carboxy-PROXYL, there was no difference in the histograms between control and cancer-bearing mice. The data show that the penetration of nitroxide in cells and tissues is obligatory for imaging of cancer, based on its redox activity. The principle of the method is applicable also to biopsy specimens, using MRI or EPR spectroscopy. We provide direct evidence that the nitroxide redox cycle could be used as a sensing platform for functional imaging of different pathologies, based on changes in cellular and tissue redox activity, as in the case of cancer.
本研究表明，基于其功能——组织氧化还原活性，疏水性且具有细胞穿透性的哌啶型氮氧自由基SLENU和TEMPOL，而非亲水性且部分穿透或不穿透的吡咯烷型氮氧自由基氨甲酰基 - PROXYL和羧基 - PROXYL，是用于癌症磁共振成像（MRI）的合适造影剂。实验在麻醉的小鼠身上进行：包括健康小鼠以及处于癌症发展中期的荷神经母细胞瘤小鼠。该方法基于氮氧自由基的氧化还原循环，以及MRI信号的出现或消失。氮氧自由基增强的MRI信号在相应组织中的半衰期（τ(1/2)）被用作评估组织对氮氧自由基氧化还原活性的标志物。对于SLENU和TEMPOL，对照组和荷癌小鼠之间的直方图存在很大差异。荷癌生物体的所有组织（癌组织和非癌组织）都具有长寿命的MRI信号（τ(1/2) > 14分钟），表明氧化活性高。健康生物体的组织具有短寿命的MRI信号（τ(1/2) = 1 - 3分钟），表明还原活性高。对于氨甲酰基 - PROXYL和羧基 - PROXYL，对照组和荷癌小鼠之间的直方图没有差异。数据表明，基于其氧化还原活性，氮氧自由基在细胞和组织中的穿透对于癌症成像至关重要。该方法的原理也适用于活检标本，可使用MRI或电子顺磁共振光谱法。我们提供了直接证据，即基于细胞和组织氧化还原活性的变化，如在癌症情况下，氮氧自由基氧化还原循环可作为不同病理功能成像的传感平台。
