Chopra Arvind
National Center for Biotechnology Information, NLM, Bethesda, MD 20894
The mitochondrial metabolism of cancerous cells is altered to meet their high nutritional and energy demands, and this results in the production of reactive oxygen species that are believed to assist in the transformation of normal cells to the neoplastic phenotype (1). Changes in the bioenergetics of these organelles increases the negative mitochondrial potential (compared with that of mitochondria in normal cells), which can be measured with cationic organic dyes, such as rhodamine B (a fluorescent dye) and its derivatives (e.g., Lissamine rhodamine B (LRB)), because they tend to accumulate in the mitochondria (2). Therefore, several types of fluorescent tracers have been used with optical imaging techniques and have been shown to be suitable for the visualization of tumors (3, 4). In addition, C-labeled ( = 20.4 min) or F-labeled ( = 110 min) lipophilic phosphonium cation derivatives, which are rapidly taken up by the mitochondria, have also been used to detect tumors with positron emission tomography (PET) (5) and as myocardial perfusion imaging agents (6) in preclinical studies. In another study, the biodistribution of [C]rhodamine-123 was investigated in mice, and it was concluded that this tracer is not suitable to measure levels of the P-glycoprotein transporter (P-gp; rhodamine dyes are known to target this transporter in the cells) (7). However, the short half-life and the generation of high background signals by this radionuclide in the normal organs of animals limits its application in the clinic (2). In a continuing effort to develop a radiolabeled probe that would target the cellular mitochondria and would be suitable for the visualization of cancerous tumors, LRB was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and labeled with Cu ([Cu]DOTA-LRB) (2). The main advantage of using Cu over C or F to label LRB is that the former radionuclide has a longer half-life ( = 12.7 h) and high specific activity. In addition, Cu is commercially available for institutions that lack an on-site cyclotron, which is required to produce Cu (2). The biodistribution of [Cu]DOTA-LRB was investigated in athymic nude mice bearing U87MG cell glioma xenograft tumors, which express very little P-gp (2). This tracer was also evaluated for the visualization of tumors using PET (2). Yan et al. compared the biodistribution and tumor imaging properties of [Cu]DOTA-LRB (designated as [Cu]L1 in this study) with those of three other of Cu-labeled rhodamine derivatives (designated as [Cu]L2–L4) in nude mice bearing either U87MG cell tumors or MDA-MB-435 cell tumors (these cells are known to express high levels of P-gp) (8). In addition, the use of nonradioactive [Cu]L1 was evaluated for the visualization of the U87MG cell tumors or MDA-MB-435 cell tumors in the animals.
癌细胞的线粒体代谢发生改变，以满足其对营养和能量的高需求，这导致活性氧的产生，据信这些活性氧有助于正常细胞转变为肿瘤表型(1)。这些细胞器生物能量学的变化增加了线粒体的负电位(与正常细胞中的线粒体相比)，这可以用阳离子有机染料来测量，如罗丹明B(一种荧光染料)及其衍生物(如丽丝胺罗丹明B(LRB))，因为它们倾向于在线粒体中积累(2)。因此，几种类型的荧光示踪剂已与光学成像技术一起使用，并已被证明适用于肿瘤的可视化(3,4)。此外，C标记(=20.4分钟)或F标记(=110分钟)的亲脂性鏻阳离子衍生物，它们能迅速被线粒体摄取，也已被用于在临床前研究中用正电子发射断层扫描(PET)(5)检测肿瘤以及作为心肌灌注显像剂(6)。在另一项研究中，对[C]罗丹明-123在小鼠体内的生物分布进行了研究，得出的结论是，这种示踪剂不适用于测量P-糖蛋白转运体(P-gp；已知罗丹明染料在细胞中靶向这种转运体)的水平(7)。然而，这种放射性核素在动物正常器官中的短半衰期和高背景信号的产生限制了其在临床上的应用(2)。为了持续努力开发一种靶向细胞线粒体且适用于癌性肿瘤可视化的放射性标记探针，将LRB与1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)偶联并用Cu([Cu]DOTA-LRB)标记(2)。用Cu而不是C或F标记LRB的主要优点是，前一种放射性核素具有更长的半衰期(=12.7小时)和高比活度。此外，对于缺乏现场回旋加速器(生产Cu所需)的机构来说，Cu是可商购的(2)。在携带U87MG细胞胶质瘤异种移植肿瘤的无胸腺裸鼠中研究了[Cu]DOTA-LRB的生物分布，这些肿瘤表达的P-gp非常少(2)。还使用PET对这种示踪剂进行了肿瘤可视化评估(2)。Yan等人在携带U87MG细胞肿瘤或MDA-MB-435细胞肿瘤(已知这些细胞表达高水平的P-gp)的裸鼠中，比较了[Cu]DOTA-LRB(在本研究中指定为[Cu]L1)与其他三种Cu标记的罗丹明衍生物(指定为[Cu]L2-L4)的生物分布和肿瘤成像特性(8)。此外，还评估了使用非放射性的[Cu]L1对动物体内U87MG细胞肿瘤或MDA-MB-435细胞肿瘤的可视化情况。
