Liu Shuang, Kim Young-Seung, Zhai Shizhen, Shi Jiyun, Hou Guihua
Purdue University, West Lafayette, Indiana.
Bioconjug Chem. 2009 Apr;20(4):790-8. doi: 10.1021/bc800545e.
In this study, we evaluated the potential of (64)Cu(DO3A-xy-TPEP) (DO3A-xy-TPEP = (2-(diphenylphosphoryl)ethyl)diphenyl(4-((4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl)methyl)benzyl)phosphonium) as a PET (positron emission tomography) radiotracer for noninvasive monitoring of multidrug resistance (MDR) transport function in several xenografted tumor models (MDR-negative: U87MG; MDR-positive: MDA-MB-435, MDA-MB-231, KB-3-1, and KB-v-1). It was found that (64)Cu(DO3A-xy-TPEP) has a high initial tumor uptake (5.27 +/- 1.2%ID/g at 5 min p.i.) and shows a steady uptake increase between 30 and 120 min p.i. (2.09 +/- 0.53 and 3.35 +/- 1.27%ID/g at 30 and 120 min p.i., respectively) in the MDR-negative U87MG glioma tumors. (64)Cu(DO3A-xy-TPEP) has a greater uptake difference between U87MG glioma and MDR-positive tumors (MDA-MB-231: 1.57 +/- 0.04, 1.00 +/- 0.17, and 0.93 +/- 0.15; MDA-MB-435: 1.15 +/- 0.19, 1.12 +/- 0.20, and 0.81 +/- 0.11; KB-3-1: 1.45 +/- 0.31, 1.43 +/- 0.16, and 1.08 +/- 0.19; and KB-v-1: 1.63 +/- 0.47, 1.81 +/- 0.31, and 1.14 +/- 0.22%ID/g at 30, 60, and 120 min p.i., respectively) than (99m)Tc-Sestamibi. Regardless of the source of MDR, the overall net effect is the rapid efflux of (64)Cu(DO3A-xy-TPEP) from tumor cells, which leads to a significant reduction of its tumor uptake. It was concluded that (64)Cu(DO3A-xy-TPEP) is more efficient than (99m)Tc-Sestamibi as the substrate for MDR P-glycoproteins (MDR Pgps) and multidrug resistance-associated proteins (MRPs), and might be a more efficient radiotracer for noninvasive monitoring of the tumor MDR transport function. (64)Cu(DO3A-xy-TPEP) and (99m)Tc-Sestamibi share almost identical subcellular distribution patterns in U87MG glioma tumors. Thus, it is reasonable to believe that (64)Cu(DO3A-xy-TPEP), like (99m)Tc-Sestamibi, is able to localize in mitochondria due to the increased plasma and mitochondrial transmembrane potentials in tumor cells.
在本研究中，我们评估了（64）Cu（DO3A-xy-TPEP）（DO3A-xy-TPEP =（2-（二苯基磷酰基）乙基）二苯基（4-（（4,7,10-三（羧甲基）-1,4,7,10-四氮杂环十二烷-1-基）甲基）苄基）鏻）作为正电子发射断层扫描（PET）放射性示踪剂，用于在几种异种移植肿瘤模型（MDR阴性：U87MG；MDR阳性：MDA-MB-435、MDA-MB-231、KB-3-1和KB-v-1）中无创监测多药耐药（MDR）转运功能的潜力。研究发现，（64）Cu（DO3A-xy-TPEP）在MDR阴性的U87MG胶质瘤肿瘤中具有较高的初始肿瘤摄取率（注射后5分钟时为5.27±1.2%ID/g），并且在注射后30至120分钟之间摄取率稳步增加（注射后30分钟和120分钟时分别为2.09±0.53和3.35±1.27%ID/g）。与（99m）Tc-司他比相比，（64）Cu（DO3A-xy-TPEP）在U87MG胶质瘤与MDR阳性肿瘤（MDA-MB-231：注射后30、60和120分钟时分别为1.57±0.04、1.00±0.17和0.93±0.15；MDA-MB-435：分别为1.15±0.19、1.12±0.20和0.81±0.11；KB-3-1：分别为1.45±0.31、1.43±0.16和1.08±0.19；KB-v-1：分别为1.63±0.47、1.81±0.31和1.14±0.22%ID/g）之间具有更大的摄取差异。无论MDR的来源如何，总体净效应是（64）Cu（DO3A-xy-TPEP）从肿瘤细胞中快速流出，这导致其肿瘤摄取显著降低。得出结论为，作为MDR P-糖蛋白（MDR Pgps）和多药耐药相关蛋白（MRPs）的底物，（64）Cu（DO3A-xy-TPEP）比（99m）Tc-司他比更有效，并且可能是用于无创监测肿瘤MDR转运功能的更有效放射性示踪剂。在U87MG胶质瘤肿瘤中，（64）Cu（DO3A-xy-TPEP）和（99m）Tc-司他比具有几乎相同的亚细胞分布模式。因此，有理由相信，与（99m）Tc-司他比一样，（64）Cu（DO3A-xy-TPEP）能够由于肿瘤细胞中血浆和线粒体跨膜电位的增加而定位于线粒体。
