Evaluation of 64Cu(DO3A-xy-TPEP) as A Potential PET Radiotracer for Monitoring Tumor Multidrug Resistance

摘要

In this study, we evaluated the potential of ⁶⁴Cu(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 ⁶⁴Cu(DO3A-xy-TPEP) has a high initial tumor uptake (5.27 ± 1.2 %ID/g at 5 min p.i.) and show 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. ⁶⁴Cu(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 ^99mTc-Sestamibi. Regardless of the source of MDR, the overall net effect is the rapid efflux of ⁶⁴Cu(DO3A-xy-TPEP) from tumor cells, which leads to a significant reduction of its tumor uptake. It was concluded that ⁶⁴Cu(DO3A-xy-TPEP) is more efficient than ^99mTc-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. ⁶⁴Cu(DO3A-xy-TPEP) and ^99mTc-Sestamibi share almost identical subcellular distribution patterns in U87MG glioma tumors. Thus, it is reasonable to believe that ⁶⁴Cu(DO3A-xy-TPEP), like ^99mTc-Sestamibi, is able to localize in mitochondria due to the increased plasma and mitochondrial transmembrane potentials in tumor cells.