Evaluation of (64)Cu(DO3A-xy-TPEP) as a potential PET radiotracer for monitoring tumor multidrug resistance.
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.
Liu
Shuang
S
Purdue University, West Lafayette, Indiana. lius@pharmacy.purdue.edu
Kim
Young-Seung
YS
Zhai
Shizhen
S
Shi
Jiyun
J
Hou
Guihua
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D016572:Cyclosporine / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008657:Metabolic Clearance Rate; D051379:Mice; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009942:Organometallic Compounds / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011849:Radioactive Tracers; D014018:Tissue Distribution
D018435:ATP Binding Cassette Transporter, Subfamily B; D003300:Copper; D016572:Cyclosporine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D011849:Radioactive Tracers