Imaging probes for non-invasive tumoral detection and functional monitoring of cancer multidrug resistance

Aim: Several cationic radiotracers originally developed as myocardial perfusion agents have shown potential for both early detection of cancer and non-invasive monitoring of multiple drug resistance (MDR) by single photon emission computed tomography. We have introduced two cationic complexes, ^99mTc-DMEOP [di-methoxy-tris-pyrazolyl-^99mTc-(CO)₃] and ^99mTc-TMEOP [tri-methoxy-tris-pyrazolyl-^99mTc-(CO)₃], which showed excellent preclinical results as cardiac imaging probes, namely a persistent heart uptake with rapid blood and liver clearance. This study aimed at the evaluation of their usefulness for tumoral detection and functional assessment of MDR. Methods: The uptake and efflux kinetics of ^99mTc-DMEOP and ^99mTc-TMEOP were evaluated in human prostate, lung, and breast cancer cell lines, including drug-resistant cell lines that are known to overexpress the MDR P-glycoprotein (Pgp). The effects of MDR modulators were also studied. In vivo studies were performed in xenografted tumor models, and the MDR phenotype of the tumors was confirmed by Western blot. Results: The uptake kinetics of both complexes in human cancer cell lines is comparable with the one found for ^99mTc-Sestamibi, increasing over time. The uptake of ^99mTc-TMEOP is greatly reduced in cells overexpressing Pgp and increased in the presence of a Pgp modulator. In nude mice, the tumor uptake of ^99mTc-TMEOP was higher in the MCF-7 xenografts compared with the MCF7 Pgp tumors. Conclusion: The uptake kinetics of both complexes in human cancer cell lines is comparable with the one found for ^99mTc-Sestamibi, increasing over time. The uptake of ^99mTc-TMEOP is greatly reduced in cells overexpressing Pgp, and increased in the presence of a Pgp modulator. In nude mice, the tumor uptake of ^99mTc-TMEOP was higher in the MCF-7 xenografts compared with the MCF7 Pgp tumors.