Does the ATSM-Cu(II) Biomarker Integrate into the Human Cellular Copper Cycle?

Hypoxia is commonly encountered in the tumor microenvironment and drives proliferation, angiogenesis, and resistance to therapy. Imaging of hypoxia is important in many disease states in oncology, cardiology, and neurology. Finding clinically approved imaging biomarkers for hypoxia has proved challenging. Candidate biomarkers have shown low uptake into tumors and low signal to background ratios that adversely affect imaging quality. Copper complexes have been identified as potential biomarkers for hypoxia owing to their redox ability. Active uptake of copper complexes into cells could ensure selectivity and high sensitivity. We explored the reactivity and selectivity of the ATSM-Cu(II) biomarker to proteins that are involved in the copper cycle using electron paramagnetic resonance (EPR) spectroscopy and UV-vis measurements. We show that the affinity of the ATSM-Cu(II) complex to proteins in the copper cycle is low and the cell probably does not actively uptake ATSM-Cu(II).