Electrochemical Detection of a Novel Pt(IV) Prodrug with the Metronidazole Axial Ligand in the Hypoxic Area
Daniil V. Spector, Alexander S. Erofeev, Petr V. Gorelkin, Alexander N. Vaneev, Roman Akasov, Nikolay V. Ul’yanovskiy, Вита Н. Никитина, Alevtina S. Semkina, Kseniya Yu. Vlasova, Mikhail A. Soldatov, Alexander L. Trigub, Dmitry A. Skvortsov, Alexander V. Finko, Н. В. Зык, Dmitry Sakharov, Alexander G. Majouga, Елена К. Белоглазкина, Olga O. Krasnovskaya
Abstract
We report herein a Pt(IV) prodrug with metronidazole in axial positions Pt-Mnz. The nitroaromatic axial ligand was conjugated with a cisplatin scaffold to irreversibly reduce under hypoxic conditions, thereby retaining the Pt(IV) prodrug in the area of hypoxia. X-ray near-edge adsorption spectroscopy (XANES) on dried drug-preincubated tumor cell samples revealed a gradual release of cisplatin from the Pt-Mnz prodrug instead of rapid intracellular degradation. The ability of the prodrug to penetrate into three-dimensional (3D) spheroid cellular cultures was evaluated by a novel electrochemical assay via a platinum-coated carbon nanoelectrode, capable of single-cell measurements. Using a unique technique of electrochemical measurements in single tumor spheroids, we were able to both detect the real-time response of the axial ligand to hypoxia and establish the depth of penetration of the drug into the tumor model.