Lysosome-targeting amplifiers of reactive oxygen species as anticancer prodrugs

Cancer cells produce elevated amounts of reactive oxygen species that has been used to design cancer specific prodrugs. Their activation relies on at least a bimolecular process, where a prodrug reacts with ROS. However, at low µM concentrations of the prodrugs and ROS the activation is usually inefficient. Herein we suggested and validated a potentially general approach for solving this intrinsic problem of ROS-dependent prodrugs. In particular, known 4-(N-ferrocenyl-N-benzylaminocarbonyloxymethyl)phenylboronic acid pinacol ester was converted to its lysosome specific analogue. Since lysosomes contain the higher concentration of active ROS than cytoplasm, activation of the latter prodrug was facilitated with respect to the parent compound. In particular, it was found to exhibit high anticancer activity in a variety of cancer cell lines (IC50 3.5-7.2 µM) and in vivo (40 mg/kg, NK/Ly murine model), but remained weakly toxic towards non-malignant cells (IC50 15-30 µM).