Over 90% of cancer patients succumb to metastasis, yet conventional frontline therapy struggles to halt the progression of metastatic tumors. Targeted radionuclide therapy, which delivers radiation precisely to tumor sites, shows promise for treating metastasis. The rational design of a prodrug activation platform using radionuclides would be an ideal approach to synergize chemotherapy with targeted radionuclide therapy, yet it has not been established. Here, we present targeted radionuclide therapy-induced cleavage chemistry that enables the controlled release of oxaliplatin and its axis ligands from oxaliplatin(IV) complexes in living systems. Of note, this strategy demonstrates feasibility over clinically relevant β-emitting radionuclides and exhibits dose dependence. These advantages were taken into account, and a Lutetium-177-activatable platinum(IV) based prodrug system was designed that could achieve localized activation at the tumor site with high efficiency, thereby suppressing subcutaneous and metastatic 4T1 tumors. In summary, our approach highlights the potential of radionuclides as reaction switches, bridging the gap between the radiotherapy-induced reaction and internal radiation. It may provide a new perspective for future combination therapy.
© 2024 The Authors. Published by American Chemical Society.