Targeted Radionuclide Therapy Activates Prodrugs for\nTreating Metastasis

Over 90% of cancer\npatients succumb to metastasis, yet conventional\nfrontline therapy struggles to halt the progression of metastatic\ntumors. Targeted radionuclide therapy, which delivers radiation precisely\nto tumor sites, shows promise for treating metastasis. The rational\ndesign of a prodrug activation platform using radionuclides would\nbe an ideal approach to synergize chemotherapy with targeted radionuclide\ntherapy, yet it has not been established. Here, we present targeted\nradionuclide therapy-induced cleavage chemistry that enables the controlled\nrelease of oxaliplatin and its axis ligands from oxaliplatin(IV) complexes\nin living systems. Of note, this strategy demonstrates feasibility\nover clinically relevant β-emitting radionuclides and exhibits\ndose dependence. These advantages were taken into account, and a Lutetium-177-activatable\nplatinum(IV) based prodrug system was designed that could achieve\nlocalized activation at the tumor site with high efficiency, thereby\nsuppressing subcutaneous and metastatic 4T1 tumors. In summary, our\napproach highlights the potential of radionuclides as reaction switches,\nbridging the gap between the radiotherapy-induced reaction and internal\nradiation. It may provide a new perspective for future combination\ntherapy.