Radiotherapy Activates Drug–Drug Conjugates for Platinum-Based Combinational Chemotherapy

Platinum-based combination chemotherapy is a standard first-line treatment for major cancers. However, its dose-limiting toxicity significantly compromises the clinical utility. Here, we established a radiotherapy-activated platinum(IV) prodrug platform for selective activation in tumors, thereby reducing the systemic toxicity in concurrent chemoradiotherapy. A library of Pt(IV) prodrugs functionalized with amino-, hydroxyl-, and carboxyl-containing moieties via carbamate, carbonate, and ester linkages was synthesized and screened for favorable stability and radiation-triggered reactivity in biological environments. The optimized platform was then extended to incorporate bioactive ligands that release cytotoxic agents upon irradiation. Critically, a human serum albumin (HSA)-binding motif was integrated to prolong the systemic circulation time and enhance tumor accumulation. In summary, we established a chemical platform that leverages the radiation-induced reduction of Pt(IV) to enable platinum-based combinational therapy, achieved by selectively releasing two bioactive agents in tumors. This system also exploits albumin-mediated transport to improve pharmacokinetic profiles, facilitate selective drug activation, and enhance antitumor efficacy.