Radiotherapy‐Induced Cleavage of Quaternary Ammonium Groups Activates Prodrugs in Tumors

Abstract Cleavage chemistry offers a new chance to activate chemotherapeutic prodrugs in a tumor‐selective manner, yet developing spatiotemporally controllable cleavage chemistry with deep tissue penetration is still a great challenge. Herein, we present a novel radiotherapy‐triggered cleavage chemistry that enables controlled drug release in tumors. Quaternary ammonium groups are identified as masking groups that can be efficiently removed by hydrated electrons (e − aq ) from water radiolysis. The subsequently released tertiary amines can be anti‐cancer toxins or readily release functional molecules via 1,6‐elimination. This radiotherapy‐induced cleavage works successfully in living cells and tumor‐bearing mice, showing remarkable treatment efficacy when the mice are given carfilzomib prodrug and radiotherapy. This strategy provides a new perspective for combinational radiochemotherapy, which is the first‐line treatment for over 50 % of cancer patients.