A Universal Single-Activated-Dual-Release Vehicle: Enabling Synergistic Antitumor Therapy

Activatable combined therapeutic strategy exhibits significant potential for the management of malignant tumors. Ensuring the timely and spatially effective release of different therapeutic agents is a great challenge for maximizing the efficacy of combination therapy. Herein, based on the 1,4-and 1,6-elimination behaviors, the study proposes a novel universal single-activated-dual-release platform that can be triggered by various stimulants of interest. As a proof-of-concept, the study develops an example of a synergistic therapy called CyI-Cbl-NTR, which can be selectively activated by nitroreductase (NTR) to release the photosensitizer (CyI-OH) and DNA alkylating agent chlorambucil (Cbl), thereby enabling a combination of chemo- and photodynamic therapy. Both in vitro and in vivo experiments fully demonstrate the remarkable combined therapeutic effect of Cyl-Cbl-NTR and the feasibility of this strategy. This work provides a promising platform for the future development of activatable synergistic therapy.