An activatable unimolecular phototheranostic agent for synergistic chemo-photodynamic therapy

Precise control over spatiotemporal release of cancer therapeutics remains a significant challenge in developing effective combination therapies. Herein, we report a hydrogen peroxide (H₂O₂)-activatable unimolecular platform (ICy-Cb) that integrates cancer imaging and synchronized dual-modal therapy. An iodized hemicyanine photosensitizer and chlorambucil are integrated into a single molecular structure that selectively reacts to the high concentration of H₂O₂ present in the tumor microenvironment. ICy-Cb initially exhibits no fluorescence and is therapeutically inert due to the suppression of its intramolecular charge transfer (ICT) effect. Upon exposure to tumor-associated H₂O₂, ICy-Cb simultaneously releases both therapeutic components, demonstrating exceptional tumor selectivity (5 to 8 folds higher activation in cancer cells), deep penetration in 3D tumor models (180 μm), and persistent tumor accumulation in vivo. Most importantly, this synchronized chemo-photodynamic agent achieves superior tumor growth inhibition (92%) compared to either monotherapy. This theranostic agent represents a significant advancement for precision cancer treatment by enabling spatiotemporally controlled combination therapy within the tumor microenvironment.