GSH-activatable copper-elsinochrome off-on photosensitizer for combined specific NIR-II two-photon photodynamic/chemodynamic therapy

The complexity of cancer therapy has led to the emergence of combination therapy as a promising approach to enhance treatment efficacy and safety. The integration of glutathione (GSH)-activatable two-photon photodynamic therapy (TP-PDT) and chemodynamic therapy (CDT) offers the possibility to advance precision and efficacy in anti-cancer treatments. In this study, a GSH-activatable photosensitizer (PS), namely copper-elsinochrome (CuEC), is synthesized and utilized for combination second near-infrared (NIR-II) TP-PDT/CDT. The Cu²⁺ acts as a “lock”, suppressing the fluorescence and ¹O₂ generation ability of EC in a normal physiological environment (“OFF” state). However, the overexpressed GSH in the tumor microenvironment acts as the “key”, resulting in the release of EC (“ON” state) and Cu⁺ (reduced by GSH). The released EC can be utilized for fluorescence imaging and TP-PDT under NIR-II (λ = 1000 nm) two-photon excitation, while Cu⁺ can generate highly toxic hydroxyl radicals (^•OH) via Fenton-like reaction for CDT. Additionally, this process consumes GSH and diminishes the tumor's antioxidant capacity, thereby augmenting the efficacy of combination therapy. The CuEC achieves significant tumor cell ablation in both 2D monolayer cells and 3D multicellular tumor spheres through the combination of NIR-II TP-PDT and CDT. © 2025 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.