Rational design of a GSH-responsive, water-soluble, heavy-atom-free anthracene-BODIPY photosensitizer for near-infrared fluorescence imaging guided photodynamic therapy

Developing heavy-atom-free photosensitizers (PS) for photodynamic therapy (PDT) faces significant challenges in simultaneously achieving high fluorescence emission and reactive oxygen species (ROS) generation, together with poor aqueous solubility that limits biological applicability. Herein, a molecular design strategy that addresses these limitations by exploiting spin-orbit charge transfer intersystem crossing (SOCT-ISC) in an orthogonal donor-acceptor (D-A) dyad was proposed. An anthracene donor and a BODIPY (boron-dipyrromethene) acceptor were covalently linked to promote photoinduced charge transfer and enhance SOCT-mediated ISC without incorporation of heavy atoms, thereby reconciling appreciable fluorescence with effective triplet population and ¹O₂ production. Introducing piperazinium moieties confers high aqueous solubility and favorable biocompatibility through permanent cationic character. Furthermore, an activatable photosensitizer, BDP-1, was developed for selective switching on by elevated intracellular glutathione (GSH) levels to restore fluorescence response and concomitantly enable ¹O₂ generation under 660 nm illumination, triggering apoptosis in cancer cells and enabling safe tumor ablation in vivo. This work demonstrates a versatile platform for designing activatable, hydrophilic, heavy-atom-free PS that balance emissive properties and phototoxicity for translational phototherapeutic applications, and achieving fluorescence imaging guided photodynamic therapy for tumor-bearing mice in vivo efficiently.