A lysosome-targeted and polarity-responsive photosensitizer for tumor specific imaging and photodynamic therapy

Photodynamic therapy (PDT) represents an effective and promising strategy for cancer treatment. Nevertheless, the poor targeting specificity of conventional photosensitizers has severely impeded its clinical application. Consequently, the development of novel photosensitizers that integrate imaging-guided diagnosis and synergistic phototherapeutic efficacy is highly desirable to improve PDT performance. In this work, we designed and synthesized a lysosome-targeted photosensitizer HBT-CUR with D-π-A feature based on 2-(2'-hydroxyphenyl) benzothiazole (HBT) and difluoroborate moieties for tumor image-guided PDT. HBT-CUR exhibits near-infrared (NIR) fluorescence emission, along with high polarity sensitivity, excellent stability, high lysosome-targeting specificity and good biocompatibility. By exploiting the distinct polarity differences between normal and tumor cells, HBT-CUR enables specific NIR fluorescence imaging of tumor tissues, with a fluorescence intensity ∼6-fold higher than that in normal tissues. Moreover, HBT-CUR exhibits a fast in vivo response (10 min) and prolonged duration (6 h with robust fluorescence emission). More importantly, HBT-CUR can efficiently generate singlet oxygen under light irradiation (Φ_Δ = 0.70 in dioxane), thereby achieving effective photodynamic tumor ablation in MCF-7 tumor-bearing mouse models. Density functional theory (DFT) calculations reveal that the synergistic interplay between excited-state intramolecular proton transfer (ESIPT) and intramolecular charge transfer (ICT) processes contributes to the superior luminescence performance of HBT-CUR. This work presents a promising phototheranostic agent for tumor-specific image-guided photodynamic therapy, offering a new strategy for the rational design and development of tumor PDT systems.