A simple hydrogen peroxide-activatable Bodipy for tumor imaging and type I/II photodynamic therapy

Tumor microenvironment-activatable photosensitizers have gained significant attention for cancer theranostics. Considering the hypoxic environment of solid tumors, activatable phototheranostic agents with type I PDT are desired to obtain improved cancer treatment efficiency. Herein, we report a simple, effective and multifunctional Bodipy photosensitizer for tumor imaging and type I/II photodynamic therapy. The photosensitizer featuring a methylphenylboronic acid pinacol ester group at the meso-position of Bodipy specifically responds to tumor-abundant H₂O₂. Its photophysical properties were characterized using steady-state and time-resolved transient optical spectroscopies. The fluorescence (Φ_F = 0.09%) and singlet oxygen efficacy (Φ_Δ = 10.2%) of the Bodipy units were suppressed in the caged dyads but significantly enhanced (Φ_F = 0.72%, Φ_Δ = 20.3%) upon H₂O₂ activation. Fluorescence emission spectroscopy and continuous wave electron paramagnetic resonance (EPR) spectroscopy confirmed that the Bodipy photosensitizer generates reactive oxygen species (ROS) via both electron transfer-mediated type I and energy transfer-mediated type II mechanisms. In vitro experiments demonstrated rapid internalization into tumor cells, enhanced brightness stimulated by tumor microenvironments, and tumor cell death (phototoxicity, IC₅₀ = 0.5 μM). In vivo fluorescence imaging indicated preferential accumulation of this Bodipy photosensitizer in tumor sites, followed by decaging by tumor-abundant H₂O₂, further elevating the signal-to-background ratio (SBR) of imaging. Besides outstanding performance in tumor imaging, a prominent inhibition of tumor growth was observed. Given its simple molecular skeleton, this Bodipy photosensitizer is a competitive candidate for cancer theranostics.