Smart Aza-BODIPY Photosensitizer for Tumor Microenvironment-Enhanced Cancer Phototherapy

Photoactivated cancer therapeutic methods emerging in recent decades, such as photothermal therapy (PTT) and photodynamic therapy (PDT), have drawn worldwide research interest. Herein, a smart near-infrared (NIR) photosensitizer 4-(4-(7-(4-Bromophenyl)-1,9-bis(3,4-dimethoxyphenyl)-5,5-difluoro-5H-5l4,6l4-dipyrrolo[1,2-c:2′,1′-f][1,3,5,2]triazaborinin-3-yl)phenyl)morpholine (MAB) with morpholine decorating on the aza-BODIPY core is synthesized to achieve dual-modal imaging-guided synergistic PDT/PTT, exhibiting a tumor microenvironment (TME) enhanced cancer theranostic performance. The introduction of electron-donating morpholine offers MAB-enhanced intramolecular charge transfer (ICT) and a pronounced red-shift with maximum absorption peak (λ_max) at 730 nm. After encapsulating with amphiphilic polymer DSPE-mPEG₂₀₀₀, as-obtained MAB nanoparticles (NPs) with good biocompatibility can enrich targeting in the lysosomes of tumor cells and afterward be activated under the acidic microenvironment inside the lysosome (pH 5.0) to generate intracellular reactive oxygen species (ROS) for enhanced PDT through interruption of photoinduced electron transfer (PET). Through in vitro cytotoxicity assay studies, the half-maximal inhibitory concentration (IC₅₀) of MAB NPs under irradiation with the 730 nm laser is ∼10 μg/mL, indicating an excellent phototherapy effect. Furthermore, an in vivo study illustrates a prominent PDT/PTT synergistic therapeutic effect, and MAB NPs can be rapidly metabolized.