Photocaged DNA-Binding Photosensitizer Enables Photocontrol of Nuclear Entry for Dual-Targeted Photodynamic Therapy

Photodynamic therapy (PDT) is a clinically approved cancer
treatment
that requires a photosensitizer (PS), light, and molecular oxygena
combination which produces reactive oxygen species (ROS) that can
induce cancer cell death. To enhance the efficacy of PDT, dual-targeted
strategies have been explored where two photosensitizers are administered
and localize to different subcellular organelles. To date, a single
small-molecule conjugate for dual-targeted PDT with light-controlled
nuclear localization has not been achieved. We designed a probe composed
of a DNA-binding PS (Br-DAPI) and a photosensitizing photocage (WinterGreen).
Illumination with 480 nm light removes WinterGreen from the conjugate
and produces singlet oxygen mainly in the cytosol, while Br-DAPI localizes
to nuclei, binds DNA, and produces ROS using one- or two-photon illumination.
We observe synergistic photocytotoxicity in MCF7 breast cancer cells,
and a reduction in size of three-dimensional (3D) tumor spheroids,
demonstrating that nuclear/cytosolic photosensitization using a single
agent can enhance PDT efficacy.