Photocaged DNA-Binding Photosensitizer Enables Photocontrol of Nuclear Entry for Dual-Targeted Photodynamic Therapy
- J Med Chem. 2022 Dec 22;65(24):16679-16694. doi: 10.1021/acs.jmedchem.2c01504.
- 1. Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, OntarioL5L 1C6, Canada.
- 2. Department of Chemistry, Iowa State University, Ames, Iowa50011, United States.
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.