Heavy-atom-free BODIPY-based photodynamic therapy agents activated at long wavelengths†

Photodynamic therapy (PDT) is an emerging clinical tool that uses light as an agent unleashing cytotoxic activity for treating cancer and other diseases, including those showing drug resistance. One of the main areas of research to fully implement PDT as a real alternative to chemo or radiotherapy is the development of improved photosensitizers (PSs). This work aims to contribute to the design of novel PSs able to generate reactive oxygen species (ROS) upon activation with light within the biological window (deep red or near-infrared region) while being non-toxic under dark conditions (heavy-atom-free). For this, we have chosen BODIPY-based covalent dimers directly linked through their 3-position as model structures. This molecular scaffold has been previously tested as a fluorescent probe to stain cells, but not as a PS for ROS generation under red illumination. Using readily available synthetic protocols, we have changed the steric hindrance around the linkage and added functional groups suited to enhance targetable biorecognition and solubility in physiological media. The spectroscopic characterization confirms that these dimers are photoactivated in a spectral window approaching 700 nm and display noticeable fluorescence signals beyond this wavelength, together with a notable generation of singlet oxygen. Encouraged by these photophysical signatures, we conducted in vitro trials in cancer cells. These assays ratify the ability of most of the herein reported dimers to sensitize ROS and induce cell death upon long-wavelength illumination.