Nitric Oxide Activatable Photodynamic Therapy Agents Based on BODIPY-Copper Complexes

In this work, two BODIPY-bipyridine Cu²⁺ ion complexes for targeted nitric oxide (NO) activatable photodynamic therapy are reported. The design is based on the relatively high concentration of these small gas molecules in the tumor microenvironment. Copper(II) ion complexation to the photosensitizer renders it in the OFF position in terms of fluorescence and reactive oxygen species (ROS) production. The interaction of the Cu²⁺-BODIPY complex with nitric oxide interchanges both fluorescence and therapy mode into the ON state through the detachment of the cation. Therefore, targeting the cancer cells would be expected to be achieved in this way. Moreover, one of the compounds, AP5, has increased aqueous solubility due to the polar structure. The designed structures also have near-infrared (IR) absorption ability up to 800 nm aqueous solutions. In addition, through using in vitro cell culture studies with HeLa and RAW264.7 cell lines, we confirmed that AP5 and AP6 could be activated in the presence of NO, and cell photocytotoxicity occurred extensively compared with the NO-absent cells. We believe that this work will provide new opportunities for the increased efficacy of the photodynamic treatment of cancer and smart photosensitizer design.