Redox-Inactive Terpyridine Zn(II)-Azide Complexes for Photodynamic and Photoactivatable Chemotherapy

The rational design of metal complexes exhibiting both photodynamic therapy (PDT) and photoactivatable chemotherapy (PACT) remains a significant challenge in the phototherapeutic regimen. Herein, we developed a series of terpyridine zinc(II)-azide complexes; among them, lead complex Tpatpy@ZnN₃ shows both type I and type II PDT, along with the photorelease of azidyl radicals. The Tpatpy@ZnN₃ complex targets mitochondria; upon blue light activation (456 nm), it generates singlet oxygen (¹O₂), hydroxyl radical (^•OH), and azidyl radical (N₃^•). The produced reactive oxygen and nitrogen species induce oxidative stress, ultimately leading to mitochondrial-mediated cellular apoptosis. The complex demonstrated significant efficacy in both two-dimensional (2D) cancer cells and three-dimensional (3D) multicellular tumor spheroids. Notably, the zinc(II) complex is biocompatible, cost-effective, and redox-inactive, exhibiting negligible dark toxicity. This study highlights the efficacy of Tpatpy@ZnN₃ for synergistic and enhanced therapeutic potential with spatial and temporal precision, paving the way for the development of photoactivatable zinc complexes for cancer therapy.