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.