Promising G-Quadruplex-Targeted Dibenzoquinoxaline Type-1 Photosensitizer Triggers DNA Damage in Triple-Negative Breast Cancer Cells

Abstract

G-quadruplexes (G4s) are potential drug targets in cancer treatment. However, the G4-targeted ligands seem to lack sufficient selectivity between tumors and normal tissues, appealing for a new modified anticancer strategy on the basis of them. Type-1 photodynamic therapy (PDT) is a promising strategy possessing excellent spatiotemporal precision for solid tumors with a hypoxic microenvironment. However, type-1 photosensitizers that target G4s and induce in situ photodamage have never been previously reported. In this study, we reported a promising type-1 photosensitizer based on a G4-targeted, high-contrast fluorescent ligand (TR2). The subsequent studies demonstrated that TR2 could transfer from lysosomes to nuclei and induce elevated G4 formation as well as DNA damage upon irradiation. Notably, it was observed that TR2 may not activate DNA damage repair machinery upon irradiation, suggesting a durable, strong effect on inducing DNA damage. Consequently, light-irradiated TR2 exhibited excellent photocytotoxicity on triple-negative breast cancer cell proliferation (at nanomolar concentration) and showed obvious inhibition on the growth of three-dimensional (3D) tumor spheroids. Finally, RNA-seq analysis demonstrated that TR2-mediated PDT may have a negative impact on enhancing the DNA damage repair machinery and may activate the antitumor immunity pathways. Overall, this study provided a promising chemical tool for image-guided PDT.