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

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.