Synthesis of Mitochondria-Anchored Nitroimidazoles with a Versatile NIR Fluorophore for Hypoxic Tumor-Targeting Imaging and Chemoradiotherapy

Nitroimidazoles are one of the most
common radiosensitizers investigated
to combat hypoxia-induced resistance to cancer radiotherapy. However,
due to poor selectivity distinguishing cancer cells from normal cells,
effective doses of radiosensitization are much closer to the doses
of toxicity induced by nitroimidazoles, limiting their clinical application.
In this work, a tumor-targeting near-infrared (NIR) cyanine dye (IR-808)
was utilized as a targeting ligand and an NIR fluorophore tracer to
chemically conjugate with different structures of hypoxia-affinic
nitroimidazoles. One of the NIR fluorophore-conjugated nitroimidazoles
(808-NM2) was identified to preferentially accumulate in hypoxic tumor
cells, sensitively outline the tumor contour, and effectively inhibit
tumor growth synergistically by chemotherapy and radiotherapy. More
importantly, nitroimidazoles were successfully taken into cancer cell
mitochondria via 808-NM2 conjugate to exert the synergistic effect
of chemoradiotherapy. Regarding the important roles of mitochondria
on cancer cell survival and metastasis under hypoxia, 808-NM2 may
be hopeful to fight against hypoxic tumors.