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.
Cancer phototherapy activates immunogenic cell death (ICD) and elicits a systemic antitumor immune response, which is an emerging approach for tumor treatment. Most available photosensitizers require a combination of immune adjuvants or checkpoint inhibitors to trigger antitumor immunity because of the immunosuppressive tumor microenvironment and the limited phototherapeutic effect. A class of tumor‐targeting heptamethine cyanine photosensitizers modified with an endoplasmic reticulum (ER)‐targeting group (benzenesulfonamide) are synthesized. Phototherapy of tumor cells markedly amplifies ER stress and promotes tumor antigen release, as the ER is required for protein synthesis, secretion, and transport. More importantly, different electron‐donating or ‐withdrawing substitutions are introduced into benzenesulfonamide to modulate the nonradiative decay pathways through intramolecular charge transfer, including singlet–triplet intersystem crossing (photodynamic effect) and internal thermal conversion (photothermal effect). Thus, a heptamethine cyanine photosensitizer containing a binitro‐substituted benzenesulfonamide (ER‐Cy‐poNO2) is identified that preferentially accumulates in the ER of tumor cells. It significantly enhances the phototherapeutic effect by inducing excessive ER stress and robust ICD. Consequently, this small molecular photosensitizer triggers a sufficient antitumor immune response and effectively suppresses the growth of both primary and distant metastatic tumors, whereas no apparent toxicity is observed. This heptamethine cyanine photosensitizer has the potential to enhance cancer‐targeted immunotherapy.
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