Defeating Relapsed and Refractory Malignancies Through a Nano-enabled Mitochondria-mediated Respiratory Inhibition and Damage Pathway

Hypoxia, which frequently reduces the sensitivity to many therapeutic interventions, including chemotherapy, radiotherapy and phototherapy, has been acknowledged as an important reason for poor prognosis. Burgeoning evidences have proved that the tumor hypoxia microenvironment can reduce the therapeutic effect on tumor through inhibiting the drug efficacy, limiting immune cell infiltration of tumors and accelerating tumor recurrence and metastasis. However, the relationship between oxygen supply and the proliferation of cancer cells is still ambiguous and argued. Different from the current commonly used oxygen supply strategies, this study concentrated on the reduction of endogenous oxygen consumption. Specifically, a novel photosensitizers (IR780) and metformin are packaged in PEG-PCL liposomes. Once such nanoparticles accumulated in tumor tissues, the tumor foci were irradiated through 808 nm laser, generated ROS to further release metformin and IR780. Metformin can directly inhibit the activity of complex Ⅰ in the mitochondrial electron transport chain, thus performed a potent inhibitor of cell respiration. After overcoming tumor hypoxia, the combination of mitochondria-targeted photodynamic therapy (PDT) and photothermic therapy (PTT) via IR780 may achieve superior synergistically therapeutic efficacy. Benefit from excellent characteristics of IR780, such synergistic PDT PTT with the inhibition of mitochondrial respiration can be monitored through near-infrared/photoacoustic dual-modal imaging. Such a conception of reducing endogenous oxygen consumption may offer a novel way to solve the important puzzles of hypoxia-induced tumor resistance to therapeutic interventions, not limited to phototherapy.