A novel photosensitizer (hE26) for photodynamic therapy enhances anticancer efficacy via reactive oxygen species-induced mitochondrial apoptosis in non-small cell lung cancer.

Introduction: Non-small cell lung cancer (NSCLC) remains a leading cause of mortality and thus requires novel therapeutic interventions. Although our previously synthesized phosphorus tetraphenylporphyrin (E26) effectively induces cell death via photodynamic therapy (PDT), its 610-nm excitation wavelength limits deep-tissue penetration. To address this limitation, we developed a novel hydrogenated derivative, hE26, in which excitation is shifted to an optimized longer wavelength of 660 nm. Methods: The anticancer potential of the novel hE26-mediated PDT and the former compound E26 was compared in human NSCLC cells via MTT, wound healing, immunohistochemistry, and qPCR analyses. Results: In A549, EBC-1, and ACC-MESO-4 cells, hE26-mediated PDT significantly reduced cell viability in a dose-dependent manner in low-dose ranges compared with E26. At the same dose (15 nM), significant inhibition of cell proliferation and migration was observed in hE26-treated NSCLC cells. hE26 selectively targeted the mitochondria in A549 cells, triggering potent reactive oxygen species (ROS) generation post-irradiation. The Bax/Bcl-xL ratio and number of apoptotic cells were significantly elevated following treatment with 15 nM hE26-mediated PDT compared with both the untreated control and cells treated with an equivalent dose of E26. Cytochrome c release from mitochondria into the cytosol and expression of cleaved caspase-3 were observed at 24 h after hE26-mediated PDT. Conclusion: The novel mitochondria-targeting photosensitizer hE26, with an optimized excitation wavelength of 660 nm, induces potent ROS generation even at low doses, resulting in enhanced anticancer efficacy against NSCLC cells via the mitochondrial apoptotic pathway. hE26 represents a promising candidate for the development of potent new photosensitizers that offer enhanced therapeutic efficacy with minimized systemic toxicity.