The efficacy of photodynamic therapy (PDT) is often limited by the reductive microenvironment in tumor cells due to the high level of glutathione (GSH) and glutathione peroxidase 4 (GPX4), which maintain redox homeostasis. Therefore, designing a GSH-responsive photosensitizer that depletes intracellular GSH is a promising strategy to enhance PDT selectivity and efficacy. Herein, we present a GSH-selective sequentially responsive theranostic photosensitizer, Cy-Res. This cyanine agent targeting mitochondria effectively depletes two GSH molecules, leading to the generation of abundant ROS and exacerbating oxidative stress. Additionally, it achieves an 80-fold fluorescence enhancement upon response to GSH, enabling selective imaging of tumor cells. By mitigating GSH's impact on PDT, Cy-ResNPs achieves synergistic and efficient PDT treatment of invasive melanoma under low-power irradiation (808 nm, 80 mW/cm²). The inhibitory processes downregulate GPX4, increase apoptotic proteins like Bax, and promote mixed cell death involving both ferroptosis and apoptosis. Overall, this study offers new insights and strategies for the development of GSH-responsive theranostic agents, highlighting their potential for application in tumor diagnosis and therapy.

中文翻译：

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一种用于序贯双位点 GSH 耗竭和 ROS 增强癌症光动力疗法的新型花青光敏剂


由于维持氧化还原稳态的谷胱甘肽 （GSH） 和谷胱甘肽过氧化物酶 4 （GPX4） 水平高，光动力疗法 （PDT） 的疗效通常受到肿瘤细胞中还原微环境的限制。因此，设计一种消耗细胞内 GSH 的 GSH 响应性光敏剂是提高 PDT 选择性和功效的一种很有前途的策略。在此，我们提出了一种 GSH 选择性顺序响应治疗诊断光敏剂 Cy-Res。这种靶向线粒体的花青剂可有效消耗两个 GSH 分子，导致产生丰富的 ROS 并加剧氧化应激。此外，它在对 GSH 的反应后实现了 80 倍的荧光增强，从而能够对肿瘤细胞进行选择性成像。通过减轻 GSH 对 PDT 的影响，Cy-ResNPs 在低功率照射 （808 nm， 80 mW/cm²） 下实现了侵袭性黑色素瘤的协同和有效的 PDT 治疗。抑制过程下调 GPX4，增加凋亡蛋白（如 Bax），并促进涉及铁死亡和细胞凋亡的混合细胞死亡。总体而言，本研究为 GSH 反应性治疗诊断剂的开发提供了新的见解和策略，突出了它们在肿瘤诊断和治疗中的应用潜力。