Dey Anup, Kumar E K Pramod, Kim Chan Ho, Li Yuce, Park Jae Hyung
School of Chemical Engineering, College of Engineering, Sungkyunkwan University (SKKU), Seobu-ro 2066, Jangan-gu ,Suwon 16419, Republic of Korea.
College of Life Sciences and Health, Wuhan University of Science and Technology (WUST), Wuhan 430065, China.
ACS Omega. 2024 Jul 15;9(29):32124-32132. doi: 10.1021/acsomega.4c04260. eCollection 2024 Jul 23.
Disrupting the redox balance through reactive oxygen species (ROS) generation and intracellular glutathione (GSH) depletion presents a promising strategy for cancer therapy. Megadoses of ascorbic acid (AA) can induce oxidative stress in cancer cells, leading to cell death. However, achieving enhanced oxidative stress using ultrahigh doses of AA is challenging because of the intricate delivery of high-concentration AA to the targeted sites while the cancer cells could also re-establish more robust redox homeostasis by upregulating antioxidants such as GSH. Recently, quinone methide and its analogues (QMs) have been recognized as effective GSH scavengers, offering a new dimension to accelerate oxidative stress. In this study, we formulated a dual stimuli-responsive nanoprecursor of AA and QM using gold nanoparticles. The nanoprecursor can release AA in response to the intracellular acidic pH in tumor cells, elevating the intracellular ROS levels and triggering the production of ample QMs to quench excessive GSH. This positive feedback mechanism significantly amplifies oxidative stress and disrupts redox homeostasis in cancer cells at a relatively low concentration of AA, leading to selective apoptosis without affecting normal cells. These results highlight the potential of the nanoprecursor as an effective anticancer therapeutic.
通过活性氧（ROS）生成和细胞内谷胱甘肽（GSH）耗竭来破坏氧化还原平衡是一种很有前景的癌症治疗策略。大剂量的抗坏血酸（AA）可在癌细胞中诱导氧化应激，导致细胞死亡。然而，使用超高剂量的AA来增强氧化应激具有挑战性，因为要将高浓度的AA复杂地递送至靶位点，同时癌细胞还可通过上调抗氧化剂如GSH来重新建立更强健的氧化还原稳态。最近，醌甲基化物及其类似物（QMs）已被认为是有效的GSH清除剂，为加速氧化应激提供了一个新的维度。在本研究中，我们使用金纳米颗粒制备了一种AA和QM的双刺激响应纳米前体。该纳米前体可响应肿瘤细胞内的酸性pH释放AA，提高细胞内ROS水平并触发大量QM的产生以淬灭过量的GSH。这种正反馈机制在相对低浓度的AA下显著放大氧化应激并破坏癌细胞中的氧化还原稳态，导致选择性凋亡而不影响正常细胞。这些结果突出了该纳米前体作为一种有效抗癌治疗剂的潜力。
