School of Pharmaceutical Science & Technology, Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) , Tianjin University , Tianjin 300072 , China.
Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin 300120 , China.
Nano Lett. 2019 Nov 13;19(11):7866-7876. doi: 10.1021/acs.nanolett.9b02904. Epub 2019 Oct 10.
Nanoscale photodynamic therapy (PDT) is an appealing antitumor modality for which apoptosis is the major mechanism of toxicity induction. It was postulated that the highly reactive singlet oxygen in PDT could deplete glutathione (GSH) and activate ferroptosis, the extent to which could be further manipulated by a redox-responsive nanocarrier. To validate this, a disulfide-bearing imidazole ligand coordinated with zinc to form an all-active metal organic framework (MOF) nanocarrier where a photosensitizer (chlorin e6/Ce6) was encapsulated. Regardless of light irradiation, the Ce6-loaded nanocarrier caused the depletion of intracellular GSH via the disulfide-thiol exchange reaction in a murine mammary carcinoma cell line (4T1). The GSH depletion further caused the inactivation of glutathione peroxide 4 (GPX4) and the enhancement of cytotoxicity that was alleviated by ferroptosis inhibitors. The superior antitumor efficacy of the all-active nanocarrier was corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression and animal survival rate. The coadministration of an iron chelator weakened the antitumor potency of the nanocarrier due to ferroptosis inhibition, which was supported by the fact of tumor growth upsurge and the recovered GPX4 activity. The current work highlights the contribution of ferroptotic machinery to antitumor PDT via an activatable, adaptable, all-active MOF nanocarrier.
纳米级光动力疗法（PDT）是一种有吸引力的抗肿瘤方式，其主要毒性诱导机制为细胞凋亡。有观点认为 PDT 中高反应性的单线态氧可以消耗谷胱甘肽（GSH）并激活铁死亡，其程度可以通过氧化还原响应的纳米载体进一步控制。为了验证这一点，一种带有二硫键的咪唑配体与锌配位形成全活性金属有机骨架（MOF）纳米载体，其中封装了一种光敏剂（氯代叶绿素 e6/Ce6）。无论是否进行光照，负载 Ce6 的纳米载体通过二硫键-巯基交换反应在小鼠乳腺癌细胞系（4T1）中消耗细胞内 GSH。GSH 的耗竭进一步导致谷胱甘肽过氧化物酶 4（GPX4）失活，并增强细胞毒性，铁死亡抑制剂可缓解该毒性。在 4T1 荷瘤小鼠模型中，全活性纳米载体在抑制肿瘤生长和提高动物存活率方面表现出优异的抗肿瘤疗效。铁螯合剂的联合给药由于铁死亡抑制而削弱了纳米载体的抗肿瘤效力，这一事实得到了肿瘤生长上升和恢复的 GPX4 活性的支持。本工作强调了通过可激活、可适应的全活性 MOF 纳米载体，铁死亡机制对肿瘤 PDT 的贡献。
