Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan, 430072, PR China.
Key Laboratory of Biomedical Polymers of Ministry of Education & Department of Chemistry, Wuhan University, Wuhan, 430072, PR China.
Biomaterials. 2019 Dec;224:119500. doi: 10.1016/j.biomaterials.2019.119500. Epub 2019 Sep 17.
Redox homeostasis inside malignant cells is a defense mechanism against the reactive oxygen species (ROS)-induced therapy means, but little importance has been paid to this innate barrier. The present study intends to make cancer cells more sensitive to the ROS-induced therapy by disturbing cellular redox homeostasis. To verify this concept, a porous metal-organic framework (MOF) serves not only as the photodynamic therapy (PDT) agent but also as the carrier to transport alkaloid piperlongumine (PL), a thioredoxin reductase (TrxR) inhibitor used to disturb cellular redox homeostasis. The PL-loaded MOF was further coated with cancer cell membranes to gain homologous tumor-targeting capability. Inside tumor cells, the released PL can effectively block the TrxR-mediated ROS elimination pathway. The resultant data show that compared to traditional PDT alone, the combination of PDT and TrxR inhibition causes profound promotions in cellular ROS level by about 1.6 times, in cytotoxicity by about 2 times, and in cellular apoptosis/necrosis rate by about 3 times. Consequently, this strategy based on the interference with cellular redox homeostasis has demonstrated high potency to improve the anticancer PDT performance, adumbrating a new way to boost the power of ROS-induced therapy.
细胞内的氧化还原稳态是抵抗活性氧（ROS）诱导治疗手段的一种防御机制，但人们对这种内在障碍重视不够。本研究旨在通过扰乱细胞内氧化还原稳态使癌细胞对 ROS 诱导的治疗更敏感。为了验证这一概念，一种多孔金属有机骨架（MOF）不仅可用作光动力治疗（PDT）剂，还可用作载体来输送生物碱胡椒碱（PL），一种硫氧还蛋白还原酶（TrxR）抑制剂，用于扰乱细胞内氧化还原稳态。负载 PL 的 MOF 进一步用癌细胞膜包被以获得同源肿瘤靶向能力。在肿瘤细胞内，释放的 PL 可以有效地阻断 TrxR 介导的 ROS 消除途径。结果表明，与单独传统 PDT 相比，PDT 和 TrxR 抑制的联合作用使细胞内 ROS 水平提高了约 1.6 倍，细胞毒性提高了约 2 倍，细胞凋亡/坏死率提高了约 3 倍。因此，这种基于干扰细胞内氧化还原稳态的策略已被证明具有提高抗癌 PDT 性能的高潜力，为增强 ROS 诱导治疗的效果提供了一种新途径。
