Zhou Mengxue, Zhou Chuang, Geng Huan, Huang Zhiwei, Lin Zhiyuan, Wang Ying, Zhu Yin, Shi Jiang, Tan Junfeng, Guo Li, Zhao Yanni, Zhang Yue, Peng Qunhua, Yu Haijun, Dai Weidong, Lv Haipeng, Lin Zhi
Key Laboratory of Tea Biology and Resource Utilization of Ministry of Agriculture, Tea Research Institute, Chinese Academy of Agricultural Sciences, Hangzhou, 310008, P. R. China.
School of Food and Biological Engineering, Shaanxi University of Science & Technology, Xi'an, 710021, P. R. China.
Small. 2025 Apr;21(14):e2406245. doi: 10.1002/smll.202406245. Epub 2024 Nov 19.
The presence of dense collagen fibers is a typical characteristic of triple-negative breast cancer (TNBC). Although these fibers hinder drug penetration and reduce treatment efficacy, the depletion of the collagen matrix is associated with tumor metastasis. To address this issue, epigallocatechin-3-gallate (EGCG) is first exploited for disrupting the dense collagenous stroma and alleviate fibrosis by specifically blocking the TGF-β/Smad pathway in fibroblasts and tumor cells when intraperitoneally administrated in TNBC tumor-bearing mice. A methotrexate (MTX)-loaded dual phosphate- and pH-responsive nanodrug (pHA@MOF-Au/MTX) is next engineered by integrating Fe-based metal-organic frameworks and gold nanoparticles for improved chemo/chemodynamic therapy of TNBC. Surface modification with pH (low)-insertion peptide substantially enhanced the binding of the nanodrug to 4T1 cells owing to tumor stroma remodeling by EGCG. High-concentration EGCG inhibited glutathione peroxidase by regulating mitochondrial glutamine metabolism, thus facilitating tumor cell ferroptosis. Furthermore, sequential EGCG and pHA@MOF-Au/MTX treatment showed remarkable anti-tumor effects in a mouse model of TNBC, with a tumor growth inhibition rate of 79.9%, and a pulmonary metastasis rate of 96.8%. Altogether, the combination strategy developed in this study can improve the efficacy of chemo/chemodynamic therapy in TNBC and represents an innovative application of EGCG.
致密胶原纤维的存在是三阴性乳腺癌（TNBC）的典型特征。尽管这些纤维阻碍药物渗透并降低治疗效果，但胶原基质的耗竭与肿瘤转移有关。为了解决这个问题，表没食子儿茶素-3-没食子酸酯（EGCG）首先被用于破坏致密的胶原基质，并通过在携带TNBC肿瘤的小鼠腹腔注射时特异性阻断成纤维细胞和肿瘤细胞中的TGF-β/Smad途径来减轻纤维化。接下来，通过整合铁基金属有机框架和金纳米颗粒来设计一种负载甲氨蝶呤（MTX）的双磷酸盐和pH响应纳米药物（pHA@MOF-Au/MTX），以改善TNBC的化学/化学动力学治疗。由于EGCG对肿瘤基质的重塑作用，用pH（低）插入肽进行表面修饰大大增强了纳米药物与4T1细胞的结合。高浓度的EGCG通过调节线粒体谷氨酰胺代谢抑制谷胱甘肽过氧化物酶，从而促进肿瘤细胞铁死亡。此外，EGCG和pHA@MOF-Au/MTX的序贯治疗在TNBC小鼠模型中显示出显著的抗肿瘤效果（肿瘤生长抑制率为79.9%，肺转移率为96.8%）。总之，本研究开发的联合策略可以提高TNBC化学/化学动力学治疗的疗效，是EGCG的一种创新应用。
