Wang Ke, Geng Siqi, Wang Fang, Fang Baoru, Qian Huifeng, Li Ying, Zhou Yiqing, Chen Yanping, Yu Zhangsen
School of Life and Environmental Sciences, Shaoxing University, Shaoxing, 312000, Zhejiang, China.
Laboratory of Nanomedicine, Medical Science Research Center, School of Medicine, Shaoxing University, Shaoxing, 312000, Zhejiang, China.
J Nanobiotechnology. 2024 Dec 24;22(1):793. doi: 10.1186/s12951-024-03069-0.
Anthracycline doxorubicin (DOX) remains the first-line chemotherapeutic drug for the efficient treatment of breast cancer, but its severe cardiotoxicity limits its long-term application in clinical tumor chemotherapy. Until now, the pathogenesis mechanism of DOX-induced cardiotoxicity (DIC) is still not fully understood. According to current studies, the oxidative stress caused by the imbalance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) production and mitochondrial dysfunction in myocardial cells are closely related to DIC. Presently, the usual technology to solve the DIC problem is to use a multifunctional nanoplatform to load DOX and obtain a new medicinal agent, thereby enhancing the efficacy of chemotherapeutic drugs and reducing toxic side effects.Herein, the present investigation employed the Mannich condensation reaction, initiated by L-cysteine and (-)-epigallocatechin-3-gallocarboxylate (EGCG), to synthesize EGCG&Cys nanoformulation with both anti-tumor and anti-oxidant properties. The EGCG&Cys were then employed as the DOX carrier to construct a novel chemotherapeutic drug, EGCG&Cys(DOX), for high-efficiency breast cancer treatment. The tumor growth inhibition index of EGCG&Cys(DOX) in tumor-bearing mice was 12.56% superior to the DOX group with the same concentration. Meanwhile, the anti-oxidant properties of EGCG can effectively eliminate a large amount of free radicals produced by DOX and significantly alleviate DIC by improving mitochondrial functional pathways. Ultrasound echocardiography (UCG) showed that the mean LVEF and LEFS values in the 5 mg/kg DOX treatment group were significantly reduced by 54.4% and 63.4%, and the EGCG&Cys(DOX) group mice were consistent with those of the non-chemotherapy group. Moreover, electrocardiogram, serum biochemical indicators, and histopathological analysis results also demonstrate that the cardiotoxicity of EGCG&Cys(DOX) novel chemotherapy drugs is significantly reduced. Consequently, this study presents a new technology for preparing highly efficient and safe nano-chemotherapeutic drugs and an in-depth evaluation of the antitumor efficacy and safety of the synthesized novel drugs, which gave fresh life to the development of nanomedicine in the clinical treatment of breast cancer.
蒽环类药物阿霉素（DOX）仍然是有效治疗乳腺癌的一线化疗药物，但其严重的心脏毒性限制了它在临床肿瘤化疗中的长期应用。到目前为止，阿霉素诱导的心脏毒性（DIC）的发病机制仍未完全明确。根据目前的研究，心肌细胞中活性氧（ROS）和活性氮（RNS）产生失衡所导致的氧化应激以及线粒体功能障碍与DIC密切相关。目前，解决DIC问题的常用技术是使用多功能纳米平台来负载DOX并获得一种新的药剂，从而提高化疗药物的疗效并降低毒副作用。在此，本研究采用由L-半胱氨酸和（-）-表没食子儿茶素-3-没食子酸酯（EGCG）引发的曼尼希缩合反应，合成具有抗肿瘤和抗氧化特性的EGCG&Cys纳米制剂。然后将EGCG&Cys用作DOX载体，构建一种新型化疗药物EGCG&Cys(DOX)，用于高效治疗乳腺癌。EGCG&Cys(DOX)在荷瘤小鼠中的肿瘤生长抑制指数比相同浓度的DOX组高12.56%。同时，EGCG的抗氧化特性可以有效消除DOX产生的大量自由基，并通过改善线粒体功能途径显著减轻DIC。超声心动图（UCG）显示，5mg/kg DOX治疗组的平均左心室射血分数（LVEF）和左心室短轴缩短率（LEFS）值分别显著降低了54.4%和63.4%，而EGCG&Cys(DOX)组小鼠的值与非化疗组一致。此外，心电图、血清生化指标和组织病理学分析结果也表明，EGCG&Cys(DOX)新型化疗药物的心脏毒性显著降低。因此，本研究提出了一种制备高效安全纳米化疗药物的新技术，并对合成的新型药物的抗肿瘤疗效和安全性进行了深入评估，为纳米医学在乳腺癌临床治疗中的发展注入了新的活力。
