Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
College of Science, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
Theranostics. 2024 Feb 24;14(5):1939-1955. doi: 10.7150/thno.92663. eCollection 2024.
Cancer continues to be a significant public health issue. Traditional treatments such as surgery, radiotherapy, and chemotherapy often fall short because of intrinsic issues such as lack of specificity and poor drug delivery, leading to insufficient drug concentration at the tumor site and/or potential side effects. Consequently, improving the delivery of conventional chemotherapy drugs like doxorubicin (DOX) is crucial for their therapeutic efficacy. Successful cancer treatment is achieved when regulated cell death (RCD) of cancer cells, which includes apoptotic and non-apoptotic processes such as ferroptosis, is fundamental to successful cancer treatment. The developing field of nanozymes holds considerable promise for innovative cancer treatment approaches. A dual-metallic nanozyme system encapsulated with DOX was created, derived from metal-organic frameworks (MOFs), designed to combat tumors by depleting glutathione (GSH) and concurrently liberating DOX. The initial phase of the study examined the GSH oxidase-mimicking function of the dimetallic nanozyme (ZIF-8/SrSe) through enzyme kinetic assays and Density Functional Theory (DFT) simulations. Following this, we probed the ability of ZIF-8/SrSe@DOX to release DOX in response to the tumor microenvironment , alongside examining its anticancer capabilities and mechanisms prompting apoptosis or ferroptosis in cancer cells. Moreover, we established tumor-bearing animal models to corroborate the anti-tumor effectiveness of our nanozyme complex and to identify the involved apoptotic and ferroptotic pathways implicated. Enzyme kinetic analyses demonstrated that the ZIF-8/SrSe nanozyme exhibits substantial GSH oxidase-like activity, effectively oxidizing reduced GSH to glutathione disulfide (GSSG), while also inhibiting glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). This inhibition led to an imbalance in iron homeostasis, pronounced caspase activation, and subsequent induction of apoptosis and ferroptosis in tumor cells. Additionally, the ZIF-8/SrSe@DOX nanoparticles efficiently delivered DOX, causing DNA damage and further promoting apoptotic and ferroptotic pathways. This research outlines the design of a novel platform that combines chemotherapeutic agents with a Fenton reaction catalyst, offering a promising strategy for cancer therapy that leverages the synergistic effects of apoptosis and ferroptosis.
癌症仍然是一个重大的公共卫生问题。由于缺乏特异性和药物递送效果差等内在问题,手术、放疗和化疗等传统疗法往往效果不佳,导致肿瘤部位药物浓度不足和/或潜在的副作用。因此,提高阿霉素(DOX)等常规化疗药物的递送效率对于提高其治疗效果至关重要。成功的癌症治疗需要调节癌细胞死亡(RCD),这包括细胞凋亡和非细胞凋亡过程,如铁死亡。纳米酶作为一种新兴的癌症治疗方法,具有广阔的前景。本研究构建了一种载 DOX 的双金属纳米酶系统,该系统来源于金属有机框架(MOFs),通过耗竭谷胱甘肽(GSH)和同时释放 DOX 来对抗肿瘤。研究的初始阶段通过酶动力学测定和密度泛函理论(DFT)模拟研究了双金属纳米酶(ZIF-8/SrSe)的谷胱甘肽氧化酶模拟功能。在此之后,我们研究了 ZIF-8/SrSe@DOX 在肿瘤微环境下释放 DOX 的能力,并考察了其抗癌能力及其在诱导癌细胞凋亡或铁死亡方面的作用机制。此外,我们建立了荷瘤动物模型,以验证我们的纳米酶复合物的抗肿瘤效果,并确定涉及的凋亡和铁死亡途径。酶动力学分析表明,ZIF-8/SrSe 纳米酶具有很强的谷胱甘肽氧化酶样活性,可有效将还原型 GSH 氧化为谷胱甘肽二硫化物(GSSG),同时抑制谷胱甘肽过氧化物酶 4(GPX4)和溶质载体家族 7 成员 11(SLC7A11)。这种抑制导致铁稳态失衡,显著激活半胱天冬酶,随后诱导肿瘤细胞凋亡和铁死亡。此外,ZIF-8/SrSe@DOX 纳米颗粒能够有效地递送 DOX,导致 DNA 损伤,进一步促进凋亡和铁死亡途径。本研究概述了一种将化疗药物与芬顿反应催化剂相结合的新型平台的设计,为利用细胞凋亡和铁死亡协同作用的癌症治疗提供了一种有前景的策略。
J Colloid Interface Sci. 2025-4
ACS Appl Mater Interfaces. 2021-12-1
Colloids Surf B Biointerfaces. 2021-9
Int J Nanomedicine. 2025-5-1
J Nanobiotechnology. 2025-2-20
Pharmaceuticals (Basel). 2024-5-17
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2024-5-15
Int J Mol Sci. 2023-9-10
Nat Chem Biol. 2023-6
Nat Commun. 2022-12-27
Front Bioeng Biotechnol. 2022-7-6