2D-CuPd nanozyme overcome tamoxifen resistance in breast cancer by regulating the PI3K/AKT/mTOR pathway

作者：Jiang, Wenwei; Zhong, Suqin; Chen, Ziying; Qian, Jieying; Huang, Xiaowan; Zhang, Hao; Wen, Longping^*; Zhang, Yunjiao^*; Yao, Guangyu^*

来源：Biomaterials, 2023, 294: 121986.

DOI：10.1016/j.biomaterials.2022.121986

• Nanozymes
• Tamoxifen-resistant breast cancer
• 2D CuPd nanosheet
• Degradation

Tamoxifen is the most commonly used treatment for estrogen-receptor (ER) positive breast cancer patients, but its efficacy is severely hampered by resistance. PI3K/AKT/mTOR pathway inhibition was proven to augment the benefit of endocrine therapy and exhibited potential for reversing tamoxifen-induced resistance. However, the vast majority of PI3K inhibitors currently approved for clinical use are unsatisfactory in terms of safety and efficacy. We developed two-dimensional CuPd (2D-CuPd) nanosheets with oxidase and peroxidase nanozyme activities to offer a novel solution to inhibit the activity of the PI3K/AKT/mTOR pathway. 2D-CuPd exhibit superior dual nanozyme activities converting hydrogen peroxide accumulated in drug-resistant cells into more lethal hydroxyl radicals while compensating for the insufficient superoxide anion produced by tamoxifen. The potential clinical utility was further demonstrated in an orthotopically implanted tamoxifen-resistant PDX breast cancer model. Our results reveal a novel nanozyme ROS-mediated protein mechanism for the regulation of the PI3K subunit, illustrate the cellular pathways through which increased p85 beta protein expression contributes to tamoxifen resistance, and reveal p85 beta protein as a potential therapeutic target for overcoming tamoxifen resistance. 2D-CuPd is the first reported nanomaterial capable of degrading PI3K subunits, and its high perfor-mance combined with further materials engineering may lead to the development of nanozyme-based tumor catalytic therapy.

• 单位
  南方医科大学; 广东省人民医院