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

  • Biomaterials. 2022 Dec 30;294:121986. doi: 10.1016/j.biomaterials.2022.121986.
Wenwei Jiang  1 ,  Suqin Zhong  2 ,  Ziying Chen  2 ,  Jieying Qian  2 ,  Xiaowan Huang  2 ,  Hao Zhang  2 ,  Longping Wen  3 ,  Yunjiao Zhang  4 ,  Guangyu Yao  5
Affiliations
  • 1. Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, P. R. China.
  • 2. School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China.
  • 3. Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 510080, Guangzhou, P. R. China. Electronic address: [email protected].
  • 4. School of Medicine, School of Biomedical Sciences and Engineering, South China University of Technology, 510006, Guangzhou, P. R. China; National Engineering Research Center for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, 510006, Guangzhou, P. R. China. Electronic address: [email protected].
  • 5. Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, P. R. China. Electronic address: [email protected].
PMID: 36623325 DOI: 10.1016/j.biomaterials.2022.121986
Abstract

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 p85β protein expression contributes to tamoxifen resistance, and reveal p85β 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 performance combined with further Materials engineering may lead to the development of nanozyme-based tumor catalytic therapy.

Keywords
2D CuPd nanosheet; Degradation; Nanozymes; Tamoxifen-resistant breast cancer.
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