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In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy

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  • Da-Yong Hou

    (National Center for Nanoscience and Technology (NCNST)
    Harbin Medical University
    Harbin Medical University Cancer Hospital, Heilongjiang Key Laboratory of Scientific Research in Urology)

  • Dong-Bing Cheng

    (Wuhan University of Technology)

  • Ni-Yuan Zhang

    (National Center for Nanoscience and Technology (NCNST))

  • Zhi-Jia Wang

    (National Center for Nanoscience and Technology (NCNST)
    Harbin Medical University
    Harbin Medical University Cancer Hospital, Heilongjiang Key Laboratory of Scientific Research in Urology)

  • Xing-Jie Hu

    (National Center for Nanoscience and Technology (NCNST))

  • Xin Li

    (Wuhan University of Technology)

  • Mei-Yu Lv

    (Harbin Medical University)

  • Xiang-Peng Li

    (National Center for Nanoscience and Technology (NCNST)
    Harbin Medical University
    Harbin Medical University Cancer Hospital, Heilongjiang Key Laboratory of Scientific Research in Urology)

  • Ling-Rui Jian

    (Harbin Medical University
    Harbin Medical University Cancer Hospital, Heilongjiang Key Laboratory of Scientific Research in Urology)

  • Jin-Peng Ma

    (Harbin Medical University
    Harbin Medical University Cancer Hospital, Heilongjiang Key Laboratory of Scientific Research in Urology)

  • Taolei Sun

    (Wuhan University of Technology)

  • Zeng-Ying Qiao

    (National Center for Nanoscience and Technology (NCNST))

  • Wanhai Xu

    (Harbin Medical University
    Harbin Medical University Cancer Hospital, Heilongjiang Key Laboratory of Scientific Research in Urology)

  • Hao Wang

    (National Center for Nanoscience and Technology (NCNST))

Abstract

Emerging evidence indicates that the activation of ferroptosis by glutathione peroxidase 4 (GPX4) inhibitors may be a prominent therapeutic strategy for tumor suppression. However, the wide application of GPX4 inhibitors in tumor therapy is hampered due to poor tumor delivery efficacy and the nonspecific activation of ferroptosis. Taking advantage of in vivo self-assembly, we develop a peptide-ferriporphyrin conjugate with tumor microenvironment specific activation to improve tumor penetration, endocytosis and GPX4 inhibition, ultimately enhancing its anticancer activity via ferroptosis. Briefly, a GPX4 inhibitory peptide is conjugated with an assembled peptide linker decorated with a pH-sensitive moiety and ferriporphyrin to produce the peptide-ferriporphyrin conjugate (Gi-F-CAA). Under the acidic microenvironment of the tumor, the Gi-F-CAA self-assembles into large nanoparticles (Gi-F) due to enhanced hydrophobic interaction after hydrolysis of CAA, improving tumor endocytosis efficiency. Importantly, Gi-F exhibits substantial inhibition of GPX4 activity by assembly enhanced binding (AEB) effect, augmenting the oxidative stress of ferriporphyrin-based Fenton reaction, ultimately enabling antitumor properties in multiple tumor models. Our findings suggest that this peptide-ferriporphyrin conjugate design with AEB effect can improve the therapeutic effect via induction of ferroptosis, providing an alternative strategy for overcoming chemoresistance.

Suggested Citation

  • Da-Yong Hou & Dong-Bing Cheng & Ni-Yuan Zhang & Zhi-Jia Wang & Xing-Jie Hu & Xin Li & Mei-Yu Lv & Xiang-Peng Li & Ling-Rui Jian & Jin-Peng Ma & Taolei Sun & Zeng-Ying Qiao & Wanhai Xu & Hao Wang, 2024. "In vivo assembly enhanced binding effect augments tumor specific ferroptosis therapy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44665-2
    DOI: 10.1038/s41467-023-44665-2
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    References listed on IDEAS

    as
    1. Yuan Gao & Junfeng Shi & Dan Yuan & Bing Xu, 2012. "Imaging enzyme-triggered self-assembly of small molecules inside live cells," Nature Communications, Nature, vol. 3(1), pages 1-8, January.
    2. Shujuan Xu & Huizhen Zheng & Ronglin Ma & Di Wu & Yanxia Pan & Chunyang Yin & Meng Gao & Weili Wang & Wei Li & Sijin Liu & Zhifang Chai & Ruibin Li, 2020. "Vacancies on 2D transition metal dichalcogenides elicit ferroptotic cell death," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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