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Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy

Author

Listed:
  • Jing Gao

    (Tongji University
    Chinese Academy of Sciences)

  • Bo Hou

    (Chinese Academy of Sciences
    East China Normal University)

  • Qiwen Zhu

    (Chinese Academy of Sciences)

  • Lei Yang

    (Nanjing University of Chinese Medicine)

  • Xingyu Jiang

    (Nanjing University of Chinese Medicine)

  • Zhifeng Zou

    (Chinese Academy of Sciences
    East China Normal University)

  • Xutong Li

    (Chinese Academy of Sciences)

  • Tianfeng Xu

    (Chinese Academy of Sciences)

  • Mingyue Zheng

    (Chinese Academy of Sciences)

  • Yi-Hung Chen

    (Wuhan University)

  • Zhiai Xu

    (East China Normal University)

  • Huixiong Xu

    (Fudan University)

  • Haijun Yu

    (Chinese Academy of Sciences
    Nanjing University of Chinese Medicine)

Abstract

PROteolysis TArgeting Chimeras (PROTACs) has been exploited to degrade putative protein targets. However, the antitumor performance of PROTACs is impaired by their insufficient tumour distribution. Herein, we present de novo designed polymeric PROTAC (POLY-PROTAC) nanotherapeutics for tumour-specific protein degradation. The POLY-PROTACs are engineered by covalently grafting small molecular PROTACs onto the backbone of an amphiphilic diblock copolymer via the disulfide bonds. The POLY-PROTACs self-assemble into micellar nanoparticles and sequentially respond to extracellular matrix metalloproteinase-2, intracellular acidic and reductive tumour microenvironment. The POLY-PROTAC NPs are further functionalized with azide groups for bioorthogonal click reaction-amplified PROTAC delivery to the tumour tissue. For proof-of-concept, we demonstrate that tumour-specific BRD4 degradation with the bioorthogonal POLY-PROTAC nanoplatform combine with photodynamic therapy efficiently regress tumour xenografts in a mouse model of MDA-MB-231 breast cancer. This study suggests the potential of the POLY-PROTACs for precise protein degradation and PROTAC-based cancer therapy.

Suggested Citation

  • Jing Gao & Bo Hou & Qiwen Zhu & Lei Yang & Xingyu Jiang & Zhifeng Zou & Xutong Li & Tianfeng Xu & Mingyue Zheng & Yi-Hung Chen & Zhiai Xu & Huixiong Xu & Haijun Yu, 2022. "Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32050-4
    DOI: 10.1038/s41467-022-32050-4
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    References listed on IDEAS

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    1. Keriann M. Backus & Bruno E. Correia & Kenneth M. Lum & Stefano Forli & Benjamin D. Horning & Gonzalo E. González-Páez & Sandip Chatterjee & Bryan R. Lanning & John R. Teijaro & Arthur J. Olson & Denn, 2016. "Proteome-wide covalent ligand discovery in native biological systems," Nature, Nature, vol. 534(7608), pages 570-574, June.
    2. Steven M. Banik & Kayvon Pedram & Simon Wisnovsky & Green Ahn & Nicholas M. Riley & Carolyn R. Bertozzi, 2020. "Lysosome-targeting chimaeras for degradation of extracellular proteins," Nature, Nature, vol. 584(7820), pages 291-297, August.
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    1. Jing Gao & Xingyu Jiang & Shumin Lei & Wenhao Cheng & Yi Lai & Min Li & Lei Yang & Peifeng Liu & Xiao-hua Chen & Min Huang & Haijun Yu & Huixiong Xu & Zhiai Xu, 2024. "A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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