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Enzyme Responsive Rigid-Rod Aromatics Target “Undruggable” Phosphatases to Kill Cancer Cells in a Mimetic Bone Microenvironment

Cite this: J. Am. Chem. Soc. 2022, 144, 29, 13055–13059
Publication Date (Web):July 18, 2022
https://doi.org/10.1021/jacs.2c05491
Copyright © 2022 American Chemical Society

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    Abstract

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    Bone metastasis remains a challenge in cancer treatment. Here we show enzymatic responsive rigid-rod aromatics acting as the substrates of “undruggable” phosphatases to kill cancer cells in a mimetic bone microenvironment. By phosphorylation and conjugating nitrobenzoxadiazole (NBD) to hydroxybiphenylcarboxylate (BP), we obtained pBP-NBD (1P) as a substrate of both acid and alkaline phosphatases. 1P effectively kills both metastatic castration-resistant prostate cancer cells (mCRPCs) and osteoblast mimic cells in their coculture. 1P enters Saos2 almost instantly to target the endoplasmic reticulum (ER) of the cells. Co-culturing with Saos2 cells boosts the cellular uptake of 1P by mCRPCs. Cryo-EM reveals the nanotube structures of both 1P (2.4 Å resolution, pH 5.6) and 1 (2.2 Å resolution, pH 7.4). The helical packing of both nanotubes is identical, held together by strong pi-stacking interactions. Besides reporting the atomistic structure of nanotubes formed by the assembly of rigid-rod aromatics, this work expands the pool of molecules for designing EISA substrates that selectively target TME.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.2c05491.

    • Materials and detailed experimental procedures, TEM and CLSM images, cell viabilities, chemical structures of the compounds (PDF)

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    Cited By

    This article is cited by 11 publications.

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    2. Zhiyu Liu, Jiaqi Guo, Yuchen Qiao, Bing Xu. Enzyme-Instructed Intracellular Peptide Assemblies. Accounts of Chemical Research 2023, 56 (21) , 3076-3088. https://doi.org/10.1021/acs.accounts.3c00542
    3. Xiangyang Zhang, Yinghao Ding, Zhenghao Zhang, Yiping Ma, Xuan Sun, Ling Wang, Zhimou Yang, Zhi-Wen Hu. In Situ Construction of Ferrocene-Containing Membrane-Bound Nanofibers for the Redox Control of Cancer Cell Death and Cancer Therapy. Nano Letters 2023, 23 (16) , 7665-7674. https://doi.org/10.1021/acs.nanolett.3c02362
    4. Parul Rathee, Nicole Edelstein-Pardo, Francesca Netti, Lihi Adler-Abramovich, Amit Sitt, Roey J. Amir. Architecture-Based Programming of Polymeric Micelles to Undergo Sequential Mesophase Transitions. ACS Macro Letters 2023, 12 (6) , 814-820. https://doi.org/10.1021/acsmacrolett.3c00153
    5. Vincent P. Conticello. Peptide-based nanomaterials: Building back better & beyond. Current Opinion in Solid State and Materials Science 2023, 27 (2) , 101066. https://doi.org/10.1016/j.cossms.2023.101066
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    7. Adrianna N. Shy, Jiashu Xu, Beom Jin Kim, Bing Xu. An Exploration of Multiple Component Peptide Assemblies by Enzyme‐Instructed Self‐Assembly. ChemSystemsChem 2023, 104 https://doi.org/10.1002/syst.202200041
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    10. Huilei Dong, Mingshui Wang, Shihui Fan, Chuanliu Wu, Chunhui Zhang, Xia Wu, Bin Xue, Yi Cao, Junjie Deng, Dan Yuan, Junfeng Shi. Redox‐Regulated Conformational Change of Disulfide‐Rich Assembling Peptides. Angewandte Chemie 2022, 134 (44) https://doi.org/10.1002/ange.202212829
    11. Huilei Dong, Mingshui Wang, Shihui Fan, Chuanliu Wu, Chunhui Zhang, Xia Wu, Bin Xue, Yi Cao, Junjie Deng, Dan Yuan, Junfeng Shi. Redox‐Regulated Conformational Change of Disulfide‐Rich Assembling Peptides. Angewandte Chemie International Edition 2022, 61 (44) https://doi.org/10.1002/anie.202212829

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