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Hydrogen-bonded organic framework-based bioorthogonal catalysis prevents drug metabolic inactivation

Nature Catalysis volume 6, pages 729–739 (2023)Cite this article

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Abstract

Bioorthogonal chemistry provides a new avenue for disease treatment by generating therapeutic agents in situ. However, two crucial issues have to be considered for future practical applications. One is the prevention of metabolic inactivation of the in situ-synthesized drug molecules. The other is enhancing the biocompatibility and tumour cell selectivity of the bioorthogonal catalyst. Here, to tackle the above issues, we design a biocompatible hydrogen-bonded organic framework-based dual prodrugs activation platform (namely Apt@E-F@PHOF-1). The ferric porphyrin ligands of hydrogen-bonded organic framework-based bioorthogonal pre-catalyst are reduced to ferrous porphyrin by the abundant glutathione in tumour, which then catalyses the cleavage reaction to synthesize 5-fluorouracil (5FU) and 5-ethynyluracil. The 5FU catabolic enzyme inhibitor 5-ethynyluracil prevents 5FU metabolic inactivation. As an example of hydrogen-bonded organic framework-based bioorthogonal prodrug activation, this work provides insights into prevention of drug inactivation by using bioorthogonal chemistry, thus enhancing tumour inhibition and reducing therapeutic side effects demonstrated by both in vitro and orthotopic metastatic mouse model experiments.

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Fig. 1: HOF-based bioorthogonal prodrug activation for chemotherapy.
Fig. 2: Crystal structure of PHOF-1. CCDC code 2231664.
Fig. 3: Characterization of HOF-based bioorthogonal catalyst.
Fig. 4: Catalytic performance of Apt@PHOF-1 in pro-dye activation model.
Fig. 5: Catalytic performance of Apt@PHOF-1 in cell.
Fig. 6: Cellular killing effect of the HOF-based bioorthogonal catalyst.
Fig. 7: Chemotherapy in a subcutaneous xenograft mouse model.

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Data availability

Crystallographic data for the structures reported in this paper have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2231664. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The data that support the findings of this study are presented in the text and Supplementary Information. Source data are provided with this paper. All other data that support the findings reported herein are available on reasonable request from the corresponding author.

References

  1. Li, S. et al. SuFExable polymers with helical structures derived from thionyl tetrafluoride. Nat. Chem. 13, 858–867 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cheng, Y. et al. Diversity oriented clicking delivers beta-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors. Proc. Natl Acad. Sci. USA 119, e2208540119 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Schumann, B. et al. Bump-and-hole engineering identifies specific substrates of glycosyltransferases in living cells. Mol. Cell 78, 824–834.e815 (2020).

  4. Cambier, C. J., Banik, S. M., Buonomo, J. A. & Bertozzi, C. R. Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity. eLife 9, e60648 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ngai, W. S. C. et al. Bioorthogonally activatable base editing for on-demand pyroptosis. J. Am. Chem. Soc. 144, 5411–5417 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Liu, Z. et al. Cell membrane-camouflaged liposomes for tumor cell-selective glycans engineering and imaging in vivo. Proc. Natl Acad. Sci. USA 118, e2022769118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Weiss, J. T. et al. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat. Commun. 5, 3277 (2014).

    Article  PubMed  Google Scholar 

  8. Clavadetscher, J., Indrigo, E., Chankeshwara, S. V., Lilienkampf, A. & Bradley, M. In-cell dual drug synthesis by cancer-targeting palladium catalysts. Angew. Chem. Int. Ed. 56, 6864–6868 (2017).

  9. Zheng, Y. et al. Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide. Nat. Chem. 10, 787–794 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sancho-Albero, M. et al. Cancer-derived exosomes loaded with ultrathin palladium nanosheets for targeted bioorthogonal catalysis. Nat. Catal. 2, 864–872 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wang, F. et al. A biocompatible heterogeneous MOF–Cu catalyst for in vivo drug synthesis in targeted subcellular organelles. Angew. Chem. Int. Ed. 58, 6987–6992 (2019).

  12. Wang, Q. et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature 579, 421–426 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Wang, W. et al. In situ activation of therapeutics through bioorthogonal catalysis. Adv. Drug Deliv. Rev. 176, 113893 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang, Z. et al. A bimetallic metal–organic framework encapsulated with DNAzyme for intracellular drug synthesis and self-sufficient gene therapy. Angew. Chem. Int. Ed. 60, 12431–12437 (2021).

  15. Geng, J. et al. Switching on prodrugs using radiotherapy. Nat. Chem. 13, 805–810 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang, X. et al. Degradable ZnS-supported bioorthogonal nanozymes with enhanced catalytic activity for intracellular activation of therapeutics. J. Am. Chem. Soc. 144, 12893–12900 (2022).

    Article  CAS  PubMed  Google Scholar 

  17. You, Y. et al. DNA-based platform for efficient and precisely targeted bioorthogonal catalysis in living systems. Nat. Commun. 13, 1459 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhang, Y. H. et al. SphK2 confers 5-fluorouracil resistance to colorectal cancer via upregulating H3K56ac-mediated DPD expression. Oncogene 39, 5214–5227 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Glorieux, C. et al. Overexpression of NAD(P)H:quinone oxidoreductase 1 (NQO1) and genomic gain of the NQO1 locus modulates breast cancer cell sensitivity to quinones. Life Sci. 145, 57–65 (2016).

    Article  CAS  PubMed  Google Scholar 

  20. Florianczyk, B. & Grzybowska, L. Metallothionein levels in cell fractions from breast cancer tissues. Acta Oncol. 39, 141–143 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Zhong, L., Shen, H., Huang, C., Jing, H. & Cao, D. AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group. Toxicol. Appl. Pharmacol. 255, 40–47 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rustum, Y. M. et al. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. J. Clin. Oncol. 15, 389–400 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Church, D. et al. ‘Toxgnostics’: an unmet need in cancer medicine. Nat. Rev. Cancer 14, 440–445 (2014).

    Article  CAS  PubMed  Google Scholar 

  24. Sasmal, P. K. et al. Catalytic azide reduction in biological environments. ChemBioChem 13, 1116–1120 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Cao-Milan, R. et al. Thermally gated bioorthogonal nanozymes with supramolecularly confined porphyrin catalysts for antimicrobial uses. Chem 6, 1113–1124 (2020).

  26. Huang, R. et al. Polymer-based bioorthogonal nanocatalysts for the treatment of bacterial biofilms. J. Am. Chem. Soc. 142, 10723–10729 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Balendiran, G. K., Dabur, R. & Fraser, D. The role of glutathione in cancer. Cell Biochem. Funct. 22, 343–352 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Lin, R. B. et al. Multifunctional porous hydrogen-bonded organic framework materials. Chem. Soc. Rev. 48, 1362–1389 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Wang, B., Lin, R. B., Zhang, Z., Xiang, S. & Chen, B. Hydrogen-bonded organic frameworks as a tunable platform for functional materials. J. Am. Chem. Soc. 142, 14399–14416 (2020).

    Article  CAS  PubMed  Google Scholar 

  30. Song, X. et al. Design rules of hydrogen-bonded organic frameworks with high chemical and thermal stabilities. J. Am. Chem. Soc. 144, 10663–10687 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. Liang, W. et al. Enzyme encapsulation in a porous hydrogen-bonded organic framework. J. Am. Chem. Soc. 141, 14298–14305 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Chen, G. et al. Protein-directed, hydrogen-bonded biohybrid framework. Chem 7, 2722–2742 (2021).

    Article  CAS  Google Scholar 

  33. Tang, Z. et al. A biocatalytic cascade in an ultrastable mesoporous hydrogen-bonded organic framework for point-of-care biosensing. Angew. Chem. Int. Ed. 60, 23608–23613 (2021).

  34. Tang, J. et al. In situ encapsulation of protein into nanoscale hydrogen-bonded organic frameworks for intracellular biocatalysis. Angew. Chem. Int. Ed. 60, 22315–22321 (2021).

  35. Wied, P. et al. Combining a genetically engineered oxidase with hydrogen-bonded organic frameworks (HOFs) for highly efficient biocomposites. Angew. Chem. Int. Ed. 61, e202117345 (2022).

  36. Chen, G. et al. Hydrogen-bonded organic framework biomimetic entrapment allowing non-native biocatalytic activity in enzyme. Nat. Commun. 13, 4816 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yu, D. et al. Hydrogen-bonded organic framework (HOF)-based single-neural stem cell encapsulation and transplantation to remodel impaired neural networks. Angew. Chem. Int. Ed. 61, e202201485 (2022).

  38. Yin, Q. et al. An ultra-robust and crystalline redeemable hydrogen-bonded organic framework for synergistic chemo-photodynamic therapy. Angew. Chem. Int. Ed. 57, 7691–7696 (2018).

  39. Wang, B. et al. Microporous hydrogen-bonded organic framework for highly efficient turn-up fluorescent sensing of aniline. J. Am. Chem. Soc. 142, 12478–12485 (2020).

    Article  CAS  PubMed  Google Scholar 

  40. Liu, B. T. et al. Ionic hydrogen-bonded organic frameworks for ion-responsive antimicrobial membranes. Adv. Mater. 32, e2005912 (2020).

    Article  PubMed  Google Scholar 

  41. Liu, B. T. et al. Construction of function-oriented core-shell nanostructures in hydrogen-bonded organic frameworks for near-infrared-responsive bacterial inhibition. Angew. Chem. Int. Ed. 60, 25701–25707 (2021).

  42. Wang, Y. et al. Chemically engineered porous molecular coatings as reactive oxygen species generators and reservoirs for long-lasting self-cleaning textiles. Angew. Chem. Int. Ed. 61, e202115956 (2022).

  43. Zhang, H. et al. NIR-II hydrogen-bonded organic frameworks (HOFs) used for target-specific amyloid-beta photooxygenation in an Alzheimer’s disease model. Angew. Chem. Int. Ed. 61, e202109068 (2022).

  44. Xuan, W. et al. Molecular self-assembly of bioorthogonal aptamer-prodrug conjugate micelles for hydrogen peroxide and pH-independent cancer chemodynamic therapy. J. Am. Chem. Soc. 142, 937–944 (2020).

    Article  CAS  PubMed  Google Scholar 

  45. Lu, T. & Chen, F. Multiwfn: a multifunctional wavefunction analyzer. J. Comput. Chem. 33, 580–592 (2012).

    Article  PubMed  Google Scholar 

  46. Yu, C. et al. Copper azide nanoparticle-encapsulating MOF-derived porous carbon: electrochemical preparation for high-performance primary explosive film. Small 18, e2107364 (2022).

    Article  PubMed  Google Scholar 

  47. Giovani, S., Singh, R. & Fasan, R. Efficient conversion of primary azides to aldehydes catalyzed by active site variants of myoglobin. Chem. Sci. 7, 234–239 (2016).

    Article  CAS  PubMed  Google Scholar 

  48. Dubey, M., Bernasek, S. L. & Schwartz, J. Highly sensitive nitric oxide detection using X-ray photoelectron spectroscopy. J. Am. Chem. Soc. 129, 6980–6981 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Harriman, A. Luminescence of porphyrins and metalloporphyrins. J. Chem. Soc. Faraday Trans. 1 77, 369–377 (1981).

    Article  CAS  Google Scholar 

  50. Zhang, Y. H., Luo, D. D., Wan, S. B. & Qu, X. J. S1PR2 inhibitors potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer. Pharmacol. Res. 155, 104717 (2020).

    Article  CAS  PubMed  Google Scholar 

  51. Wang, Y. et al. Cancer-cell-activated in situ synthesis of mitochondria-targeting AIE photosensitizer for precise photodynamic therapy. Angew. Chem. Int. Ed. 60, 14945–14953 (2021).

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Acknowledgements

This work was supported by the National Key R&D Program of China (2022YFA1205804; 2021YFF1200700, J.R.), the National Nature Science Foundation of China (21820102009, X.Q.; 91856205, X.Q.; 22237006, J.R.; 22122704, C.Z.), the Key Program of Frontier of Sciences (CAS QYZDJ-SSW-SLH052, X.Q.) and the Jilin Innovation Project (2023DJ02). We thank Figdraw for providing materials for the graphics.

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  1. These authors contributed equally: Congcong Huang, Chuanqi Zhao.

Authors and Affiliations

  1. Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, P. R. China

    Congcong Huang, Chuanqi Zhao, Qingqing Deng, Haochen Zhang, Dongqin Yu, Jinsong Ren & Xiaogang Qu

  2. University of Science and Technology of China, Hefei, P. R. China

    Congcong Huang, Chuanqi Zhao, Qingqing Deng, Haochen Zhang, Dongqin Yu, Jinsong Ren & Xiaogang Qu

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Contributions

X.Q. and J.R. designed research; C.H., C.Z. and Q.D. performed research and analysed data; H.Z. and D.Y. analysed data; C.H., C.Z. and X.Q. wrote the paper.

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Correspondence to Xiaogang Qu.

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Supplementary Information

Supplementary Methods, Tables 1–6, Note 1 and Figs. 1–46.

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Supplementary Data 1

The single-crystal structure of PHOF-1.

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Huang, C., Zhao, C., Deng, Q. et al. Hydrogen-bonded organic framework-based bioorthogonal catalysis prevents drug metabolic inactivation. Nat Catal 6, 729–739 (2023). https://doi.org/10.1038/s41929-023-00999-0

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