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Mechanochemical bond scission for the activation of drugs

An Author Correction to this article was published on 06 May 2021

This article has been updated

Abstract

Pharmaceutical drug therapy is often hindered by issues caused by poor drug selectivity, including unwanted side effects and drug resistance. Spatial and temporal control over drug activation in response to stimuli is a promising strategy to attenuate and circumvent these problems. Here we use ultrasound to activate drugs from inactive macromolecules or nano-assemblies through the controlled scission of mechanochemically labile covalent bonds and weak non-covalent bonds. We show that a polymer with a disulfide motif at the centre of the main chain releases an alkaloid-based anticancer drug from its β-carbonate linker by a force-induced intramolecular 5-exo-trig cyclization. Second, aminoglycoside antibiotics complexed by a multi-aptamer RNA structure are activated by the mechanochemical opening and scission of the nucleic acid backbone. Lastly, nanoparticle–polymer and nanoparticle–nanoparticle assemblies held together by hydrogen bonds between the peptide antibiotic vancomycin and its complementary peptide target are activated by force-induced scission of hydrogen bonds. This work demonstrates the potential of ultrasound to activate mechanoresponsive prodrug systems.

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Fig. 1: Schematic depiction of US activation of drugs.
Fig. 2: US-induced release of UMB and CPT from β-carbonate disulfide polymer.
Fig. 3: Deactivation and activation of aminoglycoside antibiotics bound to R23 polyaptamer in response to US.
Fig. 4: Fabrication and characterization of Van–DADA mechanophore-based PN systems and their response to US.
Fig. 5: Fabrication and US-induced disassembly of Van–DADA mechanophore-based NN systems.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. Raw data used for graphs in Figs. 2a–e, 3e,f, 4b,c and 5f are available in comma-separated-values format as source data. Enquiries regarding raw data published within the Supplementary Information are welcomed by the corresponding authors. This includes free induction decay files of nuclear magnetic resonance measurements, elugrams of gel permeation and high-performance liquid chromatography, spectra of ultraviolet–visible, fluorescence and infrared spectroscopy, and MIC and IC50 measurements in comma-separated-values format.

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Acknowledgements

The work was financially supported by the European Union (European Research Council Advanced Grant SUPRABIOTICS, no. 694610). R.G. is grateful for support by a Freigeist-Fellowship of the Volkswagen Foundation (no. 92888). Parts of the analytical investigation were performed at the Center for Chemical Polymer Technology, CPT, and were supported by the European Commission and the federal state of North Rhine-Westphalia (no. 300088302). Financial support is acknowledged from the European Commission (EUSMI, no. 731019). P.Z. is grateful for financial support from the China Scholarship Council. M.Z. is grateful for financial support from the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 713482.

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Contributions

For the β-carbonate disulfides, Z.S., R.G. and A.H. conceived and designed the experiments. Z.S. synthesized and characterized the materials; Z.S., R.G. and A.H. interpreted the analyses, Z.S., R.G. and A.H. co-wrote and revised the corresponding part of the manuscript. For the polyaptamers, P.Z., S.H., R.G. and A.H. conceived and designed the experiments. P.Z. synthesized and characterized the materials; P.Z., R.G. and A.H. interpreted the analyses, P.Z., R.G. and A.H. co-wrote and revised the corresponding part of the manuscript. For the PN- and NN assemblies, S.H., R.G. and A.H. conceived and designed the experiments. S.H. synthesized and characterized the materials; S.H., R.G. and A.H. interpreted the analyses, S.H., R.G. and A.H. co-wrote and revised the corresponding part of the manuscript. X.Y, E.W. and M.L. assisted with Van and Paromo syntheses and purifications. All authors commented on the manuscript. R.G. and A.H. supervised the entire project.

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Correspondence to Robert Göstl or Andreas Herrmann.

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Supplementary Information

Preparative and analytical procedures and data. Supplementary Schemes 1–6, Figs. 1–43 and Tables 1–4.

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Source data

Source Data Fig. 2

Statistical source data for Fig. 2a–e.

Source Data Fig. 3

Statistical source data for Fig. 3e,f; unprocessed gels of Fig. 3a,c.

Source Data Fig. 4

Statistical source data for Fig. 4b,c.

Source Data Fig. 5

Statistical source data for Fig. 5f.

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Huo, S., Zhao, P., Shi, Z. et al. Mechanochemical bond scission for the activation of drugs. Nat. Chem. 13, 131–139 (2021). https://doi.org/10.1038/s41557-020-00624-8

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