Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts

Nature Chemistry volume 7, pages 597–603 (2015)Cite this article

Subjects

Abstract

Bioorthogonal catalysis broadens the functional possibilities of intracellular chemistry. Effective delivery and regulation of synthetic catalytic systems in cells are challenging due to the complex intracellular environment and catalyst instability. Here, we report the fabrication of protein-sized bioorthogonal nanozymes through the encapsulation of hydrophobic transition metal catalysts into the monolayer of water-soluble gold nanoparticles. The activity of these catalysts can be reversibly controlled by binding a supramolecular cucurbit[7]uril ‘gate-keeper’ onto the monolayer surface, providing a biomimetic control mechanism that mimics the allosteric regulation of enzymes. The potential of this gated nanozyme for use in imaging and therapeutic applications was demonstrated through triggered cleavage of allylcarbamates for pro-fluorophore activation and propargyl groups for prodrug activation inside living cells.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Figure 1: Bioorthogonal nanozyme design and supramolecular regulation of intracellular catalysis.
Figure 2: Catalytic activity of nanozymes in solution.
Figure 3: Lineweaver–Burk plot showing competitive binding of CB[7] to nanozyme.
Figure 4: Triggered allylcarbamate cleavage in living cells using gated nanozymes.
Figure 5: Prodrug activation in living cells using supramolecularly controlled nanozymes.

References

  1. Patterson, D. M., Nazarova, L. A. & Prescher, J. A. Finding the right (bioorthogonal) chemistry. ACS Chem. Biol. 9, 592–605 (2014).

    Article  CAS  PubMed  Google Scholar 

  2. Ramil, C. P. & Lin, Q. Bioorthogonal chemistry: strategies and recent developments. Chem. Commun. 49, 11007–11022 (2013).

    Article  CAS  Google Scholar 

  3. Bertozzi, C. R. A decade of bioorthogonal chemistry. Acc. Chem. Res. 44, 651–653 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Koo, H. et al. Bioorthogonal copper-free click chemistry in vivo for tumor-targeted delivery of nanoparticles. Angew. Chem. Int. Ed. 51, 11836–11840 (2012).

    Article  CAS  Google Scholar 

  5. Devaraj, N. K., Thurber, G. M., Keliher, E. J., Marinelli, B. & Weissleder, R. Reactive polymer enables efficient in vivo bioorthogonal chemistry. Proc. Natl Acad. Sci. USA 109, 4762–4767 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Komatsu, H., Shindo, Y., Oka, K., Hill, J. P. & Ariga, K. Ubiquinone-Rhodol (UQ-Rh) for fluorescence imaging of NAD(P)H through intracellular activation. Angew. Chem. Int. Ed. 53, 3993–3995 (2014).

    Article  CAS  Google Scholar 

  7. Sletten, E. M. & Bertozzi, C. R. From mechanism to mouse: a tale of two bioorthogonal reactions. Acc. Chem. Res. 44, 666–676 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Saxon, E. & Bertozzi, C. R. Cell surface engineering by a modified Staudinger reaction. Science 287, 2007–2010 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Li, J. & Chen, P. R. Palladium-triggered deprotection chemistry for protein activation in living cells. Nature Chem. 6, 352–361 (2014).

    Article  CAS  Google Scholar 

  10. Sasmal, P. K., Streu, C. N. & Meggers, E. Metal complex catalysis in living biological systems. Chem. Commun. 49, 1581–1587 (2013).

    Article  CAS  Google Scholar 

  11. Unciti-Broceta, A., Johansson, E. M. V., Yusop, R. M., Sánchez-Martín, R. M. & Bradley, M. Synthesis of polystyrene microspheres and functionalization with Pd(0) nanoparticles to perform bioorthogonal organometallic chemistry in living cells. Nature Protoc. 7, 1207–1218 (2012).

    Article  CAS  Google Scholar 

  12. Streu, C. & Meggers, E. Ruthenium-induced allylcarbamate cleavage in living cells. Angew. Chem. Int. Ed. 45, 5645–5648 (2006).

    Article  CAS  Google Scholar 

  13. Yusop, R. M., Unciti-Broceta, A., Johansson, E. M. V., Sánchez-Martín, R. M. & Bradley, M. Palladium-mediated intracellular chemistry. Nature Chem. 3, 239–243 (2011).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. Do, J. H., Kim, H. N., Yoon, J., Kim, J. S. & Kim, H-J. A rationally designed fluorescence turn-on probe for the gold(III) ion. Org. Lett. 12, 932–934 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Yoon, H. J., Kuwabara, J., Kim, J-H. & Mirkin, C. A. Allosteric supramolecular triple-layer catalysts. Science 330, 66–69 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. De, M., Ghosh, P. S. & Rotello, V. M. Applications of nanoparticles in biology. Adv. Mater. 20, 4225–4241 (2008).

    Article  CAS  Google Scholar 

  19. Murphy, C. J. et al. Gold nanoparticles in biology: beyond toxicity to cellular imaging. Acc. Chem. Res. 41, 1721–1730 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Boisselier, E. & Astruc, D. Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity. Chem. Soc. Rev. 38, 1759–1782 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Tonga, G. Y., Saha, K. & Rotello, V. M. Interfacing nanoparticles and biology new strategies for biomedicine. Adv. Mater. 26, 359–370 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Mout, R. & Rotello, V. M. Bio and nano working together: engineering the protein–nanoparticle interface. Isr. J. Chem. 53, 521–529 (2013).

    Article  CAS  Google Scholar 

  23. Kim, B. et al. Tuning payload delivery in tumour cylindroids using gold nanoparticles. Nature Nanotech. 5, 465–472 (2010).

    Article  CAS  Google Scholar 

  24. Ghosh, P. et al. Intracellular delivery of a membrane-impermeable enzyme in active form using functionalized gold nanoparticles. J. Am. Chem. Soc. 132, 2642–2645 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kim, C. K. et al. Entrapment of hydrophobic drugs in nanoparticle monolayers with efficient release into cancer cells. J. Am. Chem. Soc. 131, 1360–1361 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Manea, F., Houillon, F. B., Pasquato, L. & Scrimin, P. Nanozymes: gold-nanoparticles-based transphosphorylation catalysts. Angew. Chem. Int. Ed. 43, 6165–6169 (2004).

    Article  CAS  Google Scholar 

  27. Wang, Z. et al. Nanoparticle-based artificial RNA silencing machinery for antiviral therapy. Proc. Natl Acad. Sci. USA 109, 12387–12392 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Pengo, P., Baltzer, L., Pasquato, L. & Scrimin, P. Substrate modulation of the activity of an artificial nanoesterase made of peptide-functionalized gold nanoparticles. Angew. Chem. Int. Ed. 46, 400–404 (2007).

    Article  CAS  Google Scholar 

  29. Wei, H. & Wang, E. Nanomaterials with enzyme-like characteristics (nanozymes): next-generation artificial enzymes. Chem. Soc. Rev. 42, 6060–6093 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Natalio, F. et al. Vanadium pentoxide nanoparticles mimic vanadium haloperoxidases and thwart biofilm formation. Nature Nanotech. 7, 530–535 (2012).

    Article  CAS  Google Scholar 

  31. Hastings, C. J., Backlund, M. P., Bergman, R. G. & Raymond, K. N. Enzyme-like control of carbocation deprotonation regioselectivity in supramolecular catalysis of the Nazarov cyclization. Angew. Chem. Int. Ed. 50, 10570–10573 (2011).

    Article  CAS  Google Scholar 

  32. Ghosh, S. & Isaacs, L. Biological catalysis regulated by cucurbit[7]uril molecular containers. J. Am. Chem. Soc. 132, 4445–4454 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Masson, E., Ling, X., Joseph, R., Kyeremeh-Mensah, L. & Lu, X. Cucurbituril chemistry: a tale of supramolecular success. RSC Adv. 2, 1213–1247 (2012).

    Article  CAS  Google Scholar 

  34. Lee, J. W., Samal, S., Selvapalam, N., Kim, H-J. & Kim, K. Cucurbituril homologues and derivatives: new opportunities in supramolecular chemistry. Acc. Chem. Res. 36, 621–630 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Kim, K. et al. Functionalized cucurbiturils and their applications. Chem. Soc. Rev. 36, 267–279 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Ambrogio, M. W., Thomas, C. R., Zhao, Y-L., Zink, J. I. & Stoddart, J. F. Mechanized silica nanoparticles: a new frontier in theranostic nanomedicine. Acc. Chem. Res. 44, 903–913 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kim, H. et al. Glutathione-induced intracellular release of guests from mesoporous silica nanocontainers with cyclodextrin gatekeepers. Adv. Mater. 22, 4280–4283 (2010).

    Article  CAS  PubMed  Google Scholar 

  38. Liu, S. et al. The cucurbit[n]uril family: prime components for self-sorting systems. J. Am. Chem. Soc. 127, 15959–15967 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Khashab, N. M. et al. pH-responsive mechanised nanoparticles gated by semirotaxanes. Chem. Commun. 5371–5373 (2009).

  40. Hong, R. et al. Control of protein structure and function through surface recognition by tailored nanoparticle scaffolds. J. Am. Chem. Soc. 126, 739–743 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Kim, C., Agasti, S. S., Zhu, Z., Isaacs, L. & Rotello, V. M. Recognition-mediated activation of therapeutic gold nanoparticles inside living cells. Nature Chem. 2, 962–966 (2010).

    Article  CAS  Google Scholar 

  42. Angelos, S. et al. pH clock-operated mechanized nanoparticles. J. Am. Chem. Soc. 131, 12912–12914 (2009).

    Article  CAS  PubMed  Google Scholar 

  43. Alcaide, B., Almendros, P. & Alonso, J. M. A practical ruthenium-catalyzed cleavage of the allyl protecting group in amides, lactams, imides, and congeners. Chem. Eur. J. 12, 2874–2879 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Sasmal, P. K., Carregal-Romero, S., Parak, W. J. & Meggers, E. Light-triggered ruthenium-catalyzed allylcarbamate cleavage in biological environments. Organometallics 31, 5968–5970 (2012).

    Article  CAS  Google Scholar 

  45. Zhu, Z-J. et al. Determination of the intracellular stability of gold nanoparticle monolayers using mass spectrometry. Anal. Chem. 84, 4321–4326 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jeon, W. S. et al. Complexation of ferrocene derivatives by the cucurbit[7]uril host: a comparative study of the cucurbituril and cyclodextrin host families. J. Am. Chem. Soc. 127, 12984–12989 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Lineweaver, H. & Burk, D. The determination of enzyme dissociation constants. J. Am. Chem. Soc. 56, 658–666 (1934).

    Article  CAS  Google Scholar 

  48. Miller, D. J., Surfraz, M. B-U., Akhtar, M., Gani, D. & Allemann, R. K. Removal of the phosphate group in mechanism-based inhibitors of inositol monophosphatase leads to unusual inhibitory activity. Org. Biomol. Chem. 2, 671–688 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Verma, A. et al. Surface-structure-regulated cell-membrane penetration by monolayer-protected nanoparticles. Nature Mater. 7, 588–595 (2008).

    Article  CAS  Google Scholar 

  50. Gu, Z., Biswas, A., Zhao, M. & Tang, Y. Tailoring nanocarriers for intracellular protein delivery. Chem. Soc. Rev. 40, 3638–3655 (2011).

    Article  CAS  PubMed  Google Scholar 

  51. Cai, S. X. et al. Design and synthesis of rhodamine 110 derivative and caspase-3 substrate for enzyme and cell-based fluorescent assay. Bioorg. Med. Chem. Lett. 11, 39–42 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Saif, M. W., Choma, A., Salamone, S. J. & Chu, E. Pharmacokinetically guided dose adjustment of 5-fluorouracil: a rational approach to improving therapeutic outcomes. J. Natl Cancer Inst. 101, 1543–1552 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-Fluorouracil: mechanisms of action and clinical strategies. Nature Rev. 3, 330–338 (2003).

    CAS  Google Scholar 

  54. Wang, Z. J., Clary, K. N., Bergman, R. G., Raymond, K. N. & Toste, F. D. A supramolecular approach to combining enzymatic and transition metal catalysis. Nature Chem. 5, 100–103 (2013).

    Article  CAS  Google Scholar 

  55. Marr, A. C. & Liu, S. Combining bio- and chemo-catalysis: from enzymes to cells, from petroleum to biomass. Trends Biotechnol. 29, 199–204 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from the National Institutes of Health (EB014277). T.M. acknowledges the Japan Society for the Promotion of Sciences for a Postdoctoral Fellowship for Research Abroad and for the Strategic Young Researcher Overseas Visits Program for Accelerating Brain Circulation. The authors thank L. Isaacs (University of Maryland) for providing cucurbit[7]uril.

Author information

Author notes

  1. Gulen Yesilbag Tonga and Youngdo Jeong: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Chemistry, University of Massachusetts Amherst, 710 North Pleasant Street, Amherst, 01003, Massachusetts, USA

    Gulen Yesilbag Tonga, Youngdo Jeong, Bradley Duncan, Tsukasa Mizuhara, Rubul Mout, Riddha Das, Sung Tae Kim, Yi-Cheun Yeh, Bo Yan, Singyuk Hou & Vincent M. Rotello

Authors
  1. Gulen Yesilbag Tonga
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Youngdo Jeong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bradley Duncan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tsukasa Mizuhara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rubul Mout
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Riddha Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sung Tae Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yi-Cheun Yeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bo Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Singyuk Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Vincent M. Rotello
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G.Y.T., Y.J. and V.M.R. conceived and designed the experiments. G.Y.T., Y.J., B.D., T.M., R.M., R.D., S.T.K., Y-C.Y., B.Y. and S.H. performed the experiments. All authors analysed and discussed the data. G.Y.T., Y.J., B.D. and V.M.R. co-wrote the paper. V.M.R. revised the paper. G.Y.T. and Y.J. contributed equally to this work.

Corresponding author

Correspondence to Vincent M. Rotello.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 3630 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tonga, G., Jeong, Y., Duncan, B. et al. Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts. Nature Chem 7, 597–603 (2015). https://doi.org/10.1038/nchem.2284

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchem.2284

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing