Article | Published:

Magnetic field remotely controlled selective biocatalysis

Nature Catalysisvolume 1pages7381 (2018) | Download Citation

Abstract

Many applications for medical therapy, biotechnology and biosensors rely on efficient delivery and release of active substances. Here, we demonstrate a platform that explores magnetic-field-responsive compartmentalization of biocatalytic reactions for well-controlled release of chemicals or biological materials on demand. This platform combines two different kinds of core–shell magnetic nanoparticle: one loaded with enzymes and another with substrate-bound therapeutic (bio)chemicals. Both cargos are shielded with a polymer brush structure of the nanoparticle shell, which prevents any enzyme–substrate interactions. The shield’s barrier is overcome when a relatively weak (a fraction of 1 T) external magnetic field is applied and the enzyme and the substrate are merged and forced to interact in the generated nanocompartment. The merged biocatalytic nanoparticles liberate the substrate-bound therapeutic drugs when the enzymes degrade the substrate. The developed platform provides a proof of concept for the remotely controlled release of drugs or (bio)chemicals using the energy of a non-invasive, weak magnetic field.

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References

  1. 1.

    Torchilin, V. P. Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery. Nat. Rev. Drug Discov. 13, 813–827 (2014).

  2. 2.

    Kudina, O. et al. Highly efficient phase boundary biocatalysis with enzymogel nanoparticles. Angew. Chem. Int. Ed. 53, 483–487 (2014).

  3. 3.

    Popat, A. et al. Mesoporous silica nanoparticles for bioadsorption, enzyme immobilisation, and delivery carriers. Nanoscale 3, 2801–2818 (2011).

  4. 4.

    Katz, E. & Willner, I. Integrated nanoparticle-biomolecule hybrid systems: synthesis, properties, and applications. Angew. Chem. Int. Ed. 43, 6042–6108 (2004).

  5. 5.

    Tokarev, A., Yatvin, J., Trotsenko, O., Locklin, J. & Minko, S. Nanostructured soft matter with magnetic nanoparticles. Adv. Funct. Mater. 26, 3761–3782 (2016).

  6. 6.

    Hu, J. M., Zhang, G. Q. & Liu, S. Y. Enzyme-responsive polymeric assemblies, nanoparticles and hydrogels. Chem. Soc. Rev. 41, 5933–5949 (2012).

  7. 7.

    de la Rica, R., Aili, D. & Stevens, M. M. Enzyme-responsive nanoparticles for drug release and diagnostics. Adv. Drug Deliv. Rev. 64, 967–978 (2012).

  8. 8.

    Stuart, M. A. C. et al. Emerging applications of stimuli-responsive polymer materials. Nat. Mater. 9, 101–113 (2010).

  9. 9.

    Reddy, L. H., Arias, J. L., Nicolas, J. & Couvreur, P. Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. Chem. Rev. 112, 5818–5878 (2012).

  10. 10.

    Mura, S., Nicolas, J. & Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 12, 991–1003 (2013).

  11. 11.

    Katz, E., Lioubashevski, O. & Willner, I. Magnetic field effects on cytochrome c-mediated bioelectrocatalytic transformations. J. Am. Chem. Soc. 126, 11088–11092 (2004).

  12. 12.

    Katz, E., Weizmann, Y. & Willner, I. Magnetoswitchable reactions of DNA monolayers on electrodes: gating the processes by hydrophobic magnetic nanoparticles. J. Am. Chem. Soc. 127, 9191–9200 (2005).

  13. 13.

    Katz, E. & Willner, I. Switching of directions of bioelectrocatalytic currents and photocurrents at electrode surfaces by using hydrophobic magnetic nanoparticles. Angew. Chem. Int. Ed. 44, 4791–4794 (2005).

  14. 14.

    Tam, T. K., Ornatska, M., Pita, M., Minko, S. & Katz, E. Polymer brush-modified electrode with switchable and tunable redox activity for bioelectronic applications. J. Phys. Chem. C 112, 8438–8445 (2008).

  15. 15.

    Weizmann, Y., Elnathan, R., Lioubashevski, O. & Willner, I. Endonuclease-based logic gates and sensors using magnetic force-amplified readout of DNA scission on cantilevers. J. Am. Chem. Soc. 127, 12666–12672 (2005).

  16. 16.

    Hayashi, K. et al. Magnetically responsive smart nanoparticles for cancer treatment with a combination of magnetic hyperthermia and remote-control drug release. Theranostics 4, 834–844 (2014).

  17. 17.

    Uline, M. J., Rabin, Y. & Szleifer, I. Effects of the salt concentration on charge regulation in tethered polyacid monolayers. Langmuir 27, 4679–4689 (2011).

  18. 18.

    Halsey, T. C. & Toor, W. Fluctuation-induced couplings between defect lines or particle chains. J. Stat. Phys. 61, 1257–1281 (1990).

  19. 19.

    Furst, E. M. & Gast, A. P. Particle dynamics in magnetorheological suspensions using diffusing wave spectroscopy. Phys. Rev. E 58, 3372–3376 (1998).

  20. 20.

    Gulley, G. L. & Tao, R. Structures of an electrorheological fluid. Phys. Rev. E 56, 4328–4336 (1997).

  21. 21.

    Tan, Z. J., Zou, X. W., Zhang, W. B. & Jin, Z. Z. Structure transition in cluster–cluster aggregation under external fields. Phys. Rev. E 62, 734–737 (2000).

  22. 22.

    Silva, A. S., Bond, R., Plouraboue, F. & Wirtz, D. Fluctuation dynamics of a single magnetic chain. Phys. Rev. E 54, 5502–5510 (1996).

  23. 23.

    Cheng, R., Zhu, L., Huang, W. J., Mao, L. D. & Zhao, Y. P. Dynamic scaling of ferromagnetic micro-rod clusters under a weak magnetic field. Soft Matter 12, 8440–8447 (2016).

  24. 24.

    Townsend, J., Burtovyy, R., Galabura, Y. & Luzinov, I. Flexible chains of ferromagnetic nanoparticles. ACS Nano 8, 6970–6978 (2014).

  25. 25.

    Motornov, M. et al. Field-directed self-assembly with locking nanoparticles. Nano Lett. 12, 3814–3820 (2012).

  26. 26.

    Wilhelm, S. et al. Analysis of nanoparticle delivery to tumours. Nat. Rev. Mater. 1, 16014 (2016).

  27. 27.

    Sawant, R. M. et al. Nanosized cancer cell-targeted polymeric immunomicelles loaded with superparamagnetic iron oxide nanoparticles. J. Nanopart. Res. 11, 1777–1785 (2009).

  28. 28.

    Liao, C. D., Sun, Q. Q., Liang, B. L., Shen, J. & Shuai, X. T. Targeting EGFR-overexpressing tumor cells using cetuximab-immunomicelles loaded with doxorubicin and superparamagnetic iron oxide. Euro. J. Radiol. 80, 699–705 (2011).

  29. 29.

    Zhu, L. et al. Targeted delivery of methotrexate to skeletal muscular tissue by thermosensitive magnetoliposomes. Int. J. Pharm. 370, 136–143 (2009).

  30. 30.

    Yang, L. L. et al. Receptor-targeted nanoparticles for in vivo imaging of breast cancer. Clin. Cancer Res. 15, 4722–4732 (2009).

  31. 31.

    Liu, D. F. et al. Conjugation of paclitaxel to iron oxide nanoparticles for tumor imaging and therapy. Nanoscale 4, 2306–2310 (2012).

  32. 32.

    Bagalkot, V. et al. Quantum dot: aptamer conjugates for synchronous cancer imaging, therapy, and sensing of drug delivery based on bi-fluorescence resonance energy transfer. Nano Lett. 7, 3065–3070 (2007).

  33. 33.

    Karlsson, H. L., Gustafsson, J., Cronholm, P. & Moller, L. Size-dependent toxicity of metal oxide particles: a comparison between nano- and micrometer size. Toxicol. Lett. 188, 112–118 (2009).

  34. 34.

    Villanueva, A. et al. The influence of surface functionalization on the enhanced internalization of magnetic nanoparticles in cancer cells. Nanotechnology 20, doi:10.1088/0957-4484/20/11/115103 (2009).

  35. 35.

    Bumb, A. et al. Synthesis and characterization of ultra-small superparamagnetic iron oxide nanoparticles thinly coated with silica. Nanotechnology 19, 335601 (2008).

  36. 36.

    Deng, Y. H., Wang, C. C., Hu, J. H., Yang, W. L. & Fu, S. K. Investigation of formation of silica-coated magnetite nanoparticles via sol-gel approach. Colloids Surf. A 262, 87–93 (2005).

  37. 37.

    Jakubowski, W. & Matyjaszewski, K. Activator generated by electron transfer for atom transfer radical polymerization. Macromolecules 38, 4139–4146 (2005).

  38. 38.

    Miyajima, T., Mori, M., Ishiguro, S., Chung, K. H. & Moon, C. H. On the complexation of Cd(II) ions with polyacrylic acid. J. Colloid Interface Sci. 184, 279–288 (1996).

  39. 39.

    Schiller, A. A., Schayer, R. W. & Hess, E. L. Fluorescein-conjugated bovine albumin. Physical and biological properties. J. Gen. Physiol. 36, 489–505 (1953).

  40. 40.

    Leermakers, F. A. M., Ballauff, M. & Borisov, O. V. On the mechanism of uptake of globular proteins by polyelectrolyte brushes: a two-gradient self-consistent field analysis. Langmuir 23, 3937–3946 (2007).

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Acknowledgements

The authors would like to thank the National Science Foundation (grant number DMR 1426193) for funding. We would like to thank D. Asheghali, J. Xie and L. Xie, University of Georgia, USA for providing the mouse 4T1 breast tumour cells and assistance with cell culture experiments. We would also like to thank T. Enright, University of Georgia for assistance with NPs synthesis and functionalization and valuable discussions.

Author information

Affiliations

  1. Nanostructured Materials Lab, University of Georgia, Athens, GA, USA

    • Andrey Zakharchenko
    • , Amine Mohamed Laradji
    •  & Sergiy Minko
  2. Department of Chemistry and Biomolecular Science, Clarkson University, Potsdam, NY, USA

    • Nataliia Guz
    •  & Evgeny Katz

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Contributions

S.M. and E.K. conceived the central ideas and directed the project. A.Z. synthesized and characterized the NPs, studied their biocatalytic behaviour in a magnetic field including in the presence of cell culture; A.M.L. contributed to the characterization of the NPs and conjugation of proteins; N.G. performed experiments with the confocal microscope. All authors contributed to the analysis of the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sergiy Minko.

Electronic supplementary material

  1. Supplementary Information

    Supplementary Methods, Supplementary Figs. 1–19, Supplementary Tables 1–3, Supplementary References

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DOI

https://doi.org/10.1038/s41929-017-0003-3

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