Magnetic field remotely controlled selective biocatalysis

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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Fig. 1: E- and S-type superparamagnetic nanoparticles carrying the enzyme and the substrate.
Fig. 2: Monitoring of the magnetic-field-triggered release of fluorescein dye.
Fig. 3: Chains of biocatalytic nanoparticles.
Fig. 4: Magnetically controlled release of the drug.
Fig. 5: Magnetic-field-triggered blocking of cancer cell proliferation.
Fig. 6: Magnetic-field-triggered biocatalysis in the cell culture.

References

  1. 1.

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

    CAS  Article  Google Scholar 

  2. 2.

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

    CAS  Article  Google Scholar 

  3. 3.

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

    CAS  Article  Google Scholar 

  4. 4.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  8. 8.

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  10. 10.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  18. 18.

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

    Article  Google Scholar 

  19. 19.

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

    CAS  Article  Google Scholar 

  20. 20.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  24. 24.

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

    CAS  Article  Google Scholar 

  25. 25.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Google Scholar 

  29. 29.

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

    CAS  Article  Google Scholar 

  30. 30.

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

    CAS  Article  Google Scholar 

  31. 31.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  37. 37.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

Download references

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.

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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.

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Correspondence to Sergiy Minko.

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

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Zakharchenko, A., Guz, N., Laradji, A.M. et al. Magnetic field remotely controlled selective biocatalysis. Nat Catal 1, 73–81 (2018). https://doi.org/10.1038/s41929-017-0003-3

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