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Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions

Nature Nanotechnology volume 11, pages 941–947 (2016)Cite this article

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Abstract

Oxygen-depleted hypoxic regions in the tumour are generally resistant to therapies1. Although nanocarriers have been used to deliver drugs, the targeting ratios have been very low. Here, we show that the magneto-aerotactic migration behaviour2 of magnetotactic bacteria3, Magnetococcus marinus strain MC-1 (ref. 4), can be used to transport drug-loaded nanoliposomes into hypoxic regions of the tumour. In their natural environment, MC-1 cells, each containing a chain of magnetic iron-oxide nanocrystals5, tend to swim along local magnetic field lines and towards low oxygen concentrations6 based on a two-state aerotactic sensing system2. We show that when MC-1 cells bearing covalently bound drug-containing nanoliposomes were injected near the tumour in severe combined immunodeficient beige mice and magnetically guided, up to 55% of MC-1 cells penetrated into hypoxic regions of HCT116 colorectal xenografts. Approximately 70 drug-loaded nanoliposomes were attached to each MC-1 cell. Our results suggest that harnessing swarms of microorganisms exhibiting magneto-aerotactic behaviour can significantly improve the therapeutic index of various nanocarriers in tumour hypoxic regions.

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Figure 1: Assessment of the specificity of the MC-1 antibody in HCT116 colorectal xenografts in SCID beige mice.
Figure 2: MC-1 cells are preferentially located in the hypoxic regions of the xenografts.
Figure 3: Penetration of live MC-1 cells with and without magnetic field exposure in HCT116 xenografts following a peritumoral injection.
Figure 4: Superior penetration of MC-1 cells over passive diffusion in HCT116 xenografts demonstrated by two methods.
Figure 5: Targeting ratios of MC-1–LP in HCT116 xenografts.

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Acknowledgements

This project was initially supported in part by the Canada Research Chair (CRC) Tier 2 in Micro/Nanosystem Development, Fabrication and Validation and by grants from the National Sciences and Engineering Research Council of Canada (NSERC) and the Province of Québec. This work was primarily supported by the Québec Consortium for Drug Discovery (CQDM) and in part by the Research Chair of École Polytechnique in Nanorobotics, Mitacs, and later by the CRC Tier 1 in Medical Nanorobotics. The magnetotaxis system was built with financial help from the Canada Foundation for Innovation (CFI). Preliminary in vivo results were obtained with the financial help of the US National Institutes of Health (NIH) grant no. R21EB007506 from the National Institute of Biomedical Imaging and Bioengineering. The authors thank J. Caron from CQDM for her involvement in the coordination of the project. R. Gladue from Pfizer, R. M. Garbaccio from Merck & Co. and C. Reimer from AstraZeneca R&D are also thanked for their guidance and insights from the pharmaceutical industry. C.C. Tremblay (NanoRobotics Lab.) helped in determining the number of bacteria in samples and T. Johns (Biomat'x, McGill University) in the preparation of liposomes. The authors thank J. Hinsinger (University of Montreal (UdM), Institute for Research in Immunology and Cancer (IRIC)) and the histological team (UdM, IRIC) for tumour histology preparation and D. Gingras (UdM, IRIC) for transmission electron microscopy.

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  1. Ouajdi Felfoul, Mahmood Mohammadi, Samira Taherkhani and Danuta Radzioch: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Computer and Software Engineering, NanoRobotics Laboratory, Institute of Biomedical Engingeering, Polytechnique Montréal, Montréal H3T 1J4, Canada

    Ouajdi Felfoul, Mahmood Mohammadi, Samira Taherkhani, Dominic de Lanauze, Dumitru Loghin, Neila Kaou, Michael Atkin & Sylvain Martel

  2. Department of Biomedical Engineering, McGill University, Montréal H3A 2B4, Canada

    Samira Taherkhani, Sherief Essa & Maryam Tabrizian

  3. McGill University Health Centre, Montréal H4A 3J1, Canada

    Yong Zhong Xu, Sylwia Jancik, Daniel Houle & Danuta Radzioch

  4. Department of Chemistry, University of Montréal (UdM), Montréal H3C 3J7, Canada

    Sherief Essa & Michel Lafleur

  5. Department of Pathology and Cell Biology, Institute for Research in Immunology and Cancer (IRIC), University of Montréal, Montréal H3T 1J4, Canada

    Louis Gaboury

  6. Faculty of Dentistry, McGill University, Montréal H3A 1G1, Canada

    Maryam Tabrizian

  7. Department of Oncology, Segal Cancer Centre, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada

    Té Vuong & Gerald Batist

  8. Departments of Biochemistry, Medicine and Oncology, Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal H3A 1A3, Canada

    Nicole Beauchemin

Authors
  1. Ouajdi Felfoul
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Contributions

S.M. acted as principal investigator, wrote the paper with assistance from O.F., M.M., D.R., S.T. and N.B. and developed the general principles and methods. G.B. and T.V. provided clinical insights. O.F., M.M., S.T., Y.Z.X., D.d.-L., D.L. and D.H. performed the experiments with tumour-bearing animals. S.J., Y.Z.X. and D.H. carried out the IV injections, processed all blood and tissues for analysis and analysed the samples. L.G. performed immunohistochemistry, immunofluorescence and histopathological evaluations. N.K. and M.M., assisted by M.A., acted as project managers. M.M. and O.F. performed the experiments for the preliminary in vivo proofs of concept. O.F. designed the experimental platform. D.d.-L. tested the magnetotactic control process, which was executed by D.L. M.L. and S.E. synthesized the liposomes. M.T. and S.T. attached the liposomes to the MC-1 cells. M.M. cultivated and prepared the bacteria for injection. M.M., D.R., G.B., L.G., N.B. and S.M. made revisions to the manuscript and figures. Y.Z.X. and D.H. coordinated the implantations of tumour xenografts. D.L. developed and calibrated the MC-1 counting software.

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Correspondence to Sylvain Martel.

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Felfoul, O., Mohammadi, M., Taherkhani, S. et al. Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nature Nanotech 11, 941–947 (2016). https://doi.org/10.1038/nnano.2016.137

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