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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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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Nature Communications (2018)