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Multimetallic Microparticles Increase the Potency of Rifampicin against Intracellular Mycobacterium tuberculosis

  • Timothy Ellis
    Timothy Ellis
    Department of Materials and London Centre for Nanotechnology, Imperial College London, London SW7 2AZ, U.K.
  • Michele Chiappi
    Michele Chiappi
    National Heart & Lung Institute, Imperial College London, London SW7 2AZ, U.K.
  • Andrés García-Trenco
    Andrés García-Trenco
    Department of Chemistry and London Centre for Nanotechnology, Imperial College London, London SW7 2AZ, U.K.
  • Maryam Al-Ejji
    Maryam Al-Ejji
    Department of Materials and London Centre for Nanotechnology, Imperial College London, London SW7 2AZ, U.K.
  • Srijata Sarkar
    Srijata Sarkar
    Department of Environmental and Occupational Health, Rutgers School of Public Health, Piscataway, New Jersey 08854, United States
  • Theoni K. Georgiou
    Theoni K. Georgiou
    Department of Materials and London Centre for Nanotechnology, Imperial College London, London SW7 2AZ, U.K.
  • Milo S. P. Shaffer
    Milo S. P. Shaffer
    Department of Chemistry and London Centre for Nanotechnology, Imperial College London, London SW7 2AZ, U.K.
  • Teresa D. Tetley
    Teresa D. Tetley
    National Heart & Lung Institute, Imperial College London, London SW7 2AZ, U.K.
  • Stephan Schwander
    Stephan Schwander
    Department of Environmental and Occupational Health, Rutgers School of Public Health, Piscataway, New Jersey 08854, United States
    Office for Global Public Health Affairs, Rutgers School of Public Health, Piscataway, New Jersey 08854, United States
  • Mary P. Ryan
    Mary P. Ryan
    Department of Materials and London Centre for Nanotechnology, Imperial College London, London SW7 2AZ, U.K.
    More by Mary P. Ryan
  • , and 
  • Alexandra E. Porter*
    Alexandra E. Porter
    Department of Materials and London Centre for Nanotechnology, Imperial College London, London SW7 2AZ, U.K.
    *E-mail: [email protected]
Cite this: ACS Nano 2018, 12, 6, 5228–5240
Publication Date (Web):May 16, 2018
https://doi.org/10.1021/acsnano.7b08264
Copyright © 2018 American Chemical Society

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    Abstract

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    Mycobacterium tuberculosis (M.tb) has the extraordinary ability to adapt to the administration of antibiotics through the development of resistance mechanisms. By rapidly exporting drugs from within the cytosol, these pathogenic bacteria diminish antibiotic potency and drive the presentation of drug-tolerant tuberculosis (TB). The membrane integrity of M.tb is pivotal in retaining these drug-resistant traits. Silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) are established antimicrobial agents that effectively compromise membrane stability, giving rise to increased bacterial permeability to antibiotics. In this work, biodegradable multimetallic microparticles (MMPs), containing Ag NPs and ZnO NPs, were developed for use in pulmonary delivery of antituberculous drugs to the endosomal system of M.tb-infected macrophages. Efficient uptake of MMPs by M.tb-infected THP1 cells was demonstrated using an in vitro macrophage infection model, with direct interaction between MMPs and M.tb visualized with the use of electron FIB-SEM tomography. The release of Ag NPs and ZnO NPs within the macrophage endosomal system increased the potency of the model antibiotic rifampicin by as much as 76%, realized through an increase in membrane disorder of intracellular M.tb. MMPs were effective at independently driving membrane destruction of extracellular bacilli located at the exterior face of THP1 macrophages. This MMP system presents as an effective drug delivery vehicle that could be used for the transport of antituberculous drugs such as rifampicin to infected alveolar macrophages, while increasing drug potency. By increasing M.tb membrane permeability, such a system may prove effectual in improving treatment of drug-susceptible TB in addition to M.tb strains considered drug-resistant.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsnano.7b08264.

    • Final micrograph Z-stack reconstructed using Avizo (AVI)

    • Details of material characterization of Ag NPs, ZnO NPs, and MMPs; STEM-EDX point spectra of surveyed regions of Figure 2L–P; STEM-EDX maps of THP1 internalized MMPs; BF-STEM data of M.tb-infected THP1 macrophages; phase contrast images of THP1 cells; epithelial in vitro toxicity of Ag and ZnO nanomaterials; TT1 and AT2 epithelial cell health post MMP exposure (PDF)

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