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Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers

Author

Listed:
  • Mehmet S. Ozdas

    (ETH Zurich and UZH
    Neuroscience Center)

  • Aagam S. Shah

    (ETH Zurich and UZH
    Neuroscience Center)

  • Paul M. Johnson

    (ETH Zurich and UZH
    Neuroscience Center)

  • Nisheet Patel

    (ETH Zurich and UZH)

  • Markus Marks

    (ETH Zurich and UZH
    Neuroscience Center)

  • Tansel Baran Yasar

    (ETH Zurich and UZH
    Neuroscience Center)

  • Urs Stalder

    (UZH)

  • Laurent Bigler

    (UZH)

  • Wolfger Behrens

    (ETH Zurich and UZH
    Neuroscience Center)

  • Shashank R. Sirsi

    (ETH Zurich and UZH
    UT at Dallas)

  • Mehmet Fatih Yanik

    (ETH Zurich and UZH
    Neuroscience Center)

Abstract

Non-invasive, molecularly-specific, focal modulation of brain circuits with low off-target effects can lead to breakthroughs in treatments of brain disorders. We systemically inject engineered ultrasound-controllable drug carriers and subsequently apply a novel two-component Aggregation and Uncaging Focused Ultrasound Sequence (AU-FUS) at the desired targets inside the brain. The first sequence aggregates drug carriers with millimeter-precision by orders of magnitude. The second sequence uncages the carrier’s cargo locally to achieve high target specificity without compromising the blood-brain barrier (BBB). Upon release from the carriers, drugs locally cross the intact BBB. We show circuit-specific manipulation of sensory signaling in motor cortex in rats by locally concentrating and releasing a GABAA receptor agonist from ultrasound-controlled carriers. Our approach uses orders of magnitude (1300x) less drug than is otherwise required by systemic injection and requires very low ultrasound pressures (20-fold below FDA safety limits for diagnostic imaging). We show that the BBB remains intact using passive cavitation detection (PCD), MRI-contrast agents and, importantly, also by sensitive fluorescent dye extravasation and immunohistochemistry.

Suggested Citation

  • Mehmet S. Ozdas & Aagam S. Shah & Paul M. Johnson & Nisheet Patel & Markus Marks & Tansel Baran Yasar & Urs Stalder & Laurent Bigler & Wolfger Behrens & Shashank R. Sirsi & Mehmet Fatih Yanik, 2020. "Non-invasive molecularly-specific millimeter-resolution manipulation of brain circuits by ultrasound-mediated aggregation and uncaging of drug carriers," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18059-7
    DOI: 10.1038/s41467-020-18059-7
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