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

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 and Mehmet Fatih Yanik ()
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Mehmet S. Ozdas: ETH Zurich and UZH
Aagam S. Shah: ETH Zurich and UZH
Paul M. Johnson: ETH Zurich and UZH
Nisheet Patel: ETH Zurich and UZH
Markus Marks: ETH Zurich and UZH
Tansel Baran Yasar: ETH Zurich and UZH
Urs Stalder: UZH
Laurent Bigler: UZH
Wolfger Behrens: ETH Zurich and UZH
Shashank R. Sirsi: ETH Zurich and UZH
Mehmet Fatih Yanik: ETH Zurich and UZH

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18059-7

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