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Cited by 63Ultrasound and Hyperthermia ApplicationsPhotoacoustic and Ultrasonic ImagingNanoparticle-Based Drug Delivery

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

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Ozdas, Mehmet S., Shah, Aagam S., Johnson, Paul M., Patel, Nisheet, Marks, Markus, Yasar, Tansel Baran, Stalder, Urs, Bigler, Laurent +3 more·2020·Nature Communications
DOI 10.1038/s41467-020-18059-7PMC PMC7529901
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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 GABA A 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.

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  • Released drugs from liposomes can cross intact BBB without compromising integrity.

    “The released drugs can cross the intact BBB without compromising the integrity.”

    From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [259]

  • Drug-loaded liposomes tethered to lipid microbubbles can aggregate locally and uncage cargo responsively to achieve high target specificity.

    “the drug-loaded liposomes could aggregate locally first and then uncage the cargo responsively to achieve high target specificity.”

    From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [259]

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Cited by

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Authors
Ozdas, M. S., Shah, A. S., Johnson, P. M., Patel, N., Marks, M., Yasar, T. B., Stalder, U., Bigler, L., von der Behrens, W., Sirsi, S. R., & Yanik, M. F.
Affiliations
  • University of Zurich (CH)
  • The University of Texas at Dallas (US)
Corresponding author
  • Shah, Aagam S.
  • Yanik, Mehmet Fatih
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-10-01
Volume
11
Issue
1
Pages
4929-4929
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-18059-7
PMC
PMC7529901
OpenAlex
W3091567990
Cited by
63
References
5
Citations by year
2026: 5 · 2025: 7 · 2024: 12 · 2023: 18 · 2022: 10 · 2021: 10 · 2020: 1
FWCI
3.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
  • ETH Zürich Research Collection (cc-by)
  • Zurich Open Repository and Archive (University of Zurich)
Funders
  • European Commission (HORIZON2020)
  • National Cancer Institute (R01CA235756)
  • H2020 European Research Council (818179)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
  • Physical Sciences › Engineering › Biomedical Engineering › Photoacoustic and Ultrasonic Imaging
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
focused ultrasound, blood-brain barrier, GABA-A receptor agonists, motor cortex, sensory signaling, non-invasive neuromodulation, passive cavitation detection, MRI contrast agents, drug delivery, brain circuits
MeSH terms
Ultrasonic Waves, Animals, Blood-Brain Barrier, Brain Diseases, Dose-Response Relationship, Radiation, Drug Carriers, Female, Humans, Magnetic Resonance Imaging, Muscimol, Stereotaxic Techniques, Ultrasonography, Interventional, Models, Animal, Rats, GABA-A Receptor Agonists

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