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Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model

  1. Nathan J. McDannolda
  1. aFocused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115;
  2. bDepartment of Electrical and Computer Engineering, Tufts University, Medford, MA 02155
  1. Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved October 16, 2017 (received for review July 27, 2017)

Significance

Focused ultrasound is currently the only method of reversible blood–brain barrier disruption for targeted drug delivery without incision or radiation. A significant challenge for its clinical translation is a lack of reliable real-time treatment control. Here a closed-loop, real-time control paradigm is shown capable of sustaining stable microbubble oscillations at a preset level while minimizing microbubble behavior that may result in vascular damage. Tested at clinically relevant frequency in healthy and tumor-bearing rats, our approach enables targeted delivery of predefined drug concentrations within a therapeutically effective range in both normal tissue and glioma, while maintaining a safe exposure level. It can be readily implemented clinically for delivering chemotherapeutics or other agents and potentially applied to other cavitation-enhanced ultrasound therapies.

Abstract

Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood–brain barrier (BBB) for treating many neurological disorders. Unlike ultrasound thermal therapies, during which magnetic resonance thermometry can serve as a reliable treatment control modality, real-time control of modulated BBB disruption with undetectable vascular damage remains a challenge. Here a closed-loop cavitation controlling paradigm that sustains stable cavitation while suppressing inertial cavitation behavior was designed and validated using a dual-transducer system operating at the clinically relevant ultrasound frequency of 274.3 kHz. Tests in the normal brain and in the F98 glioma model in vivo demonstrated that this controller enables reliable and damage-free delivery of a predetermined amount of the chemotherapeutic drug (liposomal doxorubicin) into the brain. The maximum concentration level of delivered doxorubicin exceeded levels previously shown (using uncontrolled sonication) to induce tumor regression and improve survival in rat glioma. These results confirmed the ability of the controller to modulate the drug delivery dosage within a therapeutically effective range, while improving safety control. It can be readily implemented clinically and potentially applied to other cavitation-enhanced ultrasound therapies.

Footnotes

  • ?1To whom correspondence should be addressed. Email: taosun{at}bwh.harvard.edu.
  • Author contributions: T.S. and N.J.M. designed research; T.S., Y.Z., C.P., P.M.A., J.T.S., and M.A. performed research; T.S. and N.V. analyzed data; and T.S., J.T.S., N.V., E.L.M., and N.J.M. wrote the paper.

  • Conflict of interest statement: Two provisional patents describing the controlling system and focused ultrasound system developed in this work have been filed (inventors: N.J.M. and T.S.). N.J.M. holds another two published patents on the ultrasound technique evaluated in this work. No conflicts of interest were disclosed by the other authors.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1713328114/-/DCSupplemental.

Published under the PNAS license.

Online Impact

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