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

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 treatm...

Full description

Saved in:
Bibliographic Details
Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 48; pp. E10281 - E10290
Main Authors Sun, Tao, Zhang, Yongzhi, Power, Chanikarn, Alexander, Phillip M., Sutton, Jonathan T., Aryal, Muna, Vykhodtseva, Natalia, Miller, Eric L., McDannold, Nathan J.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 28.11.2017
SeriesPNAS Plus
Subjects
Biological Sciences
Blood-brain barrier
Cavitation
Physical Sciences
PNAS Plus
Regression analysis
Rodents
Tumors
Ultrasonic imaging
acoustic cavitation
blood–brain barrier
drug delivery
focused ultrasound
treatment control
Online AccessGet full text

Cover

More Information
Summary: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.
Bibliography:SourceType-Scholarly Journals-1
ObjectType-Feature-1
content type line 14
ObjectType-Article-1
ObjectType-Feature-2
content type line 23
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.
Edited by Robert Langer, Massachusetts Institute of Technology, Cambridge, MA, and approved October 16, 2017 (received for review July 27, 2017)
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1713328114