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...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 48; pp. E10281 - E10290 |
|---|---|
| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
28.11.2017
|
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| 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. |
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| AbstractList | 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.
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. 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. 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.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. |
| Author | Alexander, Phillip M. Sun, Tao Power, Chanikarn Sutton, Jonathan T. Zhang, Yongzhi Aryal, Muna Miller, Eric L. McDannold, Nathan J. Vykhodtseva, Natalia |
| Author_xml | – sequence: 1 givenname: Tao surname: Sun fullname: Sun, Tao organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 – sequence: 2 givenname: Yongzhi surname: Zhang fullname: Zhang, Yongzhi organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 – sequence: 3 givenname: Chanikarn surname: Power fullname: Power, Chanikarn organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 – sequence: 4 givenname: Phillip M. surname: Alexander fullname: Alexander, Phillip M. organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 – sequence: 5 givenname: Jonathan T. surname: Sutton fullname: Sutton, Jonathan T. organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 – sequence: 6 givenname: Muna surname: Aryal fullname: Aryal, Muna organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 – sequence: 7 givenname: Natalia surname: Vykhodtseva fullname: Vykhodtseva, Natalia organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 – sequence: 8 givenname: Eric L. surname: Miller fullname: Miller, Eric L. organization: Department of Electrical and Computer Engineering, Tufts University, Medford, MA 02155 – sequence: 9 givenname: Nathan J. surname: McDannold fullname: McDannold, Nathan J. organization: Focused Ultrasound Laboratory, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/29133392$$D View this record in MEDLINE/PubMed |
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| Copyright | Volumes 1–89 and 106–114, copyright as a collective work only; author(s) retains copyright to individual articles Copyright National Academy of Sciences Nov 28, 2017 2017 |
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| Keywords | acoustic cavitation blood–brain barrier drug delivery focused ultrasound treatment control |
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| Notes | 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) |
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| Snippet | Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood–brain barrier (BBB) for treating... Focused ultrasound is currently the only method of reversible blood–brain barrier disruption for targeted drug delivery without incision or radiation. A... Cavitation-facilitated microbubble-mediated focused ultrasound therapy is a promising method of drug delivery across the blood-brain barrier (BBB) for treating... |
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| SubjectTerms | Biological Sciences Blood-brain barrier Cavitation Physical Sciences PNAS Plus Regression analysis Rodents Tumors Ultrasonic imaging |
| Title | Closed-loop control of targeted ultrasound drug delivery across the blood–brain/tumor barriers in a rat glioma model |
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