MIT Libraries homeMIT Libraries logoDSpace@MIT

MIT
View Item 
  • DSpace@MIT Home
  • MIT Libraries
  • MIT Theses
  • Theses - Harvard-MIT Program of Health Sciences and Technology
  • Health Sciences and Technology - Ph.D. / Sc.D.
  • View Item
  • DSpace@MIT Home
  • MIT Libraries
  • MIT Theses
  • Theses - Harvard-MIT Program of Health Sciences and Technology
  • Health Sciences and Technology - Ph.D. / Sc.D.
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

Advances in targeted chemotherapy using MRI-guided focused ultrasound to disrupt the blood-brain barrier

Author(s)
Treat, Lisa Hsu
Thumbnail
DownloadFull printable version (28.41Mb)
Other Contributors
Harvard University--MIT Division of Health Sciences and Technology.
Advisor
Kullervo Hynynen.
Terms of use
M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582
Metadata
Show full item record
Abstract
The clinical application of chemotherapy to brain malignancies has been severely limited because many potential therapeutic agents are typically unable to penetrate the blood-brain barrier (BBB). A novel approach to overcome this barrier uses focused ultrasound to induce localized BBB disruption in a targeted region of the brain and magnetic resonance imaging (MRI) to guide and monitor the procedure. The purpose of this thesis was to develop a technique using MRI-guided focused ultrasound for trans bbb drug delivery applications. This thesis demonstrates that MRI-guided focused ultrasound can be used to achieve consistent and reproducible BBB disruption without invasive craniotomy in rats, to enable doxorubicin to accumulate in normal brain at clinically therapeutic levels, and to increase the antitumoral efficacy of doxorubicin in a rodent model of aggressive glioma. Using a microbubble-based ultrasonographic contrast agent, focal BBB opening was consistently achieved using transcranial focal pressures of 1.2 MPa or greater; locations in the posterior brain exhibited consistent BBB disruption with applied focal pressures of 0.8 MPa or greater. When combined with systemic administration of liposomal doxorubicin, we achieved local drug concentrations of 900 ± 300 ng/g tissue in the brain with minimal tissue effects, and up to 5400 ± 700 ng/g tissue with more significant tissue damage, while accumulation in non-targeted contralateral brain tissue remained significantly lower (p < 0.001). In addition, MRI signal enhancement in the sonicated region correlated strongly with doxorubicin concentration in tissue (r = 0.87), suggesting that contrast-enhanced MRI may provide useful feedback on drug penetration.
 
(cont.) Finally, glioma-bearing rats treated with ultrasound-enhanced chemotherapy exhibited significantly longer median survival times (31 versus 25 days; p = 0.0007) and slower tumor growth (average tumor volume doubling time, 3.7 ± 0.5 days, versus 2.3 ± 0.3 days) than nontreated rats; rats which received standard intravenous chemotherapy showed no significant difference in survival or tumor growth rate. In sum, this thesis research provides pre-clinical data toward the development of MRI-guided focused ultrasound as a noninvasive method for the delivery of agents such as doxorubicin across the BBB to treat patients with diseases of the central nervous system.
 
Description
Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009.
 
Includes bibliographical references (p. 107-121).
 
Date issued
2009
URI
http://hdl.handle.net/1721.1/47849
Department
Harvard University--MIT Division of Health Sciences and Technology.
Publisher
Massachusetts Institute of Technology
Keywords
Harvard University--MIT Division of Health Sciences and Technology.

Collections
  • Health Sciences and Technology - Ph.D. / Sc.D.
  • Health Sciences and Technology - Ph.D. / Sc.D.

Browse

All of DSpaceCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

My Account

Login

Statistics

OA StatisticsStatistics by CountryStatistics by Department
MIT Libraries homeMIT Libraries logo

Find us on

Twitter Facebook Instagram YouTube RSS

MIT Libraries navigation

SearchHours & locationsBorrow & requestResearch supportAbout us
PrivacyPermissionsAccessibility
MIT
Massachusetts Institute of Technology
Content created by the MIT Libraries, CC BY-NC unless otherwise noted. Notify us about copyright concerns.