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Blood-Brain
barrier opening
Principal
Investigator
Elisa
E. Konofagou, Ph.D.
Students
/ Research Scientists
Babak
Baseri, M.S.
James
J. Choi, M.S.
Thomas
Deffieux, Ph.D.
Eugenia
Han
Jennifer
Hui
Yao-Sheng
Tung, M.S.
Shougang
Wang, Ph.D.
Collaborators
Mark
A. Borden, Ph.D., Department of Chemical Engineering, Columbia
University
Truman
R. Brown, Ph.D., Department of Biomedical Engineering and
Radiology, Columbia University
Karen
E. K. Duff, Ph.D., Department of Pathology, Columbia University
Barclay
Morrison III, Ph.D., Department of Biomedical Engineering,
Columbia University
Scott
A. Small, M.D., Department of Neurology, Columbia University
Summary
Many
neurological disorders remain intractable to treatment by
therapeutic agents due to the brain’s natural defense: the
Blood-Brain
Barrier (BBB). The BBB impedes entry of virtually all molecules from
blood capillaries to brain tissue; rendering thus potent neurologically
active substances and drugs ineffective, simply because they cannot be
delivered to where they are most needed. As a result, the BBB is the
rate-limiting factor in brain drug delivery. The only truly transient,
local, and non-invasive opening of the BBB under study as of now is
with focused ultrasound (FUS).
The
purpose of this project is to understand the mechanism, ensure the
safety and efficacy, and optimize the methods of BBB opening using FUS.
Using the mouse as a model, the BBB was opened in vivo using FUS and
ultrasound contrast agents. The entire procedure was monitored with
contrast-enhanced high-resolution MRI (9.4 Tesla), allowing for
detailed spatial analysis of the opening. Histological analysis was
also performed to determine whether any damage to the neurons and the
vascular system was present. On-going studies will lead to the
development of optimal parameters to induce BBB opening, performing of
long term studies of this phenomena, and testing for the delivery of
model drugs.
Support
NIH
R21 EY018505
NSF
CAREER 0644713
Kinetics
Foundation
Recent
Journal Publications
Choi
JJ, Feshitan JA, Baseri B, Wang S, Tung Y-S, Borden MA, Konofagou
EE.
Microbubble-size
dependence on focused ultrasound-induced blood-brain
barrier opening in mice.
Trans
IEEE Biomed Eng. 2009 [in review]
Choi
JJ, Wang S, Tung Y-S, Morrison B 3rd, Konofagou EE.
Molecules
of various pharmacologically-relevant sizes can cross the
ultrasound-induced blood-brain barrier opening in vivo. Ultrasound Med
Biol. 2009 [in press]
Choi
JJ, Wang S, Brown TR, Small SA, Duff KE,
Konofagou EE.
Noninvasive
and transient blood-brain barrier opening in the
hippocampus of Alzheimer's double transgenic mice using focused
ultrasound.
Ultrason
Imaging. 2008 Jul;30(3):189-200.
Choi
J. J., Pernot M., Brown T. R., Small S. A., and Konofagou E. E.
Spatio-temporal
Analysis of Molecular Delivery through the
Blood–Brain Barrier using Focused Ultrasound
Phys
Med Biol, 2007 (in press).
Choi
J. J., Pernot M., Small S. A., and Konofagou E. E.
Noninvasive,
Transcranial and Localized Opening of the Blood-Brain
Barrier using Focused Ultrasound in mice.
Ultrasound
Med Biol, 33(1):95-104, 2007.
Recent
Abstracts and Conference Proceedings
Choi
JJ,
Feshitan JA, Baseri B, Wang S, Tung Y-S, Borden MA, Konofagou EE.
Brain
region and microbubble-size dependence of the focused
ultrasound-induced blood-brain barrier opening in mice in vivo. IEEE
International Ultrasonics Symposium, Rome, ITA. Sept. 20-23, 2009.
Konofagou
EE, Choi JJ, Baseri B, Tung Y-S.
Mechanism
and safety of FUS-induced BBB opening
9th
International
Society on Therapeutic Ultrasound, Aix-en-Provence, France, Sept.
21-24, 2009 (in press).
Choi
JJ,
Wang S, Tung Y-S, Baseri B, Morrison B 3rd, Konofagou EE.
Delivery
of pharmacologically-relevant sized molecules through the
ultrasound-induced blood-brain barrier opening in vivo. Neuroscience,
Chicago, IL, USA, Oct. 17-21. 2009.
Yao-Sheng
Tung, James
J. Choi, Elisa E. Konofagou
Identifying
the Inertial Cavitation
Threshold of Monodispersed Microbubbles and Skull Effects in a Vessel
Phantom Using Focused Ultrasound
9th
International Symposium on
Therapeutic Ultrasound, Aix-en-Provence, France, September 23-26, 2009.
Yao-Sheng
Tung,
James J. Choi, Shougang Wang, Jameel A.
Feshitan, Mark A. Borden and Elisa E. Konofagou
Identifying
the Inertial Cavitation Threshold
In a Vessel Phantom Using FUS and Microbubbles
ASA
Choi
JJ, Wang S, Lee A, Brown TR, Small SA, Duff KEK, Konofagou EE.
Noninvasive
and transient blood-brain barrier opening in the
hippocampus of Alzheimer's APP/PS1 mice using focused ultrasound
Neuroscience,
Washington, DC, USA, Nov. 15-19. 2008.
Wang
S, Choi JJ, Tung Y-S, Morrison B 3rd, Konofagou EE.
Qualitative
and quantitative analysis of the molecular delivery through
the ultrasound-enhanced blood-brain barrier opening in the murine
brain.
IEEE
International Ultrasonics Symposium, Beijing, CHN, Nov.
2-5, 2008.
Wang
S, Baseri B, Choi JJ, Tung Y-S, Morrison B 3rd, Konofagou EE.
Qualitative
and quantitative analysis of molecular delivery through the
ultrasound-induced blood-brain barrier opening in mice.
8th
International Symposium on Therapeutic Ultrasound, Minneapolis, MN,
USA, Sept. 10-13, 2008
Konofagou
EE, Choi JJ, Baseri B, Lee A.
Characterization
and optimization of trans-blood-brain barrier
diffusion in vivo.
8th
International Symposium on Therapeutic Ultrasound, Minneapolis, MN,
USA, Sept. 10-13, 2008
Choi
JJ, Feshitan JA, Wang S, Tung Y-S, Baseri B, Borden MA, Konofagou
EE.
The
dependence of the ultrasound-induced blood-brain barrier opening
characteristics on microbubble size in vivo.
8th
International
Symposium on Therapeutic Ultrasound, Minneapolis, MN, USA, Sept. 10-13,
2008
Choi
JJ, Wang S, Tung Y-S, Morrison B, Konofagou EE.
Trans-blood-brain
barrier delivery of compounds at pharmacologically
relevant molecular weights in the hippocampus of mice using Focused
Ultrasound.
Acoustics
2008, Paris, FRA. June 29 - July 4, 2008.
Choi
J.J., Wang S., Morrison B. and Konofagou E.E.,
Molecular
Delivery and Microbubble Dependence Study of the FUS-induced
Blood-Brain Barrier Opening In Vivo.
IEEE
International Ultrasonics Symposium, New York, NY, USA. Oct.
28-31, 2007.
Choi
J.J., Small S.A., Brown T.R., and Konofagou E.E.,
Non-invasive
Generation and Monitoring of Ultrasound-induced
Blood-Brain Barrier Opening in the Murine Hippocampus.
Proceedings
of the International Society of Magnetic Resonance in
Medicine, Berlin, DEU. 2007;2265.
Konofagou
E.E. and Choi J.J.,
Noninvasive
and Reversible Opening of the Blood-Brain Barrier using
Focused Ultrasound.
Leading
Edge Symposium, Atlantic City, NJ, USA. May 3, 2007. [Invited] |
