Over 4 million U.S. men and women suffer from Alzheimer's disease;1 million from Parkinson's disease;350,000 from multiple sclerosis (MS);and 20,000 from amythrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available mainly due to the impermeability of the blood-brain barrier (BBB). Safe and localized opening of the blood-brain barrier (BBB) has been proven to present a significant challenge in brain drug delivery. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. The underlying hypothesis of this study is that, through control over the ultrasound and microbubble parameters, the extent and reversibility of the BBB opening induced by FUS can be successfully predicted and manipulated for efficient trans-BBB delivery. The primary objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS. In addition, the mechanism of the BBB opening in vivo will be monitored by the use of an MR contrast agent attached to the microbubble shell, which will allow observation of the location and accumulation of the shell material following treatment. The team assembled encompasses all important specialty areas required, such as ultrasound and microbubble engineering as well as MR and fluorescence brain imaging.
The specific aims of the study are to: 1) engineer and determine the microbubble characteristics for a reversible and localized BBB opening;2) identify the mechanism of BBB opening at distinct microbubble and ultrasound parameters in vivo; 3) perform quantitative analysis of the BBB opening using MR and fluorescence imaging; and 4) image the mechanism of BBB opening and trans-BBB delivery in vivo. By achieving the goals of the proposed study, the mechanism of the FUS procedure will be more thoroughly understood and the FUS-induced BBB opening will be optimized for selectively and precisely delivering pharmacological agents to currently untreatable brain regions. Public Health Relevance Statement (provided by applicant): Due to the impermeability of the blood-brain barrier (BBB), neurological disorders and all age-related neurodegenerative diseases remain untreatable despite the thousands of pharmacological agents available. The objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB009041-05
Application #
8320353
Study Section
Special Emphasis Panel (ZEB1-OSR-B (O1))
Program Officer
Lopez, Hector
Project Start
2008-09-30
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$471,242
Indirect Cost
$176,571
Name
Columbia University (N.Y.)
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Wu, Shih-Ying; Fix, Samantha M; Arena, Christopher B et al. (2018) Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery. Phys Med Biol 63:035002
Burgess, M T; Apostolakis, I; Konofagou, E E (2018) Power cavitation-guided blood-brain barrier opening with focused ultrasound and microbubbles. Phys Med Biol 63:065009
Pouliopoulos, Antonios N; Burgess, Mark T; Konofagou, Elisa E (2018) Pulse inversion enhances the passive mapping of microbubble-based ultrasound therapy. Appl Phys Lett 113:044102
Munoz, Fabian; Aurup, Christian; Konofagou, Elisa E et al. (2018) Modulation of Brain Function and Behavior by Focused Ultrasound. Curr Behav Neurosci Rep 5:153-164
Wu, Shih-Ying; Aurup, Christian; Sanchez, Carlos Sierra et al. (2018) Efficient Blood-Brain Barrier Opening in Primates with Neuronavigation-Guided Ultrasound and Real-Time Acoustic Mapping. Sci Rep 8:7978
Samiotaki, Gesthimani; Karakatsani, Maria Eleni; Buch, Amanda et al. (2017) Pharmacokinetic analysis and drug delivery efficiency of the focused ultrasound-induced blood-brain barrier opening in non-human primates. Magn Reson Imaging 37:273-281
Karakatsani, Maria Eleni Marilena; Samiotaki, Gesthimani Mania; Downs, Matthew E et al. (2017) Targeting Effects on the Volume of the Focused Ultrasound-Induced Blood-Brain Barrier Opening in Nonhuman Primates In Vivo. IEEE Trans Ultrason Ferroelectr Freq Control 64:798-810
Sierra, Carlos; Acosta, Camilo; Chen, Cherry et al. (2017) Lipid microbubbles as a vehicle for targeted drug delivery using focused ultrasound-induced blood-brain barrier opening. J Cereb Blood Flow Metab 37:1236-1250
Wang, Shutao; Karakatsani, Maria E; Fung, Christine et al. (2017) Direct brain infusion can be enhanced with focused ultrasound and microbubbles. J Cereb Blood Flow Metab 37:706-714
Wang, Shutao; Kugelman, Tara; Buch, Amanda et al. (2017) Non-invasive, Focused Ultrasound-Facilitated Gene Delivery for Optogenetics. Sci Rep 7:39955

Showing the most recent 10 out of 50 publications