We have developed a technique that combines ultrasound bursts with a microbubble agent to temporarily disrupt the blood-brain barrier (BBB). The BBB normally protects the brain by excluding entry to most substances from the blood stream and is the primary hurdle to the use of therapeutic agents in the central nervous system. The ability to use focused ultrasound-induced BBB disruption (FUS-BBBD) to target drugs to desired volumes in the brain, along with devices that can safely and precisely focus ultrasound energy through the human skull, presents a potentially huge advance neuroscience. The method can also increase the permeability of the "blood-tumor barrier", which retains many characteristics of the normal BBB and significantly impedes the adequate delivery of chemotherapeutics into brain tumors.
We aim to overcome the major remaining limitations in translating FUS-BBBD to the clinic: the lack of effective methods to control the procedure. We also hypothesize that we can utilize imaging methods to predict drug concentrations at each target. To address these needs, we will develop and validate a comprehensive set of tools to provide effective treatment planning, monitoring, and evaluation for FUS-BBBD. For planning (Aim 1), we will use Magnetic Resonance Acoustic Radiation Force Imaging and cerebral blood flow imaging to provide measurements that reflect the local ultrasound intensity and the vascular density. We expect these factors to be predictive of the BBBD magnitude and can provide an initial estimate for the ultrasound exposure level.
In Aim 2, we will optimize, build, and test passive cavitation detectors to monitor the acoustic emission produced by the microbubbles in the ultrasound field. This emission contains information that will be used as a real-time safety monitor and as an online means to refine the ultrasound exposure level so that it is sufficient to produce robust BBBD. Finally, for treatment evaluation (Aim 3), we will compare the delivery of drugs and other substances after FUS-BBBD to that of an MRI contrast agent using mass spectroscopy imaging. This work will provide a framework to "calibrate" the post-FUS imaging so that we can make quantitative estimates of local drug delivery based on the surrogate measurements of the contrast agent. Being able to not only target the delivery of drugs noninvasively, but to also quantify the amount of drug delivered will bring a new level of control over drug therapy, allow for optimal dosing, and ensure treatment consistency. The methods will be tested in the brains of rodents and non-human primates, and their ability to ensure a consistent therapeutic outcome will be validated in two brain tumor models. Overall, if we are successful, this work will provide the tools needed to make FUS-BBBD safer and more controlled.

Public Health Relevance

Treatment of brain tumors and other disorders in the brain are hampered by the blood-brain and blood-tumor barriers, which prevents most agents from leaving the bloodstream. Ultrasound, when combined with circulating microbubbles, can temporarily permeabilize these vessels and allow drugs to be delivered. This work will develop methods to plan, monitor, and evaluate this technique to ensure a safe and effective procedure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
1P01CA174645-01
Application #
8506193
Study Section
Special Emphasis Panel (ZCA1-RPRB-W (J1))
Project Start
2013-06-05
Project End
2018-05-31
Budget Start
2013-06-05
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$365,097
Indirect Cost
$135,273
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Aryal, Muna; Arvanitis, Costas D; Alexander, Phillip M et al. (2014) Ultrasound-mediated blood-brain barrier disruption for targeted drug delivery in the central nervous system. Adv Drug Deliv Rev 72:94-109