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.
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.
|Sun, Tao; Zhang, Yongzhi; Power, Chanikarn et al. (2017) Closed-loop control of targeted ultrasound drug delivery across the blood-brain/tumor barriers in a rat glioma model. Proc Natl Acad Sci U S A 114:E10281-E10290|
|Taylor, Erik N; Ding, Yao; Zhu, Shan et al. (2017) Association between tumor architecture derived from generalized Q-space MRI and survival in glioblastoma. Oncotarget 8:41815-41826|
|Sai Chun Tang; McDannold, Nathan J; Vaninetti, Michael (2017) A wireless batteryless implantable radiofrequency lesioning device powered by intermediate-range segmented coil transmitter. Conf Proc IEEE Eng Med Biol Soc 2017:1966-1969|
|Aryal, Muna; Fischer, Krisztina; Gentile, Caroline et al. (2017) Effects on P-Glycoprotein Expression after Blood-Brain Barrier Disruption Using Focused Ultrasound and Microbubbles. PLoS One 12:e0166061|
|McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia (2017) The Effects of Oxygen on Ultrasound-Induced Blood-Brain Barrier Disruption in Mice. Ultrasound Med Biol 43:469-475|
|Arvanitis, Costas D; Crake, Calum; McDannold, Nathan et al. (2017) Passive Acoustic Mapping with the Angular Spectrum Method. IEEE Trans Med Imaging 36:983-993|
|Park, Juyoung; Aryal, Muna; Vykhodtseva, Natalia et al. (2017) Evaluation of permeability, doxorubicin delivery, and drug retention in a rat brain tumor model after ultrasound-induced blood-tumor barrier disruption. J Control Release 250:77-85|
|Kobus, Thiele; Vykhodtseva, Natalia; Pilatou, Magdalini et al. (2016) Safety Validation of Repeated Blood-Brain Barrier Disruption Using Focused Ultrasound. Ultrasound Med Biol 42:481-92|
|Top, Can Bar??; White, P Jason; McDannold, Nathan J (2016) Nonthermal ablation of deep brain targets: A simulation study on a large animal model. Med Phys 43:870-82|
|McDannold, Nathan; Livingstone, Margaret; Top, Can Bar?? et al. (2016) Preclinical evaluation of a low-frequency transcranial MRI-guided focused ultrasound system in a primate model. Phys Med Biol 61:7664-7687|
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