Over the past 20 years, we and others developed the fundamentals of transcranial MRI-guided focused ultrasound (TcMRgFUS), a noninvasive technology that will have a profound impact on all aspects of clinical neuroscience. TcMRgFUS is a disruptive technology that can improve upon or replace existing treatments and enable therapies that are not possible today. It is a radical departure from current treatment methods and involves expertise from a broad range of disciplines. While the full potential that ultrasound can have for disorders of the central nervous system is not widely known, the transformational process already begun.
Our aim i s to establish such a program to accelerate and intensify the clinical translation of new TcMRgFUS applications with a proven potential during the lifetime of this grant. Such translation can only happen if the technology is fully-developed, demonstrated to be safe, and implemented in a final form for therapies with major clinical impact. We propose to develop a large-scale, five-year program that will shepherd TcMRgFUS therapies to clinical use for brain cancer. We have developed three projects that can have transform neurosurgery (non-thermal ablation of brain tumors) and neurooncology (targeted drug delivery of chemotherapy to brain metastases). For drug delivery, we will utilize low-energy FUS bursts to temporarily disrupt the blood-brain barrier, which overcomes the major singular limitation of using most drugs in the brain. In one project, we will develop and validate new methods to plan, guide, and evaluate this procedure. In the second, we have developed a plan to move one application of this technology, delivery of anti-cancer agents to breast cancer brain metastases, to the point where it is ready for safety and efficacy clinical trials. Finally, in the third projet, we will combine FUS and a microbubble agent to enable non-thermal ablation, a noninvasive alternative to surgery and radiosurgery. With this method, we can ablate tissue volumes practically anywhere in the brain without using ionizing radiation and without any limits on repeated treatments. At the end of the grant, we aim to have completed the large-scale work needed to move these game-changing TcMRgFUS applications to patients, paving the way to future broad application in treating brain tumors and other disorders in the central nervous system.

Public Health Relevance

Currently-available treatments for diseases and disorders in the central nervous system are often ineffective or have significant side effects. Ultrasound, which can be focused noninvasively to a small volume in the brain, can be used to locally produce a broad range of bio effects that offer completely new therapeutic approaches. This work aims to advance new applications of focused ultrasound that can have a major and disruptive impact: targeted drug delivery via temporary disruption of the blood-brain barrier and non-thermal ultrasound ablation of tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Farahani, Keyvan
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Brigham and Women's Hospital
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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
Kobus, Thiele; Zervantonakis, Ioannis K; Zhang, Yongzhi et al. (2016) Growth inhibition in a brain metastasis model by antibody delivery using focused ultrasound-mediated blood-brain barrier disruption. J Control Release 238:281-8
Top, Can Barış; 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
Sassaroli, Elisabetta; Vykhodtseva, Natalia (2016) Acoustic neuromodulation from a basic science prospective. J Ther Ultrasound 4:17
McDannold, Nathan; Livingstone, Margaret; Top, Can Barış 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
Arvanitis, Costas D; Vykhodtseva, Natalia; Jolesz, Ferenc et al. (2016) Cavitation-enhanced nonthermal ablation in deep brain targets: feasibility in a large animal model. J Neurosurg 124:1450-9
McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia (2016) Nonthermal ablation in the rat brain using focused ultrasound and an ultrasound contrast agent: long-term effects. J Neurosurg 125:1539-1548
Aryal, Muna; Park, Juyoung; Vykhodtseva, Natalia et al. (2015) Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model. Phys Med Biol 60:2511-27
Tang, Sai Chun; McDannold, Nathan J (2015) Power Loss Analysis and Comparison of Segmented and Unsegmented Energy Coupling Coils for Wireless Energy Transfer. IEEE J Emerg Sel Top Power Electron 3:215-225
Kobus, Thiele; McDannold, Nathan (2015) Update on Clinical Magnetic Resonance-Guided Focused Ultrasound Applications. Magn Reson Imaging Clin N Am 23:657-67

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