When ultrasound bursts are combined with a circulating microbubble agent, a temporary disruption in the blood-brain barrier (BBB) is induced that lasts for several hours. This procedure, when combined with ultra- sound devices that can accurately and safely focus an ultrasound beam through the intact skull, has a great potential as a completely noninvasive and targeted method to deliver drugs to the brain. Numerous animal studies have shown that this method does not produce any significant damage to the brain and can also in- crease the permeability of tumor blood vessels. While this technology has potential for a wide range of brain disorders, we think it is likely that initial tests of the method will be in brain tumors. Brain metastases, for which there may already exist drugs that are effective outside the brain, may be a good target to test clinical efficacy. This project aims to perform studies that are needed before we can start a clinical trial to test the efficacy of BBB and blood-tumor barrier disruption for targeted drug delivery in brain tumors. We are aiming to be ready to test the efficacy of this technique in breast cancer brain metastases patients, and we have tai- lored the research around that application. We will perform three studies that evaluate safety and effective- ness of focused ultrasound induced BBB disruption under scenarios we will encounter in a clinical trial. First, we will evaluate the relative efficacy of the two currently-approved agents for treating HER2-positive breast cancer, trastuzumab (Herceptin(R)) and lapatinib (Tykerb(R)). Next, we will evaluate the safety and effectiveness of inducing BBB disruption in the brain and in brain tumors after radiation therapy, a scenario that we expect to encounter in patients. Finally, we will test the safety of repeatedly disrupting extensive volumes in the brain in nonhuman primates using a clinical MRI-guided transcranial focused ultrasound system. These is- sues all need to be resolved before initiating clinical trials. At the end of the grant, we expect to have the data necessary to begin clinical trials on the efficacy of this promising image-guided targeted drug delivery method.

Public Health Relevance

; Ineffective drug delivery caused by the blood-brain barrier, limited permeability of tumor blood vessels, and other factors are thought to lead to the poor outcomes of patients with breast cancer metastases in the brain. Focused ultrasound, when combined with a microbubble agent, offers a noninvasive method to get around these barriers and deliver effective doses of drugs to the brain and to brain tumors. Here we will perform the work needed before we can begin clinical trials evaluating the efficacy of this method.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA174645-02
Application #
8736336
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
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

Showing the most recent 10 out of 14 publications