The team, led by neurosurgeon Todd Mainprize, MD, and physicist Kullervo Hynynen, PhD, infused the chemotherapy agent doxorubicin, along with tiny, gas-filled bubbles, into the bloodstream of a patient with a brain tumor. They then applied focused ultrasound to areas in the tumor and surrounding brain, causing the bubbles to vibrate and loosen the tight junctions of cells comprising the blood-brain barrier and allowing high concentrations of the chemotherapy to enter targeted tissues.
"The blood-brain barrier has been a persistent impediment to delivering valuable therapies to treat tumors. We are encouraged that we were able to open this barrier... and we look forward to more opportunities to apply this revolutionary approach." – Dr. Todd Mainprize
This patient treatment is part of a pilot study of up to 10 patients to establish the feasibility, safety, and preliminary efficacy of focused ultrasound to temporarily open the blood-brain barrier to deliver chemotherapy to brain tumors. The Foundation is currently funding this clinical trial through the Cornelia Flagg Keller Memorial Fund for Brain Research. READ MORE >
The blood-brain barrier (BBB) is a protective layer of tightly joined cells that line the blood vessels of the brain. It is crucial to preventing disease and preserving health by keeping harmful substances (such as toxins and infectious agents) from entering the brain. Unfortunately, this barrier also prevents certain drugs from reaching adequate concentrations in their targets within the brain, and there are limited options to circumvent the BBB to deliver them.
The story began in 2001, when Drs. Kullervo Hynynen, Nathan McDannold, Ferenc Jolesz, and colleagues first described a controlled, temporary, and reproducible manner of opening the BBB using FUS. Since then, researchers found that the addition of microbubbles or contrast agents improved the phenomenon's efficiency and efficacy. When the FUS vibrates the microbubbles, the movement loosens the BBB’s tight junctions and allows molecules to move from the vasculature to the targeted region of the brain. This year, the group at Columbia University completed a long-term safety study of repeatedly opening the BBB with FUS and microbubbles, finding their parameters safe for up to 20 months without any long-term negative physiological or neurological effects. The goal of using FUS for opening the BBB is to allow medications or biologics (neurotrophic factors, antibodies, stem cells, or viral vectors) to reach the brain when they normally would not.
Elisa Konofagou presented her BBB findings to the FDA in November 2014
Can FUS Unlock Treatment Options for Other Neurological Diseases?
With the fundamental mechanism established for opening the BBB with FUS and microbubbles, scientists around the world are working to advance the potential of FUS to play an integral role—either alone or in combination with other therapies—in the treatment of several neurological diseases. For example, pre-clinical research has been evaluating the use of FUS to deliver therapies to treat:
Brain tumors/brain metastases with chemotherapy or immunotherapy
The Focused Ultrasound Foundation is committed to advancing the use of FUS to open the BBB and treat a range of neurological conditions. In addition to supporting research through our funding awards, we have organized several workshops exploring this topic, including a September 2013 BBB Workshop, a February 2015 Immunotherapy Workshop, and a September 2015 Alzheimer’s Workshop.
The Foundation funded Sunnybrook’s first-in-human clinical trial through the Cornelia Flagg Keller Memorial Fund for Brain Research. In addition, we have supported six major BBB studies since 2011, and our initial investment of $300,000 has yielded more than $3 million in follow-on funding.
A computer-generated illustration of nanoparticles
Gene and DNA delivery can increase the production of desirable proteins within a cell in a particular region of the body.
Microbubbles can be coated in lipids, gadolinium, or gold. Each coating changes the properties, which affects its ability to move throughout the body, and can also assist in MR visualization during delivery.
A Packaged Deal
Scientists are working on various methods of packaging drugs and biologics to do two things:
Help the therapeutic molecules travel through the BBB and brain tissue by reducing their “stickiness.”
Use focused ultrasound to “open” the package only at the precise location where they are needed.
In this type of packaging, “carrier vehicles” may more effectively deliver the proper clinical dosage to the correct region of the brain. Drugs, proteins, and genes can be packaged in microbubbles, nanoparticles, or viral vectors.
Who is Packaging Medications and Biologics?
Johns Hopkins University has a molecular packaging plant, and so do other academic institutions and private companies. Some of the companies have spun out of the academic centers and continue to collaborate with them. From Colorado to Virginia, then north to Boston and Toronto, scientists have a broad range of ideas and products that will assist the process of delivering drugs and biologics across the BBB.
Scientists at leading institutions across the globe are continually working to define and refine the technological parameters that enable the opening of the BBB with focused ultrasound. Throughout the past year, we have profiled several of the institutions, engineers, and individual researchers who are advancing this important application of the field. Read more about the teams at:
Many publications on the use of FUS to open the BBB are now available, and new findings are continually being published. We have compiled a brief, alphabetical bibliography that includes some of the more recent review papers and those that provide a broader overview of this exciting field.