Ultrasound breaches blood-brain barrier to deliver chemotherapy

For the first time, investigators used non-invasive focused ultrasound to temporarily open the blood-brain barrier (BBB) and effectively deliver chemotherapy into a patient’s malignant brain tumor.

“Some of the most exciting and novel therapeutics for the treatment of malignant brain tumors are not able to reach the tumor cells because of the blood brain barrier,” said principal investigator Todd Mainprize, MD, neurosurgeon at the Hurvitz Brain Sciences Program at Sunnybrook Health Sciences Centre, in Toronto, Canada, and Assistant Professor in the Division of Neurosurgery at the University of Toronto.

"This technique," he added, "will open up new opportunities to deliver potentially much more effective treatments to the targeted areas."

The research team—led by Dr. Mainprize and physicist Kullervo Hynynen, PhD, Director of Physical Sciences at Sunnybrook Research Institute—infused the chemotherapeutic drug doxorubicin, along with microscopic gas-filled bubbles, into the bloodstream of a patient with a malignant brain tumor.

The researchers then applied MRI-guided focused low-intensity ultrasound to target areas in the tumor and surrounding brain. The ultrasound waves repetitively compressed and expanded the microbubbles, causing them to oscillate in the vessels. This put pressure on the endothelium and forced apart the tight junctions of the blood-brain barrier.

Once the barrier was breached, the chemotherapeutic agent flowed through and deposited into the targeted regions. Doxorubicin has never before been able to cross the blood-brain barrier.

The day after the procedure, investigators removed the tumor and some surrounding tissues. These were sent to pathology to measure the concentration of chemotherapy in the tissue treated by the focused ultrasound and the area not treated. The researchers now await the results from this study.

The patient in this case was the first of about 10 participants in a phase 1 pilot study investigating the feasibility, safety, and preliminary efficacy of focused ultrasound to temporarily open the blood-brain barrier to deliver chemotherapy to brain tumors. These participants are already scheduled for traditional neurosurgery to remove parts of their brain tumor.

Before this novel experiment in a human, hundreds of procedures in preclinical animal studies have been done in mice, dogs, pigs, and primates with no significant adverse effects or hemorrhages, Dr. Mainprize said. In the preclinical studies, the blood-brain barrier was restored to its normal function after a several hours—or a day at most.

Focused ultrasound is believed to be safer than conventional ultrasound because it applies less energy in the brain. Also, it’s non-invasive, unlike radiation or incisional surgery. It uses MRI or ultrasound imaging to direct multiple intersecting beams of ultrasound energy on a single point. Each individual beam causes no effect as it passes through the tissue. But, at the focal point, the multiple beams of ultrasound energy converge to deliver the intended biological effect.

The success of this research opens up the potential for delivering not just chemotherapy but all manner of drug therapies—such as DNA-loaded nanoparticles, viral vectors, or antibodies—to parts of the brain protected by the blood-brain barrier.

“Breaching this barrier opens up a new frontier in treating brain disorders,” said Neal Kassell, MD, founder and chairman of the Focused Ultrasound Foundation. “We are encouraged by the momentum building for the use of focused ultrasound to non-invasively deliver therapies for a number of brain disorders.”

These may include treatments for various types of brain tumors, Alzheimer’s disease, Parkinson’s disease, and some psychiatric conditions.