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Accessing the Blood Brain Barrier for Chemotherapy

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Blood-Brain Barrier Opened Noninvasively with Focused Ultrasound for the First Time

Mon, 11/09/2015 – 9:26amby Focused Ultrasound Foundation
http://www.mdtmag.com/news/2015/11/blood-brain-barrier-opened-noninvasively-focused-ultrasound-first-time

The blood-brain barrier has been non-invasively opened in a patient for the first time. A team at Sunnybrook Health Sciences Centre in Toronto used focused ultrasound to enable temporary and targeted opening of the blood-brain barrier (BBB), allowing the more effective delivery of chemotherapy into a patient’s malignant brain tumor.

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, loosening the tight junctions of the 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,” said Dr. Mainprize. “We are encouraged that we were able to open this barrier to deliver chemotherapy directly into the brain, and we look forward to more opportunities to apply this revolutionary approach.”

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 Focused Ultrasound Foundation is currently funding this trial through their Cornelia Flagg Keller Memorial Fund for Brain Research.

“Breaching this barrier opens up a new frontier in treating brain disorders,” said Neal Kassell, MD, 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.”

Opening the blood-brain barrier in a localized region to deliver chemotherapy to a tumor is a predicate for utilizing focused ultrasound for the delivery of other drugs, DNA-loaded nanoparticles, viral vectors, and antibodies to the brain to treat a range of neurological conditions, including various types of brain tumors, Parkinson’s, Alzheimer’s and some psychiatric diseases.

The procedure was conducted using Insightec’s ExAblate Neuro system. “This first patient treatment is a technological breakthrough that may lead to many clinical applications,” said Eyal Zadicario, Vice President for R&D and Director of Neuro Programs, Insightec.

While the current trial is a first-in-human achievement, Dr. Kullervo Hynynen, senior scientist at the Sunnybrook Research Institute, has been performing similar pre-clinical studies for about a decade. His research has shown that the combination of focused ultrasound and microbubbles may not only enable drug delivery, but might also stimulate the brain’s natural responses to fight disease. For example, the temporary opening of the blood-brain barrier appears to facilitate the brain’s clearance of a key pathologic protein related to Alzheimer’s and improves cognitive function.

A recent study by Gerhard Leinenga and Jürgen Götz from the Queensland Brain Institute in Australia further corroborated Hynynen’s research, demonstrating opening the blood-brain barrier with focused ultrasound reduced brain plaques and improved memory in a mouse model of Alzheimer’s disease.

Based on these two pre-clinical studies, a pilot clinical trial using focused ultrasound to treat Alzheimer’s is being organized.

Blood-brain Barrier Opened Non-invasively for the First Time

http://www.biosciencetechnology.com/news/2015/11/blood-brain-barrier-opened-non-invasively-first-time

Scientists, for the first time, have non-invasively opened the blood-brain barrier (BBB) in a patient.

A team at Sunnybrook Health Sciences Centre in Toronto, led by neurosurgeon Todd Mainprize, M.D., used focused ultrasound technology to more effectively introduce chemotherapy drugs into a patient’s malignant brain tumor.  The results were verified with a post procedure MRI scan, Mainprize said at a press conference Tuesday.

The blood-brain barrier is a protective layer that keeps harmful substances such as toxins from entering from the blood vessels into the brain.  Unfortunately, it also prevents many drugs from reaching the brain in adequate doses.

At the press conference, Mainprize stressed that this is a phase one safety and concept study to show that they could pass through the BBB. He noted the operation went smoothly and the patient, a 56-year-old women, who is the first of 10 to undergo the procedure for the study, is doing well.

To breach the BBB, doctors infused a chemotherapy drug, along with tiny gas-filled bubbles, into the blood stream. Then focused ultrasound was applied to the tumor and surrounding brain, causing the bubbles to vibrate, and open the BBB so high concentrations of the chemotherapy could enter targeted tissues.

The team is actively analyzing brain tissue samples to see how much of the drug was able to enter.  The findings have not been published yet, but were presented at the Focused Ultrasound Surgery Foundation meeting, according to Mainprize.

Mainprize described the device: It has 1,024 transducers that are arranged in a helmet shape that goes around the head and the forehead, and corrects for aberrations in the skull.

While the BBB has been non-invasively opened in animals, this was the first instance in humans.

“There have been hundreds and hundreds of animal models opening the blood-brain barrier, in mice, dogs, pigs, and primates, all of which have shown a very good safety profile with no changes in function behavior or hemorrhage,” Mainprize said at the press conference.

He noted that this is a reversible procedure, and the barrier is restored back to its normal function in 24 hours.

Nathan McDannold, Ph.D., associate professor of radiology at Brigham and Women’s Hospital said, “If you compare this to alternative methods, whatever risks there are, there much less than if you were invasively injecting drugs.”

The scientists believe the technology has applications beyond brain tumors, such as in Alzheimer’s and Parkinson’s diseases.

McDannold said that groups are in the process of planning a protocol that would deliver antibodies to clear amyloid proteins, associated with Alzheimer’s, and for Parkinson’s they are looking at neuroprotectives and potential gene therapies.

The trial is being funded by the Focused Ultrasound Foundation.