Bubbling Up
By Kathy Hardy
Radiology Today
Vol. 20 No. 3 P. 24

Focused ultrasound and microbubbles show promise for delivering therapy through the blood-brain barrier.

Researchers are looking at tiny spheres of lipids full of gas as the key to using focused ultrasound to temporarily unlock the brain’s protective layer of cells, allowing the targeted application of drugs for the treatment of brain tumors or neurological diseases.

These microbubbles, used as an ultrasound contrast agent, are being used to create a temporary opening of the blood-brain barrier to enable the treatment of conditions such as primary or metastatic, malignant or benign tumors or neurological disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. By disrupting the barrier, agents such as chemotherapy drugs, immunotherapy drugs, or therapeutic drugs are better able to reach the affected areas of the brain.

Adjusting the Focus
According to Neal Kassell, MD, founder and chairman of the Focused Ultrasound Foundation in Charlottesville, Virginia, the blood-brain barrier is a single layer of cells that lines the blood vessels of the brain. The cells are held together by protein structures called tight junctions, which prevent the diffusion of most molecules between cells. This is unique to the brain, as no other organ in the body has such a barrier. The barrier keeps bacteria, viruses, and toxins from entering the brain.

“This barrier does such a good job of keeping out germs,” Kassell says. “However, it also keeps medications from being applied to areas of the brain.”

While microbubbles open just enough area to breach the barrier, the opening is not permanent, Kassell says. There is a four- to six-hour window before the barrier cells rejoin.

“Focused ultrasound is a targeted way to reversibly and repetitively open the blood-brain barrier, as needed, to allow the application of drugs to an area of the brain,” he says.

Focused ultrasound also locates the bullseye in the brain where the drugs can do their work. When considering breakthroughs in the treatment of conditions in the brain, focused ultrasound not only plays a role in the application of drugs but could also bring new life to drugs previously considered insufficient for treating cancer and neurological diseases.

“New techniques to open the blood-brain barrier also open up possibilities of new treatments with existing drugs,” says Nir Lipsman, MD, PhD, a neurosurgeon at Sunnybrook Health Sciences Centre in Toronto, Canada. Lipsman was part of a team at Sunnybrook that was involved in the first case of noninvasively opening the blood-brain barrier in a patient in 2015. Doctors used focused ultrasound to enable a temporary and targeted opening of the blood-brain barrier of a female patient, allowing more effective delivery of chemotherapy drugs to her malignant brain tumor.

Targeted Microbubbles
As Lipsman explains the process, energy is needed for focused ultrasound to “break open” the blood-brain barrier on its own. Adding microbubble ultrasound contrast agents prior to the focused ultrasound treatment reduces the amount of energy needed to disrupt the barrier.

With focused ultrasound, a neurosurgeon infuses the chemotherapy agent, or other drugs, and the tiny gas-filled microbubbles—smaller than one-hundredth of a millimeter—into the patient’s bloodstream. A technologist then applies focused ultrasound to the target areas in the tumor and surrounding areas of the brain, causing the bubbles to vibrate. The vibration loosens the tight junctions of the cells that make up the blood-brain barrier, opening small areas that will allow high concentrations of chemotherapy or other medications to enter the targeted tissues.

Kassell, a neurosurgeon, says the equipment is “relatively easy to use,” referencing the skill set to that of a “kid with video game experience. It’s not like learning something new,” Kassell says. “It’s all image guided and in real time, whether you’re using ultrasound or MRI. It’s all about how you want to look at the area in question.”

Not all focused ultrasound is MR guided. Right now, however, researchers say that focused ultrasound procedures such as penetrating the blood-brain barrier are best performed with the use of MRI for guidance.

The most well-known mechanism of MR-guided focused ultrasound (MRgFUS) is the deposition of heat from a high-intensity, focused ultrasound beam to deposit energy in a desired anatomic target. This noninvasive alternative to surgery kills only targeted cells and comes with fewer side effects than other noninvasive treatments, such as radiation.

MRgFUS is seen as having the potential for use beyond its FDA-approved treatments of uterine fibroids and pain relief for patients with bone metastases. Clinicians began looking at applications where MRgFUS could help treat areas of the brain that control movement disorders from essential tremors to Parkinson’s disease. These treatments recently received FDA approval, and others are investigating this technology for disorders such as neuropathic pain, obsessive-compulsive disorder, and depression.

Evolutionary Process
In the case of Alzheimer’s disease, Kassell says the idea is to open the blood-brain barrier to enable the delivery of antibodies into the brain, as a way of reducing the proteins that collect between neurons and inhibit cell function by forming plaques.

“There’s also a theory that just opening the [blood-brain barrier] alone reduces the concentration of proteins that lead to Alzheimer’s symptoms,” Kassell says.

With Parkinson’s disease, opening the blood-brain barrier allows for the direct application of genetic or growth factor agents, he adds.

“The focus now needs to be on tracking results from preclinical trials and advancing to actual clinical trials,” Kassell says. “Trial results need to be rigorous enough to impress the FDA and payers that this is the best method of treatment for these diseases. Then we can move to educating physicians, health care organizations, and the public.”

As clinicians follow what Kassell sees as the natural evolution from surgery to minimally invasive to noninvasive treatments, there will be challenges along the way. As with any new medical treatments, advancement revolves around evidence. Researchers need to look at safety, feasibility, and outcomes.

“There are many hurdles to overcome in the process of using focused ultrasound to open the blood-brain barrier for the treatment of conditions in the brain,” Kassell says. “We’re just at the beginning of the path that could lead to a new approach to brain tumors and neurological conditions.”

Special Delivery
One hurdle is the impact a noninvasive drug delivery method may have on drug manufacturers’ approach to research and development. Nathan McDannold, PhD, a professor of radiology at Harvard Medical School and Brigham and Women’s Hospital in Boston, has spent the last 20 years researching ways to use focused ultrasound to safely disrupt the blood-brain barrier. McDannold says this work began in the late 1990s with physicist Kullervo Hynynen, MSc, PhD, who now leads the focused ultrasound research program at Sunnybrook and Women’s, when they asked a neuro-oncologist whether there was a drug they should try in their research. They started with a chemotherapy agent that had not been beneficial previously but could be more successful with focused ultrasound to disrupt the blood-brain barrier.

“There is the potential for greater success with the enhanced delivery enabled by focused ultrasound,” McDannold says. “Going forward, there are drugs being used in preclinical trials that seem good but don’t work well and are being dropped. We could rescue some of those drugs, try a new delivery method, and maybe now they will work.”

While focused ultrasound and microbubbles bring new hope for gaining access to targeted areas of the brain, they also have the potential to reinvigorate the effectiveness of certain drug applications for various tumor and neurological disease treatments. Kassell refers to drug treatments that were tried and failed, due to the inability at the time to break through the blood-brain barrier, and apply them directly to the targeted areas of the brain where they could do the most good.

“There are 350 drugs for Alzheimer’s disease that have been tried and failed at the clinical trial stage,” Kassell says. “There’s a theory that some of those drugs didn’t work because they couldn’t reach the brain in adequate concentrations. The use of focused ultrasound could shift the emphasis from drug development to drug delivery.”

McDannold says the introduction of a new drug delivery method is a different approach for drug manufacturers.

“Changing the drug manufacturers’ mindset could be an issue,” he says. “This is a regulatory area. When you have a new drug and a disease it’s meant to treat, there could be a problem if testing doesn’t go well. But then there’s a chance to bring that drug back with a different delivery method.”

Additional Challenges
A challenge that McDannold sees on the radiology side is in determining how best to approach tumors with focused ultrasound. With the complexity of tumors, there is a need to determine the best methods for effectively breaching the blood-brain barrier as well as which contrast agents to use.

“Looking at the advancement of tumors is different in people,” McDannold says. “But with image-guided drug delivery, using MRI methods and contrast agents might help predict how much drug to target to different parts of the brain.”

Establishing clinical trials is another challenging aspect of advancing the use of focused ultrasound. Lipsman notes that funding is a key factor, along with patient recruitment. There are also a number of variables to consider, particularly as researchers look at different diseases.

“It’s important to capture the best data possible,” he says. “With focused ultrasound, we need to prove that it’s safe. When it comes to Alzheimer’s disease treatment, we’re finding in animal models that opening the barrier alone may be beneficial, without using any drugs. There also needs to be consideration of the types of patients who should be included in any clinical trials. If the patient isn’t healthy enough for surgery, they may also not be healthy enough for focused ultrasound. There are so many factors to consider.”

Because of all these variables, Lipsman finds it even more important to take a group approach to determining best practices.

“This is why teamwork is important as we research this noninvasive approach to treating conditions in the brain,” he says. “Multidisciplinary teams should be the constant in the equation.”

Looking to the future, McDannold says it’s important to gain a better understanding of what’s happening at the point of focus within the brain. For example, the microbubbles do the job of creating a disruption in the blood-brain barrier, yet they also have the potential to pop, which could damage the blood vessels.

“It’s important to understand what the disruption does afterward,” McDannold says.

Lipsman says research is still in the early stages, with phase 1 trials underway.

“We need to determine the safety of focused ultrasound to open the blood-brain barrier in humans, as well as the feasibility of the technology,” he says. “We need to optimize use of the microbubbles, considering the best frequency of use, the medication dose, and the time between application of the microbubbles and the ultrasound. We need to look at how the microbubbles interact with the ultrasound.”

— Kathy Hardy is a freelance writer based in Phoenixville, Pennsylvania. She is a frequent contributor to Radiology Today.