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New Approach Improves Treatment of Deadly Childhood Brain Cancer

Treating diffuse intrinsic pontine glioma, a deadly form of brain cancer, is so difficult that less than 1 percent of children survive five years. It has been that way for more than 40 years. Now, a group of engineers and scientists at Washington University School of Medicine in St. Louis, MO., have developed a treatment that could potentially target and treat even the most ill-fated gliomas.

When it comes to treating brain cancer, the main obstacle is the blood-brain barrier. This intricate system of blood vessels regulates conditions within the brain, protecting it by keeping out the wrong biomolecules. When tumors grow in the brain, this barrier also prevents medicines delivered through the blood system from reaching their intended target.

The researchers combine two techniques, focused ultrasound (FUS) and intranasal delivery (IN), to create a new approach the researchers call “FUSIN.” While both techniques have been around for decades, it took Hong Chen, an assistant professor of radiation oncology at the university’s School of Engineering & Applied Science, to marry the two.

Focused ultrasound uses high-intensity ultrasonic energy to heat or agitate tissues to improve the uptake of medicine. This technology has existed since the 1940s and has grown more effective, thanks to such advances as phased array transducers and imaging technology.

Today, FUS is used to treat prostate and bone cancers as well as uterine fibroids. It has remained a technique of interest for brain cancers like DIPG, but research has stalled without a way to get the drugs past the blood brain barrier.

That’s where intranasal delivery steps in. Delivering medication through the nose, which works like a common nasal spray, allows tiny particles to bypass the blood brain barrier by following the olfactory and trigeminal nerves into the brain. Yet those particles do not target tumors effectively because they are so widely dispersed throughout the brain.

The FUSIN technique combines both methods and is showing promise for treating diseases like DIPG.

“DIPG is hard to treat,” said Chen, a bioengineer whose research has been funded by the American Cancer Society, Children’s Discovery Institute of Washington University, and St. Louis Children’s Hospital. “Strategies have been investigated to improve the drug delivery for the treatment of DIPG with little success. FUSIN differs because it offers a method for noninvasive and localized brain drug delivery.”

First, an ultrasound system focused on the tumor is fitted over the patient’s head. The patient then inhales the cancer drugs through the nose. The medication enters the brain in the liquid-filled perivascular spaces surrounding the blood vessels, where it disperses.

At the same time, a clinician injects microbubbles into the bloodstream intravenously, a common practice in ultrasound imaging. These bubbles wind up in the blood vessels just under the perivascular spaces.

When the clinicians focus the ultrasound beam on the tumors, the energy causes the microbubbles to oscillate within the blood vessels. This deforms the vessels, turning them into the tubular equivalent of a diaphragm pump that attracts dispersed drug particles and drives them into the nearby glioma.

While all this is happening, a physician monitors the treatment on an MRI. In just a few minutes, the tumor is targeted, treated, and reduced – if not fully eradicated.

A Keen Understanding

Combining these two methods took a keen understanding of how the vascular system works, something on which Chen has focused her career. Chen first thought of FUSIN back in 2014, when she was a postdoctoral researcher at Columbia University. Her paper stated that FUSIN seemed to be about as effective as FUS-IV (focused ultrasound and intravenous injection) and that more research needed to be done to understand how the drugs were penetrating the tissue.

Chen published again, in 2016, this time on a mechanical process she calls the “microbubble pump effect.” Using high-speed photography, Chen found that when the microbubbles oscillate in the blood vessels, their movement causes the blood vessels to expand and contract. She also demonstrated that she could control those movements by changing ultrasound wave parameters. Adjusting the pressure and intensity of the waves is the key to getting blood vessels to behave like a pump and drive drugs into the tumor in the brain.

It took two more years for Chen to find the perfect pressure and intensity settings for focused ultrasound.

“After many failures in the first year, we almost gave up on the project,” she said. “But persistence pays off. We were able to get it to work in the second year and now we have a promising path forward.”

Chen and her team are currently working to understand how and why the drug particles flock to the oscillating tissue instead of continuing to disperse throughout the brain.

“We’re still at the early stages,” she said.



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