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Ultrasound Offers Noninvasive Method to Target Drug Delivery in Animal Brain

Talan, Jamie

doi: 10.1097/01.NT.0000552578.72809.f8
At the Bench
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A research team used ultrasound waves to break up a nanoparticle-filled anesthetic to target the visual cortex of a rat brain. The drug reached its target, inhibiting excitatory evoked potentials. The researchers plan to test the efficacy and safety of the noninvasive drug delivery technique in larger animals. The technology has potential for clinical use, particularly in epilepsy, the study authors and independent experts agreed.

Scientists at Stanford University are using an innovative technology to explore noninvasive ways to precisely deliver drugs to targeted areas in the brain.

The technique involves using ultrasound (high frequency sound waves) to shake drug molecules loose from a tiny polymer-encased shell that has been injected into the bloodstream.

In rats, this method showed that the high-frequency sound waves could loosen nanoparticle “cages” filled with an anesthetic and deliver the medication to different parts of the brain, inhibiting neural activity in each location.

The findings, described in the November 7 issue of Neuron, provide proof of principle that the technique is safe, precise, and noninvasive, the senior study author Raag Airan, MD, PhD, told Neurology Today.



Dr. Airan, an assistant professor in the division of neuroimaging and neurointervention in the department of radiology at Stanford University, first became interested in the concept for drug delivery while doing doctoral work as a medical student in the optogenetics laboratory of Stanford's Karl Deisseroth, MD, PhD.

Dr. Airan was intrigued by optogenetics, which uses optical and genetic techniques to probe neural circuits, but he wanted to explore a less invasive way to target the brain.

He had an idea that ultrasound could be paired with medications “caged” in biocompatible and biodegradable nanoparticles that release their payload when the beam is directed at a target.

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Dr. Airan and his colleagues began pairing ultrasound with nanoparticles filled with the fast-acting anesthetic drug propofol.

“We used an anesthetic drug that is commonly used in surgery to see if we could simulate the effects of surgery to turn off an area of the brain,” he explained.

The nanoparticles have a polymer shell that holds the drug. The core of the particle is made up of a liquid substance that is sensitive to ultrasound. The ultrasound energy causes the core to shake until it loosens the polymer's grip and releases the drug into tissue.

The first round of studies showed that ultrasound could be used to induce drug delivery in these nanoparticle cages, but it wasn't clear where the drug was going and how fast it delivered the cargo.

The Neuron paper's team described a series of experiments to show how the technique worked. There was no effect when they gave nanoparticles alone; applying ultrasound without nanoparticles did nothing either. Delivering the anesthesia-packed nanoparticles and turning on the ultrasound at the target — an area of the visual cortex that had been stimulated with light flashed at the animal's retina — produced an immediate drop in excitatory evoked potentials, however. The anesthesia was quieting the visual cortex.

By changing the strength and duration of the ultrasound beam, the researchers fine-tuned this inhibition. And once the beam was off, the effects were immediately reversed, with no damage to the tissue. The medication came within a millimeter of its target and did not spread to nearby tissue.

Because the scientists could track the brain's response to the local anesthesia, the technique could be used for mapping brain circuits' responses to targeted drug delivery, said Dr. Airan.

“Every part of this technique — the polymer, the drug, and focused ultrasound — has been approved for investigational use in patients,” said Dr. Airan.

The research team is expanding their experiments to test the efficacy and safety of the technique in larger animals. They hope to translate it into a technique that can be used clinically.

The technology has considerable potential for clinical use, Dr. Airan contends. The main initial challenge would be establishing the safety and toxicity profile of the new compound. The scientists are currently working to test this for use in humans.



“Once we have an investigational license, we aim to complete our initial clinical trials to use this technique for localizing and anesthetizing regions of the brain contributing to seizure activity,” he said. “Eventually the technique would be straightforward and could be used by a clinician who knows which brain region they want to anesthetize. They can just start the caged propofol infusion intravenously, point the ultrasound beam at the target and turn it on when you want the local anesthesia to start, and turn it off once you're done.”

“What if we could simulate the effects of neurosurgery — uncage an anesthetic and turn off a chunk of brain to see if we could stop seizure activity?” asked Dr. Airan. “We would not have to enter the brain to do this. It would be amazing.”

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Independent experts agreed that the methodology has potential for clinical use. “This is like reversible neurosurgery,” said Robert S. Fisher, MD, PhD, FAAN, Maslah Saul MD professor and director of the Stanford Epilepsy Center. Dr. Fisher noted that the anesthetic delivered in the current experiment put a very targeted area of the brain to sleep for a limited time. “In epilepsy this technique could be used to tell us whether the targeted area is in an eloquent area of the brain that controls important functions,” he said.

“I think this technique has great potential,” agreed Emery N. Brown, MD, PhD, professor of medical engineering and computational neuroscience at MIT and professor of anesthesia at Harvard Medical School. “This is a proof of concept that the technology will be able to deliver a drug that can inhibit tissue in a specific location. One of the most obvious areas is in seizure diagnosis and control. Suppose you can hunt out foci and use ultrasound to arrest the seizures and help localize them noninvasively?”

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The work was funded by the National Institutes of Health, the Stanford Center for Cancer Nanotechnology Excellence, the Foundation of the American Society for Neuroradiology, the Wallace H. Coulter Foundation, the Dana Foundation, and the Wu Tsai Neurosciences Institute. Provisional patents applications have been filed for the nanoparticles described in the paper by Stanford University and Johns Hopkins University.

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•. Wang JB, Aryal M, Zhong Q, Vyas DB, Airan RD. Noninvasive ultrasonic drug uncaging maps whole-brain functional networks Neuron 2018;1000(3):728–736.e7.
    © 2018 American Academy of Neurology