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Stanford University School of Medicine has developed a noninvasive way of delivering drugs to within a few millimeters of a desired point in the brain.
The method, tested in rats, uses focused ultrasound to jiggle drug molecules loose from nanoparticle "cages" that have been injected into the bloodstream.
In a proof-of-principle study, the researchers showed that pharmacologically active doses of a fast-acting drug could be released from these cages in small areas of the brain by a beam of focused ultrasound. The drug has only recently been shown to be active, but it has only been shown to be highly selective. By modifying the strength and duration of the beam, the investigators could fine-tune the neural inhibition.
While the drug used in this study was propofol, it was an anesthetic commonly used in surgery, in principle the same approach for many drugs with widely differing pharmacological actions and psychiatric applications, and even for some chemotherapeutic drugs used to combat cancer.
By turning up the ultrasound intensity and monitoring brainwide metabolic activity, Raag Airan, MD, PhD, an assistant professor of neuroradiology, said Raag Airan, MD, Ph.D. In this way, the researchers were able to noninvasively map out the connections among disparate circuits in the living brain.
A paper describing the study will be published Nov. 7 in Neuron. Airan is the senior author. Lead author is Jeffrey Wang, a student in the MD-PhD program, and postdoctoral scholar Muna Aryal, PhD.
A kindred knowledge known as optogenetics, pioneered by Karl Deisseroth, MD, PhD, a Stanford professor of bioengineering and of psychiatry and behavioral sciences. to precise experimental manipulation. Airan's approach uses noninvasive pharmacological methods to achieve similar control of neural activity.
"This important work establishes that ultrasonic drug uncaging appears to be required to tune the brain's activity by targeted drug application," said Deisseroth, who was not involved in the study. "The powerful new technique could be used to test optogenetically inspired ideas, derived from rodent studies, in large animals – and perhaps soon in clinical trials."
'We're optimistic'
The new technology could not only accelerate speed in neuroscientific research but move rapidly into clinical practice, Airan said. "While this study is done in rats, each component of the nanoparticle has been approved for at least one investigational human use by the Food and Drug Administration, and has been ultrasoundally tested at Stanford," he said. "So, we're optimistic about this procedure's translational potential."
Harmless at the low intensities routinely used for imaging bodily tissues, high-intensity focused ultrasound is approved for the ablation, or deliberate destruction, of certain tissues, including portions of a central brain structure called the thalamus to treat the condition known as essential tremor.
For the new study, "we have gone down the dials" on the ultrasound device, Airan said. The intensity of the ultrasound used in these experiments was about 1 / 10th to 1 / 100th of the intensity used in clinical ablation procedures. The ultrasound in these experiments was delivered in a series of short staccato pulses separated by periods of rest, giving the target brain tissue plenty of time to cool off between pulses. Rats exposed numerous times to the experimental protocol showed no evidence of tissue damage from it.
The nanoparticles, which are biocompatible, biodegradable, liquid-filled spheres averaging 400 nanometers (about 15-millionths of an inch) in diameter. Their surfaces consist of a matrix copolymer in which the drug of choice is encaged. Roughly 3 million molecules of a drug typically dot the surface of one of these nanoparticles.
Each nanoparticle is enclosed in a droplet of a substance called perfluorocarbon. Buffered by ultrasound waves at the right frequency, these liquid cores begin shaking and expanding until the copolymer matrix coating the surface ruptures, setting the trapped drug molecules free. Propofol, like all psychoactive drugs, easily diffused through the formidable blood-brain barrier. But having crossed this barrier, the drug is quickly soaked up by brain tissue, so it never gets farther than half a millimeter from the capillary where it's been released.
Airan and his colleagues injected these particles intravenously into experimental rats and explored focused ultrasound's potential for targeted drug delivery.
Initially, they measured nerve cells 'activity in the visual cortex, an area in the back of the brain that is activated by visual stimuli, in response to flashes of light at the rats' eyes. Focusing on the ultrasound beam on that brain area, they are seen to be plunge while the beam was being transmitted, then recovering within a few seconds after the device was shut off. This drop-off in the visual cortex's electrical activity, which is what you expect from the anesthetic of an anesthetic, grew more pronounced with increasing ultrasound intensity, and did not occur when the rats were injected instead with drug -free nanoparticles.
In contrast, activity in the motor cortex, a brain was not diminished when ultrasound was applied there. OBJECTIVE: Ultrasound targeting the lateral geniculate nucleus, a brain area that relays visual information to the visual cortex, did reduce electrical activity in the visual cortex. This report shows that propofol release in one brain structure can produce secondary effects in another.
Brainwide metabolic response
Next, Airan 's team is monitoring the brain of a radioactive analogue of glucose – glucose is the brain' s brain energy source – in rats. When the injected nanoparticles were blanks, there was no effect in ultrasound-exposed areas. But with propofol-loaded nanoparticles, the metabolism dropped, was reduced in these ultrasound-exposed regions. This inhibition increases with increasing ultrasound intensity. Cranking the ultrasound level high enough also triggered selectively diminished activity in remote brain regions known to receive inputs from the ultrasound-exposed area.
"We hope to use this technology to predict the results of excising or inactivating a patient's brain," Airan said. "Will it inactivating or removing that small piece of tissue achieve the desired effect – for example, stopping epileptic seizure activity? Will it cause any unexpected side effects?"
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Other study co-authors are postdoctoral scholar Qian Zhong, PhD, and medical student Daivik Vyas.
The National Institutes of Health (grants RF1MH114252 and U54CA199075), the Stanford Center for Cancer Nanotechnology Excellence, the Foundation for the American Society for Neuroradiology, the Wallace H. Coulter Foundation, the Dana Foundation and the Wu Tsai Neurosciences Institute .
Stanford's Office of Technology Licensing has filed patent applications with the new technology.
Stanford's Department of Radiology also supported the work.
The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http: // med.
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