Delivering drugs to precise targets in the brain may soon be feasible using MRI-guided focused ultrasound

Raag Airan, M.D., Ph.D.

Stanford University

Funded in September, 2017: $200000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Delivering drugs to precise targets in the brain may soon be feasible using MRI-guided focused ultrasound

Investigators have demonstrated in a laboratory animal model that a newly evolving drug delivery system affects precise targets in the brain.  The system uses miniscule “nanoparticles” that encapsulate a therapeutic drug. Then ultrasound, guided by MRI, gets these nanoparticles to release the drug at a precise spot in the brain to control neural activity. Called “ultrasonic drug uncaging,” this precise, noninvasive drug delivery system holds promise for improving treatment effectiveness for many neurological and psychiatric diseases.

Instead of the current practice of administering a drug that passes into the bloodstream, crosses into the brain, and acts generally on tissues there, this new technology is designed to act at a precise time solely at the spot where the deleterious neural activity is taking place. Specifically, MRI imaging identifies the target brain area. A small molecule drug is encapsulated by tiny “phase change nanoparticles” that the investigators developed, which are administered intravenously. When the nanoparticles enter the brain, clinicians direct the ultrasound waves to the targeted brain area. Only nanoparticles that are targeted by the ultrasound break apart and release (“uncage”) the drug, so the drug is delivered precisely to the targeted brain area.

The investigators hypothesize that this technology can noninvasively modulate brain activity with high spatial resolution and at precise times, and can be effectively translated into clinical use. They have gained proof of principle by testing this technology in an epilepsy animal model. They administered the small molecule anesthetic propofol encapsulated by the nanoparticles. Then they used ultrasound to uncage the nanoparticles precisely at the epileptic focal area to release the anesthetic. The seizures halted.  

Now the investigators will carry out studies needed to optimize the techniques prior to testing them in humans. These include using EEG (electroencephalography) to determine the extent of changes in neural activity induced by propofol release and to demonstrate that distinct neural circuits may be individually deactivated. Next, they will test this technology in a large animal (sheep), to obtain a better indication of likely results in humans. Investigators anticipate initiating clinical testing after the end of the grant period.

Ultimately, if shown to be safe and effective in humans, this non-invasive technology can be used in a variety of ways while patients are undergoing or participating in neurological or psychiatric treatment. For instance, the technology could be used to: 1) modify neural activity involved in specific diseases (such as epilepsy); 2) pre-surgically map essential brain areas that need to be spared in brain tumor or epilepsy surgery; and 3) modify activity in specific brain circuits while a psychiatric patient participates in cognitive behavioral therapy.

Significance : This new drug delivery system eventually may transform neurological and psychiatric brain treatment effectiveness while avoiding unnecessary side-effects.  

ABSTRACT

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Delivering drugs to precise targets in the brain may soon be feasible using MRI-guided focused ultrasound

We recently demonstrated that focused ultrasound (FUS) can be used to uncage neuromodulatory agents in the brain, thereby promising noninvasive spatiotemporally-precise control of neural activity. Specifically, we made “phase-change” nanoparticles that uncage the small molecule anesthetic propofol upon sonication. We demonstrated in a proof-of-principle experiment that these particles could safely and effectively modulate neural activity noninvasively by selectively knocking out seizure activity in a rat model. We now propose to refine this technique for noninvasive neuromodulation by using electroencephalography (EEG) to quantify the neural activity changes induced by focused ultrasonic uncaging of propofol, to define the temporal kinetics of this modulation, and to demonstrate separable modulation of distinct neural circuits. We will first optimize our technique in rats, and show independent modulation of visual and somatosensory evoked potentials. We will then apply our optimized protocol using clinical focused ultrasound equipment in sheep, as a model of the eventual clinical application. Our technique for focused ultrasonic drug uncaging could be used for pre-surgical mapping of functionally critical brain regions by anesthetizing a target brain region while the patient is awake and participating in a task. Alternatively, this technology could serve as an adjunct to psychiatric talk or exposure therapy by appropriately modulating a pathologically active brain region during the treatment session. Following the completion of the proposed work, we will be able to move quickly towards clinical translation of this novel technique for precise noninvasive neuromodulation

INVESTIGATOR BIOGRAPHIES

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Raag Airan, M.D., Ph.D.

Raag Airan MD PhD is a new Assistant Professor of Radiology (Neuroradiology) at Stanford University. He leads a multidisciplinary team of clinicians, neuroscientists, chemists, physicists, mathematicians, and engineers to develop novel noninvasive interventions for the nervous system using focused ultrasound and ultrasound-mediated drug delivery. The primary focus of his research is in developing methods for noninvasive neuromodulation using ultrasonic drug uncaging from phase-change nanoparticles. In addition to his research effort, Dr. Airan is a practicing neuroradiologist at the Stanford Hospital. For his training, he completed his undergraduate degrees in mathematics and physics from MIT in 2003, and then completed his MD and PhD in Bioengineering at Stanford University in 2010. For his PhD, he worked in the lab of Karl Deisseroth to make some of the initial advances of optogenetics. Following graduate and medical school, he completed postdoctoral research at Johns Hopkins across a variety of fields including CEST MRI, molecular imaging, resting-state fMRI, drug delivery nanotechnology, and focused ultrasound. He also completed his clinical residency in diagnostic radiology and clinical fellowship in neuroradiology at Johns Hopkins before returning to Stanford in the summer of 2016.