. There are numerous clinical needs for a technology that can modulate nervous system activity noninvasively and focally, with clinically-relevant spatial and temporal precision, with a robust and predictable mechanism of action, and that could act on any of the varied modes of neural signaling: excitatory, inhibitory, and neuromodulatory. We have developed exactly such a technology by combining focused ultrasound and drug delivery nanotechnology. Focused ultrasound systems can deliver ultrasonic energy noninvasively across the skull to any point of the brain, with FDA approved clinical systems able to do so with millimeter-scale spatial resolution and millisecond-scale temporal resolution. To complement these advances, we recently developed the technique of neuromodulatory ultrasonic drug uncaging, in which ultrasound induces drug-release from intravenously-administered nanoparticles that we have optimized for the delivery of neuromodulatory drugs. Specifically, we have shown that focused ultrasound can uncage the small molecule anesthetic propofol in the brain using nanoparticles. With ultrasonic propofol uncaging, we can induce anesthesia of the sonicated brain only when and where sonication is applied, without evidence of damage to the brain. Ultrasonic propofol uncaging can enable functional ?knock-out? studies of brain function by reversibly silencing the activity of a given brain region to allow, for instance, a neurosurgeon to noninvasively simulate the effects of their intended neurosurgery by temporarily anesthetizing the section of brain that they intend to resect or ablate. Importantly, we have recently extended this technology into a platform for localized neuromodulatory drug delivery, to noninvasively infuse nearly any drug of interest into a given brain target, with high spatial and temporal precision. Anticipating clinical translation, we have designed these nanoparticles to be made of materials that are each individually approved for investigatory human administration by the FDA. Further, we have developed production methods that can be adapted for pharmaceutical-grade nanoparticle production at human-relevant scales, with nanoparticle stability that is sufficient to enable practical experimental and clinical workflows. We now aim to build on the success that we have had in test tubes and in rats, to translate ultrasonic propofol uncaging to the clinic. In the proposed preclinical UG3 phase, we will scale up nanoparticle production to human scales and fully adapt our methods to pharmaceutical standards. We will also complete the animal testing needed to obtain regulatory approval for an initial clinical trial. In the proposed clinical UH3 phase, we will complete a first-in- human evaluation of the safety and efficacy of ultrasonic propofol uncaging by quantifying how much propofol is released relative to the ultrasound dose, and whether the uncaged propofol can modulate seizure-related activity in the expected fashion. Overall, we expect that successful completion of this proposal will provide the prototype for clinical translation of ultrasonic drug uncaging for myriad other drugs of interest.
. We have recently developed a technology that allows ultrasound-induced drug release from intravenously- administered nanoparticles, thereby allowing noninvasive modulation of the activity of millimeter-sized brain targets. We now propose to translate this technology to the clinic: first, by adapting our methods for pharmaceutical-grade human-scale nanoparticle production; then, by completing the animal studies necessary for obtaining regulatory approval for a first-in-human trial; and finally, by completing a first-in-human clinical trial to assess the safety and efficacy of ultrasonic uncaging of the anesthetic propofol in epileptic patients, to allow noninvasive assessment of whether a target for neurosurgery contributes to seizure generation, by noninvasively and temporarily silencing that target. If successful, the proposed studies will provide a powerful clinical tool for neuroscientists and clinicians to more precisely understand and treat the human brain.