PROJECT SUMMARY .
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.