Clinical Translation of Ultrasonic Ketamine Uncaging for Non-Opioid Therapy of Chronic Pain

Narcotic use in chronic pain treatment has played a major role in the ongoing opioid crisis. Convergent evidence
indicates that the activity of the anterior cingulate cortex (ACC) is critical in the pathophysiology of chronic pain.
Local therapies directed to the ACC yield benefit for chronic pain clinically and preclinical data suggest that
locally applying the drug ketamine to the ACC should yield acute-onset and long-acting remission of the pain
phenotype through a non-opioid mechanism. In this manner, local ketamine infusion into this critical brain target
is a promising non-opioid pain treatment that could yield remission of chronic pain with potentially more
predictable dose-response relationships than systemic administration, with personalization based on the imaging
defined sensitivity of the ACC to pain, and without limiting side effects due to off-target drug action in the rest of
the brain or body. To translate these results into a clinical treatment, one would ideally be able to locally apply
ketamine to only the ACC, without any off-target ketamine action and without invasive interventions to the brain.
Towards this end, we have developed ultrasonic drug uncaging for neuroscience, in which neuromodulatory
agents are uncaged from ultrasound-sensitive biocompatible and biodegradable drug-loaded nanocarriers. We
have validated that we can use this technique for selective ultrasound-induced release of ketamine, and that
ultrasonic uncaging yields drug effects that are limited precisely by when and where the ultrasound is applied.
Further, we have developed a straightforward path to translate this technology to clinical practice. We now
propose to clinically translate ultrasonic ketamine uncaging for chronic pain therapy. Given the variety of potential
therapeutic effects that are increasingly ascribed to ketamine, we anticipate that this first-in-human clinical trial
would establish the safety of this technique and generate the efficacy data necessary to enable regulatory
approval for larger clinical trials for each application of ultrasonic ketamine uncaging. Overall, we expect that
completion of this proposal will provide the prototype for subsequent translation of ultrasonic drug uncaging for
numerous other drugs of interest.
Specifically, in the proposed preclinical UG3 phase, we will scale up our nanoparticle production processes to
human scales and adapt them 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 ketamine uncaging by quantifying how much
ketamine is released relative to the ultrasound dose, and assessing whether the uncaged ketamine can modulate
the sensitivity and affective response to pain, in patients suffering from chronic osteoarthritic pain. Successful
completion of this proposal will yield a novel, noninvasive, and non-opioid therapy for chronic pain that maximizes
the therapeutic efficacy of ketamine over its side effects, by targeting its action to a critical hub of pain processing.

Grant Number: 5UG3NS115637-04
NIH Institute/Center: NIH
Principal Investigator: Raag Airan