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

麻醉药品在慢性疼痛治疗中的使用在持续的阿片类药物危机中发挥了重要作用。一致的证据 提示扣带回前皮质(ACC)的活动在慢性疼痛的病理生理学中起关键作用。 针对ACC的局部治疗对慢性疼痛的临床和临床前数据表明， 在ACC局部应用氯胺酮应该会产生急性起效和长效缓解疼痛的效果 通过非阿片类药物机制的表型。通过这种方式，局部输注氯胺酮进入这个关键的大脑靶点 是一种很有前途的非阿片类疼痛治疗方法，可以缓解慢性疼痛，并可能有更多 与全身给药相比，可预测的剂量-反应关系，以及基于成像的个性化 明确的ACC对疼痛的敏感性，并且不限制由于非靶向药物作用在其余部分的副作用 大脑或身体。为了将这些结果转化为临床治疗，理想的情况是能够在当地应用 氯胺酮仅作用于ACC，没有任何偏离靶点的氯胺酮作用，也没有对大脑的侵入性干预。 为此，我们开发了用于神经科学的超声波药物浸渍，其中神经调制 药物是从超声敏感、生物相容和可生物降解的载药纳米载体中分离出来的。我们 已经证实我们可以使用这种技术来选择性地超声波诱导释放氯胺酮，并且 超声波浸泡产生的药物效果受到超声波应用时间和地点的精确限制。 此外，我们已经开发了一条将这项技术转化为临床实践的直接途径。我们现在 建议临床翻译超声氯胺酮去势治疗慢性疼痛。考虑到潜力的多样性 越来越多地归因于氯胺酮的治疗效果，我们预计这项首个人类临床试验 将确定这项技术的安全性，并生成必要的有效性数据，以实现监管 批准每次超声氯胺酮去势的更大规模的临床试验。总体而言，我们预计 这一建议的完成将为后续的超声药物提取的翻译提供原型 许多其他感兴趣的药物。 具体地说，在拟议的临床前UG3阶段，我们将扩大我们的纳米颗粒生产工艺，以 人体称重，并使其符合制药标准。我们还将完成所需的动物测试 获得监管部门对初始临床试验的批准。在拟议的UH3临床阶段，我们将完成第一个- 用定量方法评价超声氯胺酮注射的安全性和有效性 相对于超声剂量释放氯胺酮，并评估未老化的氯胺酮是否可以调制 慢性骨关节炎疼痛患者对疼痛的敏感性和情感反应。成功 这项提议的完成将产生一种新的、非侵入性和非阿片类药物的慢性疼痛疗法，最大限度地提高 通过将氯胺酮作用于疼痛处理的关键中枢，来研究氯胺酮的治疗效果及其副作用。

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.