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

慢性疼痛治疗中麻醉剂的使用在当前的阿片类药物危机中发挥了重要作用。趋同证据 表明前扣带皮层 (ACC) 的活动在慢性疼痛的病理生理学中至关重要。 针对 ACC 的局部疗法对慢性疼痛有临床效果，临床前数据表明： 局部使用氯胺酮药物到 ACC 应该可以产生急性发作和长效的疼痛缓解 通过非阿片类机制的表型。通过这种方式，将氯胺酮局部输注到这个关键的大脑目标中 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，并可能带来更多效果 与全身给药相比，剂量反应关系可预测，并且基于成像进行个性化 明确的 ACC 对疼痛的敏感性，并且不限制其余部分由于药物脱靶作用而产生的副作用 大脑或身体。为了将这些结果转化为临床治疗，理想情况下能够在当地应用 氯胺酮仅作用于 ACC，没有任何脱靶氯胺酮作用，也没有对大脑进行侵入性干预。 为此，我们开发了用于神经科学的超声药物解笼，其中神经调节 药物从超声敏感的生物相容性和可生物降解的载药纳米载体中解脱出来。我们 已经验证我们可以使用这种技术选择性超声诱导释放氯胺酮，并且 超声波解笼产生的药物作用受到施加超声波的时间和地点的精确限制。 此外，我们还开发了一条直接的途径将该技术转化为临床实践。我们现在 建议临床上将超声氯胺酮解笼用于慢性疼痛治疗。鉴于潜力的多样性 越来越多地归因于氯胺酮的治疗效果，我们预计这项首次人体临床试验 将确定该技术的安全性并生成监管所需的功效数据 批准对超声氯胺酮解笼的每次应用进行更大规模的临床试验。总体而言，我们预计 该提案的完成将为后续将超声波药物解笼转化为原型提供基础。 许多其他感兴趣的药物。 具体来说，在拟议的临床前 UG3 阶段，我们将扩大纳米颗粒生产工艺，以 人体尺度并使其适应制药标准。我们还将完成所需的动物测试 获得初始临床试验的监管批准。在拟议的临床 UH3 阶段，我们将完成第一个- 通过量化超声氯胺酮解笼的安全性和有效性进行人体评估 氯胺酮的释放与超声剂量有关，并评估未封闭的氯胺酮是否可以调节 患有慢性骨关节炎疼痛的患者对疼痛的敏感性和情感反应。成功 该提案的完成将产生一种新颖的、非侵入性的、非阿片类药物治疗慢性疼痛的方法，最大限度地提高治疗效果。 通过将氯胺酮的作用针对疼痛处理的关键中枢，氯胺酮对其副作用的治疗效果。

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.