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

超声氯胺酮解笼治疗慢性疼痛的非阿片类药物的临床转化

• 批准号: 10475577
• 负责人: Raag D Airan
• 金额: $ 304.11万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475577
• 关键词: Ablation; Acute; Affect; Affective; Anesthetics; Animal Experiments; Animal Model; Animal Testing; Animals; Anterior; Antidepressive Agents; Brain; Brain region; Cephalic; Characteristics; Chemicals; Chronic; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Collaborations; Cyclic GMP; Data; Disease remission; Dose; Drug Kinetics; Drug Targeting; Evaluation; Excision; Fluorocarbons; Focused Ultrasound; Functional Magnetic Resonance Imaging; Functional disorder; Human; Hydrophobicity; Image; In Vitro; Individual; Infusion procedures; Institutional Review Boards; Intervention; Ketamine; Licensing; Licensure; Local Therapy; Methods; Microinjections; Modeling; Nanotechnology; Narcotics; Neurosciences; Outcome Measure; Pain; Pain management; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phenotype; Play; Polymers; Preclinical Testing; Process; Production; Protocols documentation; Rattus; Rest; Rodent Model; Role; Safety; Sterility; System; Techniques; Technology; Testing; Therapeutic Effect; Toxic effect; Toxicology; Translating; Translations; Treatment Efficacy; Ultrasonics; Validation; biomaterial compatibility; blood-brain barrier crossing; chronic pain; chronic pain management; chronic pain patient; cingulate cortex; clinical application; clinical outcome measures; clinical practice; clinical translation; clinical trial protocol; drug action; efficacy clinical trial; efficacy evaluation; experimental study; first-in-human; in vivo; interest; nanocarrier; nanoemulsion; nanoparticle; neuroregulation; next generation; non-opioid analgesic; novel; opioid epidemic; osteoarthritis pain; pain processing; pain sensitivity; pre-clinical; primary outcome; prototype; response; safety assessment; scale up; secondary outcome; side effect; targeted delivery; ultrasound

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.

慢性疼痛治疗中的麻醉剂使用在持续的阿片类药物危机中发挥了重要作用。收敛证据 表明前扣带皮层（ACC）的活动在慢性疼痛的病理生理学中是至关重要的。 针对ACC的局部治疗在临床上和临床前数据表明， 将氯胺酮局部应用于ACC应产生急性发作和长效缓解疼痛 通过非阿片类机制的表型。以这种方式，局部氯胺酮输注到这个关键的大脑目标 是一种很有前途的非阿片类药物疼痛治疗，可以缓解慢性疼痛， 与全身给药相比，可预测的剂量-反应关系，基于成像的个性化 ACC对疼痛的明确敏感性，并且在其余部分中没有由于脱靶药物作用而导致的限制性副作用。 大脑或身体。为了将这些结果转化为临床治疗，理想的情况是能够局部应用 氯胺酮仅作用于ACC，没有任何脱靶氯胺酮作用，也没有对大脑的侵入性干预。 为此，我们开发了用于神经科学的超声药物释放，其中神经调节 试剂从超声敏感的生物相容性和生物可降解的载药纳米载体中释放出来。我们 已经证实，我们可以使用这种技术来选择性地超声诱导氯胺酮的释放， 超声波撑开产生的药物效果精确地受限于何时何地应用超声波。 此外，我们已经开发了一种直接的途径将这项技术转化为临床实践。我们现在 建议临床上将超声氯胺酮撑开用于慢性疼痛治疗。考虑到各种潜在的 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，并生成必要的有效性数据， 批准对每种超声氯胺酮撑开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的超声药物撑开平移提供原型， 许多其他感兴趣的药物。 具体来说，在拟议的临床前UG 3阶段，我们将扩大我们的纳米颗粒生产工艺， 并使其适应制药标准。我们还将完成所需的动物试验， 获得监管机构对初始临床试验的批准。在拟议的临床UH 3阶段，我们将完成第一个- 通过量化氯胺酮超声撑开的安全性和有效性， 氯胺酮相对于超声剂量释放，并且评估未包裹的氯胺酮是否可以调节 慢性骨关节炎疼痛患者对疼痛的敏感性和情感反应。成功 这项提案的完成将产生一种新的，非侵入性的，非阿片类药物治疗慢性疼痛， 氯胺酮的副作用的治疗效果，通过将其作用靶向疼痛处理的关键枢纽。