Clinical Translation of Targeted and Noninvasive Ultrasonic Propofol Uncaging

靶向无创超声异丙酚解笼的临床转化

• 批准号: 9879539
• 负责人: Raag D Airan
• 金额: $ 383.31万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9879539
• 关键词: Ablation; Amygdaloid structure; Anesthesia procedures; Anesthetics; Animal Experiments; Animal Testing; Animals; Anxiety Disorders; BRAIN initiative; Behavior; Blood - brain barrier anatomy; Brain; Brain region; Characteristics; Chemicals; Clinic; Clinical; Clinical Trials; Clinical trial protocol document; Collaborations; Complement; Cyclic GMP; Data; Development; Dose; Drug Delivery Systems; Drug Kinetics; Drug Modelings; Epilepsy; Evaluation; FDA approved; Fluorocarbons; Focused Ultrasound; Functional disorder; Generations; Goals; Half-Life; Human; Hydrophobicity; In Vitro; Individual; Infusion procedures; Institutional Review Boards; Intravenous; Investigation; Knock-out; Language Disorders; Licensing; Licensure; Mediating; Memory impairment; Methods; Modeling; Nanotechnology; Nervous system structure; Neurologic; Neurosciences; Neurosurgeon; Operative Surgical Procedures; Outcome Measure; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Physiology; Polymers; Preclinical Testing; Production; Propofol; Protocols documentation; Psychiatric therapeutic procedure; Rattus; Recording of previous events; Resistance; Resolution; Role; Safety; Seizures; Sonication; Source; Sterility; System; Techniques; Technology; Testing; Toxic effect; Toxicology; Translating; Translations; Tube; Ultrasonics; Ultrasonography; Validation; biomaterial compatibility; brain size; clinical application; clinical outcome measures; clinical translation; clinically relevant; cranium; design; efficacy evaluation; experimental study; first-in-human; in vivo; individualized medicine; interest; millimeter; millisecond; nanocarrier; nanoemulsion; nanoparticle; neuroregulation; neurosurgery; neurotransmission; practical application; pre-clinical; primary outcome; prototype; receptor; scale up; secondary outcome; small molecule; success; temporal measurement; tool

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.

项目摘要。 临床需要一种能够无创调节神经系统活动的技术 重点是，具有临床相关的空间和时间精度，具有稳健且可预测的机制 作用，并且可以作用于任何不同的神经信号传导模式：兴奋性、抑制性和 神经调节。我们正是通过结合聚焦超声和药物开发了这样的技术 交付纳米技术。聚焦超声系统可以无创地在全身传递超声能量 头骨到大脑的任何一点，FDA 批准的临床系统能够以毫米级空间做到这一点 分辨率和毫秒级时间分辨率。为了补充这些进步，我们最近开发了 神经调节超声药物释放技术，其中超声诱导药物从 静脉注射纳米颗粒，我们已针对神经调节药物的输送进行了优化。 具体来说，我们已经证明聚焦超声可以释放小分子麻醉剂异丙酚 使用纳米粒子的大脑。通过超声异丙酚解笼，我们可以对超声大脑进行麻醉 仅在何时何地应用超声处理，且没有证据表明对大脑造成损害。超声波异丙酚 解锁可以通过可逆地沉默特定区域的活动来实现大脑功能的功能性“敲除”研究 例如，大脑区域允许神经外科医生无创地模拟他们预期的效果 通过暂时麻醉他们打算切除或消融的大脑部分来进行神经外科手术。重要的是， 我们最近将这项技术扩展到局部神经调节药物输送平台，以 以高空间和时间精度无创地将几乎任何感兴趣的药物注入给定的大脑目标。 考虑到临床转化，我们设计了这些纳米颗粒，由以下材料制成： FDA 单独批准用于研究性人体给药。此外，我们还开发了生产 可适用于人类相关规模的药物级纳米颗粒生产的方法， 纳米颗粒的稳定性足以实现实际的实验和临床工作流程。我们现在的目标是 以我们在试管和大鼠中取得的成功为基础，将超声波异丙酚解笼转化为 诊所。在拟议的临床前 UG3 阶段，我们将把纳米颗粒的生产规模扩大到人体规模，并充分 使我们的方法符合制药标准。我们还将完成获得所需的动物测试 初步临床试验的监管批准。在拟议的临床 UH3 阶段，我们将完成首个- 通过量化异丙酚的含量，对超声异丙酚解笼的安全性和有效性进行人体评估 相对于超声剂量的释放，以及未封存的异丙酚是否可以调节癫痫相关的活动 以预期的方式。总的来说，我们预计该提案的成功完成将提供原型 用于超声波药物解封的临床转化，用于无数其他感兴趣的药物。