Clinical Translation of Targeted and Noninvasive Ultrasonic Propofol Uncaging

项目摘要。 对于能够非侵入性地调节神经系统活动的技术，存在许多临床需求 和局部，具有临床相关的空间和时间精度，具有强大的和可预测的机制， 作用，并且可以作用于任何不同的神经信号模式：兴奋性，抑制性， 神经调节我们已经开发出这样一种技术，通过结合聚焦超声和药物， 输送纳米技术。聚焦超声系统可以无创地将超声能量输送到整个组织中。 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 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 神经调节性超声药物释放技术，其中超声诱导药物从 静脉注射的纳米颗粒，我们已经优化了神经调节药物的输送。 具体来说，我们已经证明聚焦超声可以释放体内的小分子麻醉剂异丙酚 大脑使用纳米粒子。利用超声丙泊酚撑开，我们可以对超声处理过的脑进行麻醉 只有在超声波处理的时间和地点，没有证据表明对大脑的损害。超声丙泊酚 通过可逆地沉默给定的基因的活性， 例如，神经外科医生可以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进行神经外科手术。重要的是， 我们最近将这项技术扩展到一个局部神经调节药物输送的平台， 非侵入性地将几乎任何感兴趣的药物注入到给定的脑靶中，具有高的空间和时间精度。 为了预测临床转化，我们设计了这些纳米颗粒， FDA单独批准用于人类给药。此外，我们还开发了生产 可以适用于以人类相关规模生产药物级纳米颗粒的方法， 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 在我们在试管和大鼠中取得成功的基础上，将超声波丙泊酚释放转化为 诊所在拟议的临床前UG3阶段，我们将把纳米颗粒生产规模扩大到人类规模， 使我们的方法符合制药标准。我们还将完成所需的动物试验， 监管机构批准的初步临床试验。在拟议的临床UH3阶段，我们将完成一个首次在 通过定量丙泊酚的量对超声丙泊酚撑开术的安全性和有效性的人体评价 释放相对于超声剂量，以及释放的丙泊酚是否可以调节与麻醉相关的活动 以预期的方式。总的来说，我们希望成功完成这项提案将提供原型， 用于将超声药物撑开用于无数其他感兴趣的药物的临床转化。

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.