Optimization of ultrasound-mediated drug delivery to the brain under clinically relevant conditions

总结 血脑屏障阻止大多数药物到达中枢神经系统， 在为患有脑肿瘤、神经退行性疾病的患者开发新的有效疗法方面存在的问题， 其他疾病。超声波与注射微泡剂结合使用已成为一种有效的方法， 暂时破坏屏障的方法。经过十多年的动物临床前研究， 商业系统已经开发出来，临床试验已经开始。这些试验的早期经验 显示了临床前工作预测的几个问题。临床治疗使用较低剂量的 微泡必须克服人类头骨的可变衰减，并且通常是白色物质。作为 结果，治疗效果不佳。本提案的目的是为临床成功提供路线图 用于超声介导的血脑屏障开放。我们将开发新的治疗计划方法， 人类头骨的计数，聚焦超声波束的电子转向，以及微泡的变化 不同组织结构中的浓度。这些方法将用于提高安全性和控制 程序接下来，我们将研究是否可以提高我们在白色中控制程序的能力 物质靶点，并评价重复破坏白色物质靶点血脑屏障的安全性。最后， 利用我们所学到的知识，我们将研究我们是否可以提供足够的药物来治疗高度浸润性 肿瘤模型如果成功，这项工作可能会对这项令人兴奋的技术的未来使用产生重大影响。

Summary The blood-brain barrier prevents most drugs from reaching the central nervous system and is one of the biggest problems in developing new effective therapies for patients with brain tumors, neurodegenerative diseases, and other disorders. The use of ultrasound in combination with injected microbubble agents has emerged as a prom- ising method to temporarily disrupt the barrier. After over a decade of preclinical studies in animals, multiple commercial systems have been developed and clinical trials have begun. Early experience with these trials have shown several problems that were predicted by the preclinical work. The clinical treatments use lower doses of microbubbles, have to overcome the variable attenuation of the human skull, and are often in white matter. As a result, treatments have been suboptimal. The purpose of this proposal is to provide a roadmap to clinical success for ultrasound-mediated blood-brain barrier opening. We will develop new treatment planning methods that ac- count for the human skull, electronic steering of the focused ultrasound beam, and variations in microbubble concentrations in different tissue structures. These methods will be employed to improve safety and control of the procedure. Next, we will investigate whether we can improve our ability to control the procedure in white matter targets and evaluate the safety of repeated blood-brain barrier disruption in white matter targets. Finally, using what we have learned, we will investigate whether we can deliver sufficient drugs to treat a highly infiltrating tumor model. If successful, this work could have a significant impact on future use of this exciting technology.