Targeted Blood Brain Barrier Permeability Changes with Ultrasound & Microbubbles

描述(申请人提供)：超声介导的破坏(UMD)静脉注射微泡有可能改变血脑屏障(BBB)在中枢神经系统内的特定位置的通透性。这种对血脑屏障通透性的选择性改变可能在针对原发或转移性中枢神经系统肿瘤以及阿尔茨海默氏症或帕金森氏病等神经退行性疾病的靶向药物输送方面具有显著的治疗潜力。然而，非成像治疗性超声换能器的低频率和较长的占空比增加了有害生物效应的风险，如血管周围出血和内皮损伤。新的诊断超声换能器提高了对微泡检测的灵敏度，只有当存在最大浓度的微泡时，才能利用微泡来指导短暂的高机械指数脉冲的传递。在这项应用的第一阶段提案中，我们将测试这样一个假设，即经颞叶引导的诊断超声可以安全地增强与微泡结合的化疗药物穿过血脑屏障的输送。这将通过量化导引诊断超声与治疗性超声换能器相比引起的血脑屏障通透性增强的幅度、空间分布和持续时间来实现。然后，将检查引导诊断超声换能器增强连接到微泡上的两种不同分子量的不同化疗药物进入脑脊液的能力。这些基础性研究将为第二阶段STTR方案提供基础，在治疗原发和转移性中枢神经系统肿瘤时使用引导的UMD微泡。在这个项目中，研究人员将试图确定是否可以将类似于常规诊断成像的超声波与超声造影剂(称为微泡)一起使用，以短暂地改变药物进入脑组织的能力(穿过血脑屏障)。这将使我们能够有针对性地将可能用于治疗脑癌或痴呆症(阿尔茨海默病)的药物输送到大脑。

DESCRIPTION (provided by applicant): Ultrasound mediated destruction (UMD) of intravenously injected microbubbles has the potential to alter blood brain barrier (BBB) permeability at selective locations within the central nervous system. This selective alteration in BBB permeability could have significant therapeutic potential in targeting drug delivery for primary or metastatic central nervous system tumors, as well as neuro-degenerative disorders such as Alzheimer's dementia or Parkinson's Disease. However, the lower frequencies and longer duty cycles of non-imaging therapeutic ultrasound transducers increase the risk for deleterious bioeffects such as peri-vascular hemorrhage and endothelial injury. New diagnostic ultrasound transducers have increased sensitivity for the detection of microbubbles which can then be utilized to guide the delivery of brief high mechanical index impulses only when a maximal concentration of microbubbles are present. In the Phase I proposal of this application we will test the hypothesis that transtemporal guided diagnostic ultrasound can safely enhance delivery of chemotherapeutic agents conjugated to microbubbles across the blood brain barrier. This will be achieved by quantifying the magnitude, spatial distribution, and duration of enhanced BBB permeability induced by guided diagnostic ultrasound when compared to a therapeutic ultrasound transducer. The ability of guided diagnostic ultrasound transducers to enhance the delivery of two different chemotherapeutic agents of different molecular weight conjugated to the microbubbles into the cerebrospinal fluid will then be examined. These foundational studies will then provide the basis for a Phase II STTR proposal utilizing guided UMD of microbubbles in the treatment of primary and metastatic central nervous system tumors. In this project, the investigators will try to determine if ultrasound similar to what is used for routine diagnostic imaging can be used with ultrasound contrast agents (termed microbubbles) to briefly alter the ability of drugs to reach into brain tissue (across the blood brain barrier). This will allow us to target the delivery of drugs to the brain that could potentially be used to treat brain cancer or dementia (Alzheimer's Disease).