Targeted Blood Brain Barrier Permeability Changes with Ultrasound & Microbubbles

描述（由申请人提供）：静脉注射微泡的超声介导破坏（UMD）可能改变中枢神经系统内选择性位置的血脑屏障（BBB）渗透性。BBB渗透性的这种选择性改变可能在靶向药物递送用于原发性或转移性中枢神经系统肿瘤以及神经退行性疾病如阿尔茨海默氏痴呆或帕金森氏病方面具有显著的治疗潜力。然而，非成像治疗超声换能器的较低频率和较长占空比增加了有害生物效应的风险，例如血管周围出血和内皮损伤。新的诊断超声换能器具有用于检测微泡的增加的灵敏度，其然后可以用于仅当存在最大浓度的微泡时引导短暂的高机械指数脉冲的递送。在本申请的I期提案中，我们将测试经颞叶引导的诊断超声可以安全地增强与微泡缀合的化疗剂穿过血脑屏障的递送的假设。这将通过量化引导诊断超声与治疗超声换能器相比诱导的增强BBB渗透性的幅度、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与微泡缀合的两种不同分子量的化学治疗剂递送到脑脊液中的能力。这些基础研究将为II期STTR提案提供基础，该提案利用微泡的引导UMD治疗原发性和转移性中枢神经系统肿瘤。在这个项目中，研究人员将试图确定是否可以使用类似于常规诊断成像的超声造影剂（称为微泡）来短暂改变药物进入脑组织（穿过血脑屏障）的能力。这将使我们能够将药物靶向输送到大脑，这些药物可能用于治疗脑癌或痴呆症（阿尔茨海默病）。

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).