Targeted Blood Brain Barrier Permeability Changes with Ultrasound & Microbubbles

超声有针对性地改变血脑屏障渗透性

• 批准号: 7487012
• 负责人: THOMAS R PORTER
• 金额: $ 50.73万
• 依托单位: NUVOX PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487012
• 关键词: Alzheimer' s Disease; Blood - brain barrier anatomy; Blood Vessels; Brain; Central Nervous System Neoplasms; Cerebrospinal Fluid; Contrast Media; Degenerative Disorder; Dementia; Detection; Diagnostic Imaging; Drug Delivery Systems; Frequencies; Hemorrhage; Image; Injury; Location; Malignant neoplasm of brain; Mechanics; Mediating; Microbubbles; Molecular Weight; Neuraxis; Parkinson Disease; Permeability; Pharmaceutical Preparations; Phase; Research Personnel; Risk; Small Business Technology Transfer Research; Spatial Distribution; Testing; Therapeutic; Ultrasonic Transducer; Ultrasonography; base; brain tissue; chemotherapeutic agent; indexing; novel diagnostics; targeted delivery

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).

描述（由申请人提供）：超声介导的静脉注射微泡破坏（UMD）有可能改变中枢神经系统内选择性位置的血脑屏障（BBB）通透性。这种血脑屏障通透性的选择性改变在靶向给药治疗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病）方面具有重要的治疗潜力。然而，低频率和较长的非成像治疗超声换能器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检测微泡的灵敏度，只有当微泡达到最大浓度时，才可以利用微泡来指导短暂的高机械指数脉冲的传递。在本应用程序的I期建议中，我们将测试经颞叶引导诊断超声可以安全地增强结合微泡的化疗药物通过血脑屏障的递送的假设。与治疗性超声换能器相比，这将通过量化引导诊断超声诱导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。引导诊断超声换能器增强与微泡结合的两种不同分子量的化疗药物进入脑脊液的能力，然后将进行检查。这些基础研究将为II期STTR提案提供基础，利用微泡引导UMD治疗原发性和转移性中枢神经系统肿瘤。在这个项目中，研究人员将尝试确定是否超声与常规诊断成像类似，可以与超声造影剂（称为微泡）一起使用，以短暂地改变药物进入脑组织（穿过血脑屏障）的能力。这将使我们能够靶向药物输送到大脑，可能用于治疗脑癌或痴呆症（阿尔茨海默病）。