Targeted Blood Brain Barrier Permeability Changes with Ultrasound & Microbubbles

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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).