The blood-brain barrier (BBB) consists of specialized endothelial cells that line the capillaries within the brain, whose overlapping regions are held firm by """"""""tight junctions."""""""" Among other roles it plays, the BBB is the major impediment to the flux of therapeutic drugs into the central nervous system (CNS). As a result, many therapeutic compounds known to be efficacious in vitro are prevented from entering the CNS in vivo. If a means existed to allow the targeted and transient opening of the BBB without accompanying CNS damage, then one could apply those therapeutic agents systemically yet achieve targeted delivery. Among other applications this would be useful for treating malignant astrocytomas, a uniformly and rapidly fatal grade of brain tumor that is the most common primary supratentorial cerebral neoplasm in adults. Isolated tumor cells (ITC) that migrate from the bulk tumor mass are generally thought to be responsible for recurrence following resection, likely due to their re-migration to the resection margin. To improve clinical outcome after surgery one must therefore successfully attack the ITC while maintaining the integrity of the surrounding normal brain tissue. In vivo, there is minimal success with. chemotherapy at least because the ITC are protected by an intact BBB. Therefore, opening the BBB at and beyond the resection margin would allow the targeted delivery to isolated tumor cells of chemotherapeutic agents that are introduced systemically, which should improve clinical outcome. Preliminary Results relevant to this proposal indicate that high-intensity focused Ultrasound (HIFU) applied to a rat model of normal cortex can be targeted to selectively open the BBB in a reversible, controlled manner without structural injury at or near the site of permeabilization. Specifically, we have found that MFU can open the endothelial cell tight junctions and/or induce retraction of endothelial cells, thereby permitting the flux of a large molecular complex (Evans blue-albumin; 69,500 Daltons) from the blood stream into brain tissue. Additionally HIFU mediated permeability to Evans blue reverses within 96 hours, and HIFU causes no identifiable damage to CNS tissue during this time period at and near the point of BBB opening, as assessed with light and electron microscopy.
The aim of this K-25 research proposal is to explore the mechanisms, efficacy and safety of HIFU-induced BBB opening in a clinically motivated context, while giving the PI a thorough education in the associated neuroscience and techniques.
The research aims are predicated on the view that the ability to use ultrasound to open the blood-brain barrier requires research on how ultrasound, with and without systemically-applied chemotherapy, alters the intercellular dynamics of invading isolated tumor cells and the endothelial cells that comprise the blood-brain barrier. And, it requires research on the intracellular processes that support those dynamics.
The Specific Aims are as follows. Investigate structural and intracellular effects induced by HIFU for BBB opening. Investigate electrophysiological effects induced by HIFU applied to normal cortex for BBB opening. Investigate drug flux into normal and tumor-bearing cortex induced by HIFU for BBB opening.
AIM 4. Investigate effects induced by HIFU for BBB opening on invading and re-invading ITC, and on BBB and CNS. The neuroscience-directed education the PI proposes to receive during this Career Development Award will allow him to do the proposed research and to move ahead in future, R01 -funded studies.
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