Focused ultrasound-mediated disruption of blood plasma protein binding with pharmacological molecules

聚焦超声介导破坏血浆蛋白与药理学分子的结合

• 批准号: 10046533
• 负责人: Wonhye Lee
• 金额: $ 52.69万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10046533
• 关键词: Acoustics; Address; Affinity; Albumins; Animals; Anticonvulsants; Antiepileptic Agents; Area; Behavior; Behavioral; Binding; Binding Proteins; Biological; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Brain region; Caliber; Central Nervous System Agents; Central Nervous System Diseases; Chronic; Devices; Dose; Drug Delivery Systems; Electroencephalography; Electrostatics; Ensure; Epilepsy; Exhibits; Focused Ultrasound; Frequencies; Future; Gel; Goals; Hippocampus (Brain); Histologic; Immunohistochemistry; Injections; Ipsilateral; Kainic Acid; Measures; Mediating; Methods; Molecular; Monitor; Neurologic; Partial Epilepsies; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacological Treatment; Pharmacology; Phenytoin; Physiologic pulse; Plasma; Plasma Proteins; Property; Proteins; Protocols documentation; Rattus; Recurrence; Research; Rodent; Safety; Seizures; Serum Albumin; Serum Proteins; Sonication; Sprague-Dawley Rats; Techniques; Temporal Lobe Epilepsy; Testing; Therapeutic; Tissues; Ultrasonography; Wireless Technology; aqueous; blood-brain barrier disruption; brain parenchyma; brain tissue; chemical bond; chemical property; combinatorial; cranium; design; experimental group; experimental study; flexibility; in vivo; macromolecule; millimeter; novel; pressure; uptake

Project Summary Region-specific enhancement of drug delivery to the brain, without increasing systemic drug dose or actively disrupting the blood-brain barrier, has been sought after for effective pharmacological treatment of various central nervous system disorders. Among different approaches, we propose to enhance the delivery by unbinding the drug from the plasma proteins to increase the local drug concentration that may be transported across the vasculature. The overarching goal of our research is to examine the effects of transcranial focused ultrasound (FUS) on region-specific disruption of plasma protein binding (PPB) with phenytoin (PHT) and to evaluate if the regional increase of parenchymal PHT uptake results in the suppression of temporal lobe epilepsy (TLE) in rodents. First, FUS will be noninvasively applied to an ipsilateral hippocampal area of non- epileptic Sprague-Dawley rats receiving a therapeutic dose of PHT, using varying duty cycles, pulse durations, and intensities of sonication. The parenchymal PHT uptake will be quantified using anti-PHT immunohistochemistry, and the FUS parameter that results in the highest uptake level will be identified. Then, using the parameter, multiple sessions of FUS will be applied to the epileptic brain region of chronic TLE rats receiving daily therapeutic doses of PHT. Electroencephalography (EEG) will be acquired from the animals using a wearable wireless EEG device and the frequency/duration of behavioral seizures and epileptographic EEG will be quantified. These measures will be compared among four combinatorial experimental groups of FUS(+/-) and PHT(+/-) to examine if the increased delivery of PHT, mediated by FUS, will enhance its anti- convulsant effects. The animals, both epileptic and non-epileptic, will be evaluated for potential tissue or vascular damage using histological analysis and for the presence of undesired disruption of the blood-brain barrier. The proposed method of acoustic disruption of PHT-PPB may provide an elegant and unprecedented option for suppressing seizure activity associated with focal epilepsy. Similar FUS protocols may also be applicable to increase regional delivery of a wide range of drugs that have high affinity to plasma proteins.

项目摘要 在不增加全身药物剂量或主动的情况下，药物递送到大脑的区域特异性增强 在有效的各种药理治疗中，人们一直在寻求破坏血脑屏障的破坏 中枢神经系统疾病。在不同的方法中，我们建议通过 将药物从血浆蛋白中解脱出来，以增加可能运输的局部药物浓度 跨脉管系统。我们研究的总体目标是检查以经颅为重点的影响 超声（FUS）在与苯妥英（PHT）的等离子体蛋白结合（PPB）的区域特异性破坏和TO 评估实质PHT摄取的区域增加是否导致颞叶抑制 啮齿动物中的癫痫（TLE）。首先，FUS将无创应用于非 - 癫痫sprague-dawley大鼠接受治疗剂量的PHT，使用不同的占空比，脉冲持续时间， 和超声处理的强度。实质性PHT摄取将使用抗Pht量化 将确定免疫组织化学和导致摄取水平最高的FUS参数。然后， 使用参数，将多次将FUS的疗程应用于慢性TLE大鼠的癫痫脑区域 接受每日治疗剂量的PHT。脑电图（EEG）将从动物中获取 使用可穿戴的无线脑电图设备以及行为癫痫发作和癫痫学的频率/持续时间 EEG将被量化。这些措施将在四个组合实验组之间进行比较 FUS（+/-）和PHT（+/-）检查FUS介导的PHT的增加是否会增强其抗 - 抽搐的效果。这些动物的癫痫和非癫痫症将被评估用于潜在的组织或 使用组织学分析和血脑内不希望的破坏的血管损伤 障碍。 PHT-PPB的声学破坏的提议的方法可能会提供优雅和前所未有的 抑制与局灶性癫痫相关的癫痫发作活性的选项。类似的FUS协议也可能是 适用于增加与血浆蛋白具有高亲和力的广泛药物的区域输送。