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.

项目概要 区域特异性增强药物向大脑的输送，无需增加全身药物剂量或主动 破坏血脑屏障，已被寻求对各种疾病进行有效的药物治疗 中枢神经系统疾病。在不同的方法中，我们建议通过以下方式加强交付： 将药物与血浆蛋白结合，以增加可转运的局部药物浓度 穿过脉管系统。我们研究的总体目标是检查经颅聚焦的效果 超声（FUS）对血浆蛋白结合（PPB）与苯妥英（PHT）的区域特异性破坏 评估实质 PHT 摄取的区域增加是否导致颞叶抑制 啮齿动物癫痫（TLE）。首先，FUS 将无创地应用于非非侵入性的同侧海马区域。 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 PHT 摄取将使用抗 PHT 进行量化 免疫组织化学和导致最高摄取水平的 FUS 参数将被确定。然后， 利用该参数，对慢性 TLE 大鼠的癫痫脑区进行多次 FUS 治疗 接受每日治疗剂量的 PHT。将从动物身上获取脑电图（EEG） 使用可穿戴无线脑电图设备以及行为癫痫发作和癫痫发作的频率/持续时间 脑电图将被量化。这些措施将在四个组合实验组之间进行比较 FUS(+/-) 和 PHT(+/-) 以检查 FUS 介导的 PHT 递送增加是否会增强其抗- 惊厥作用。将评估癫痫动物和非癫痫动物的潜在组织或 使用组织学分析确定血管损伤以及血脑是否存在不良破坏 障碍。所提出的 PHT-PPB 声学破坏方法可能会提供一种优雅且前所未有的方法。 抑制与局灶性癫痫相关的癫痫发作活动的选择。类似的 FUS 协议也可能是 适用于增加对血浆蛋白具有高亲和力的多种药物的区域递送。