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.

项目总结