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

项目摘要 在不增加全身药物剂量或主动增加的情况下，特定区域增强药物向大脑的输送 破坏血脑屏障，一直是各种有效的药物治疗的目标 中枢神经系统紊乱。在不同的方法中，我们建议通过以下方式加强交付 解除药物与血浆蛋白的结合以增加可能被转运的局部药物浓度 穿过血管系统。我们研究的首要目标是检查经颅聚焦治疗的效果。 超声(FUS)对苯妥英钠(PHT)与血浆蛋白结合(PPB)的区域特异性破坏 评估脑实质内PHT摄取的区域性增加是否导致颞叶的抑制 啮齿动物癫痫(TLE)。首先，FUS将被非侵入性地应用于同侧海马区。 癫痫大鼠接受治疗剂量的PHT，使用不同的占空比，脉冲持续时间， 以及声学的强度。实质中的PHT摄取将使用抗PHT进行量化 免疫组织化学，以及导致最高摄取水平的FUS参数将被确定。然后, 使用该参数，将对慢性TLE大鼠的癫痫脑区域进行多次FUS 接受每日治疗量的PHT。脑电(EEG)将从动物身上获得 使用可穿戴无线脑电设备以及行为发作和癫痫描记的频率/持续时间 脑电将被量化。这些措施将在四个组合试验组之间进行比较 FUS(+/-)和PHT(+/-)，以检查由FUS介导的PHT递送的增加是否会增强其抗 抽搐作用。这些动物，包括癫痫患者和非癫痫患者，将被评估潜在的组织或 用组织学分析血管损伤和存在不受欢迎的血脑损伤 障碍。提出的PHT-PPB声干扰方法可能提供一种优雅和前所未有的 用于抑制与局灶性癫痫相关的癫痫发作活动的选项。类似的FUS协议也可以 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。

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.