Non-invasive, Transgene-free, on-demand Pharmacological Modulation of Neural Activity

项目摘要/摘要 神经回路的细胞型特定操作是治疗神经疾病所必需的，例如 癫痫和自闭症。现有的控制神经活动的技术提供了有限的可能性。操纵 通过直接药物治疗的大脑回路受到血脑屏障选择性通透性的限制， 脑液清除迅速，缺乏特异性，导致对药物和 不良副作用。电刺激和光遗传学为神经修复提供了可能 通过直接控制大脑回路动力学而产生的功能障碍。然而，这两种技术都需要植入 破坏生物组织的装置。近年来，纳米材料的散热，特别是 磁性纳米颗粒(MNPs)和等离子体纳米结构已被提出用于无线控制 使用外部刺激的细胞信号。组织的弱磁性和低导电性 允许交变磁场(AMF)深入人体，使MNPs产生滞后加热 在治疗脑部疾病方面尤其有希望。这项研究拨款将开发一种新的无线 依赖MNPs热效应释放的药理脑调节途径 将温度敏感型聚合物的神经调节化合物嫁接到MNPs表面。 此外，我们还将制作一种由表面工程MNPs和金纳米棒组成的纳米结合物 用于光声断层扫描(PAT)引导、磁热控制的神经调节性释放的(GNRs) 化合物。初步结果表明：1)在AMFS下，MNPs的散热足以满足 从MNP表面完全释放有效载荷，2)通过抗体靶向神经细胞膜的MNP 特异性，然后是允许刺激神经活动的磁热药物治疗，以及3) 精确控制MNPs表面的聚合物生长。这项研究拨款推动了刺激方面的新进展- 用于神经活动的个性化药理调节的响应性混合纳米颗粒系统。无线 从聚合物包覆的MNPs中磁热释放多巴胺和氯丙嗪有望激发和 抑制多巴胺能神经元的活动。利用GNRS中介的PAT，该系统将被 通过使用AMFS触发热响应，定制多种剂量的按需释放。最后， 将评估磁热药物释放对临床相关神经调节的功能特性 通过体外模型和大鼠大脑。神经活动的磁热调制显示出相当大的前景 作为一种强大的药理技术，可以应用于恢复大脑功能，并在单细胞 操作设置，以更好地了解神经电路。这项工作的未来方向包括 一种允许体内PAT监测的药理调节的磁热平台的开发 神经活动。

PROJECT SUMMARY/ABSTRACT Cell-type specific manipulation of neural circuits is required for the treatment of neurological disorders such as epilepsy and autism. Existing technologies to control neural activity offer limited possibilities. Manipulation of brain circuits via direct drug treatment is restricted by the selective permeability of the blood-brain barrier, the rapid clearance of cerebral fluids and the lack of specificity, which results in poor response to drugs and undesirable side effects. Electrical stimulation and optogenetics have open the possibility of repairing neural dysfunction through direct control of brain circuit dynamics. However, both technologies require implantable devices that are damaging to biological tissues. Recently, the heat dissipation by nanomaterials, particularly magnetic nanoparticles (MNPs) and plasmonic nanostructures, has been proposed for the wireless control of cellular signaling using external stimuli. The weak magnetic properties and low electrical conductivity of tissue allow alternating magnetic fields (AMFs) to reach deep into the body, making hysteresis heating of MNPs particularly promising for the treatment of brain disorders. This research grant will develop a novel wireless pharmacological brain modulation approach that depends on MNPs heating effects to release neuromodulatory compounds from temperature-sensitive polymers grafted on the surface of MNPs. Additionally, we will fabricate a nanoconjugate composed of surface engineered MNPs and gold nanorods (GNRs) for photoacoustic tomography (PAT)-guided, magnetothermally-controlled release of neuromodulatory compounds. Preliminary results demonstrate: 1) the heat dissipated by MNPs under AMFs is sufficient for the complete release of a payload from MNP surfaces, 2) MNPs targeting to neuronal membranes via antibody specificity, followed by magnetothermal drug treatment that allows for excitation of neural activity, and 3) the precise control of polymer growth from the surface of MNPs. This research grant drives new advances in stimuli- responsive hybrid nanoparticle systems for personalized pharmacological modulation of neural activity. Wireless magnetothermal release of dopamine and chlorpromazine from polymer coated MNPs is expected to excite and inhibit activity of dopaminergic neurons. Taking advantage of GNRs-mediated PAT, this system will be customized for on-demand release in multiple dosages by triggering heat response with AMFs. Finally, the functional properties of clinically-relevant neural modulation by magnetothermal drug release will be evaluated through in vitro models and rat brains. Magnetothermal modulation of neural activity shows considerable promise as a powerful pharmacological technology that can be applied to restore brain functions, and in single-cell manipulation settings for the better understanding of neural circuits. Future directions of this work include the development of a magnetothermal platform that allow in vivo PAT-monitored pharmacological modulation of neural activity.