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

项目总结/摘要 神经回路的细胞类型特异性操纵是治疗神经系统疾病所必需的， 癫痫和自闭症。控制神经活动的现有技术提供了有限的可能性。操纵 通过直接药物治疗的脑回路受到血脑屏障的选择性渗透性的限制， 脑液的快速清除和缺乏特异性，导致对药物的反应差， 不良副作用。电刺激和光遗传学为神经修复提供了可能性， 通过直接控制大脑回路动力学来实现功能障碍。然而，这两种技术都需要植入 对生物组织造成损害的器械。最近，纳米材料的散热，特别是 磁性纳米颗粒（MNP）和等离子体纳米结构，已经被提出用于无线控制， 利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MNP的磁滞加热 特别有希望用于治疗脑部疾病。这项研究基金将开发一种新的无线 药理学脑调制方法，其依赖于MNP加热效应以释放 来自接枝在MNP表面上的温度敏感聚合物的神经调节化合物。 此外，我们将制备一种由表面工程的MNP和金纳米棒组成的纳米复合物 （GNRs）用于光声断层扫描（PAT）引导的磁热控制的神经调节剂的释放。 化合物.初步结果表明：1）MNP在AMF下的散热量足够用于 有效载荷从MNP表面完全释放，2）MNP通过抗体靶向神经元膜 特异性，然后是磁热药物治疗，允许神经活动的兴奋，和3） 精确控制聚合物从MNP表面的生长。这项研究资助推动了刺激的新进展- 用于神经活性的个性化药理学调节的响应性混合纳米颗粒系统。无线 多巴胺和氯丙嗪从聚合物包覆的MNP的磁热释放预期激发和 抑制多巴胺能神经元活性。利用GNRs介导的PAT，该系统将 通过用AMF触发热响应，定制用于多剂量的按需释放。最后 将评价磁热药物释放对临床相关神经调节的功能特性 通过体外模型和老鼠大脑。神经活动的磁热调制显示出相当大的希望 作为一种强大的药理学技术，可以应用于恢复大脑功能，并在单细胞 操纵设置，以便更好地理解神经回路。这项工作的未来方向包括 磁热平台的开发，其允许体内PAT监测的药理学调节， 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.