Non-invasive Excitation and Inhibition of Neural Activity via On-Demand Magnetothermal Drug Release

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 癫痫和帕金森氏症。对神经回路的精确控制将使 针对这些衰弱状况的神经调节疗法。控制神经活动的现有技术提供了 可能性有限。通过直接药物治疗操纵大脑回路受到选择性药物治疗的限制 血脑屏障的通透性，脑液的快速清除以及缺乏特异性 导致对药物的不良反应和不良副作用。电刺激和光遗传学已经打开 通过直接控制大脑回路动力学来修复神经功能障碍的可能性。然而，两者 技术需要对生物组织造成损害的可植入设备。最近，散热 通过纳米材料，特别是磁性纳米颗粒(MNPs)和等离子体纳米结构， 建议使用外部刺激对手机信号进行无线控制。弱磁性能和 组织的低导电性允许交变磁场(AMF)深入人体，使 MNPs的滞后加热在治疗脑部疾病方面特别有前景。这笔研究经费将 开发一种新的依赖于磁的无线药理脑刺激方法 纳米颗粒(MNPs)加热效应从温度敏感型释放神经调节化合物 聚合物接枝在MNPs表面。开发的技术将适用于多种类型的药物释放。 按需剂量，这是神经活动刺激所需的。此外，我们还将定制聚合物 神经刺激物-抑制物对的组合释放以允许大脑调制的表面化学 电路信号。初步结果表明：1)在AMFS下，MNPs的散热足以满足 从MNP表面快速且完全地释放有效载荷，2)通过 抗体特异性，随后进行磁热药物治疗，允许一次性兴奋神经 活性，以及3)MNPs表面聚合物生长的精确控制。这项研究拨款推动了新的 神经活动药理调控用刺激响应型杂化纳米颗粒系统的研究进展。 从聚合物包覆的MNPs中无线磁热释放多巴胺和氯丙嗪有望 兴奋和抑制多巴胺能神经元的活动。该系统将针对按需多个 剂量通过触发AMFS的热响应来释放。最后，与临床相关的功能特性 磁热药物释放对神经的调节作用将通过体外试验进行评估。磁热 神经活动的调节作为一种强大的药理技术显示出相当大的前景，可以 应用于恢复大脑功能，并在单细胞操作环境中更好地了解神经 电路。这项工作的未来方向包括开发一种磁热平台，使在体内 神经活动的药理调节。

Project Summary/Abstract Cell-type specific manipulation of neural circuits is required for the treatment of neurological disorders such as epilepsy and Parkinson’s disease. Precise control of neural circuits will enable the development of neuromodulation therapies for these debilitating conditions. 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 stimulation approach that depends on magnetic nanoparticles (MNPs) heating effects to release neuromodulatory compounds from temperature-sensitive polymers grafted on the surface of MNPs. The developed technology will be suitable for drug release in multiple on-demand dosages, which it is required for neural activity stimulation. Additionally, we will tailor polymer surface chemistry for the combinatorial release of neurostimulator-inhibitor pairs to allow modulation of brain circuit signals. Preliminary results demonstrate: 1) the heat dissipated by MNPs under AMFs is sufficient for the rapid and 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 one-time 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 the 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. This system will be optimized for on-demand multiple dosages release 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 assays. 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 pharmacological modulation of neural activity.