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

通过按需磁热药物释放对神经活动进行非侵入性激发和抑制

基本信息

批准号：
10457349
负责人：
Gabriela Romero Uribe
金额：
$ 26.25万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10457349
关键词：
Address Antibody Specificity Biological Brain Brain Diseases Brain Mapping Calcium ion Cell Survival Cells Cerebrum Chemicals Chemistry Chlorpromazine Complex Development Dopamine Drug Modulation Electric Conductivity Electric Stimulation Electrostatics Epilepsy Evaluation Exposure to Future Growth Heating Hybrids In Vitro Kinetics Liquid substance Magnetic nanoparticles Magnetism Membrane Modification Molecular Weight Nanostructures Neural Inhibition Neuronal Dysfunction Neurons Oligonucleotides Parkinson Disease Pharmaceutical Preparations Pharmacology Pharmacotherapy Polymer Chemistry Polymers Population Property Reporting Research Project Grants Signal Transduction Specificity Stimulus Surface System Techniques Technology Temperature Time Tissues Transgenes Translations Work biocompatible polymer blood-brain barrier permeabilization cell type chemical property clinical translation clinically relevant combinatorial combinatorial chemistry dopaminergic neuron dosage ethylene glycol fluorescence imaging heat stimulus implantable device improved in vitro Assay in vitro activity in vivo inhibitor iron oxide magnetic field mind control minimally invasive nanomaterials nanoparticle nanoscale nervous system disorder neural circuit neural network neural repair neural stimulation neuroregulation neurotransmission novel optogenetics physical property plasmonics relating to nervous system response side effect therapy design wireless

项目摘要

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.

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，癫痫和帕金森病。神经回路的精确控制将使神经调节疗法来治疗这些使人衰弱的病症。控制神经活动的现有技术提供了可能性有限。通过直接药物治疗来操纵大脑回路受到选择性的限制。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。电刺激和光遗传学具有开放性通过直接控制脑回路动力学来修复神经功能障碍的可能性。但无论这些技术需要对生物组织有损害的可植入装置。最近，散热纳米材料，特别是磁性纳米颗粒（MNP）和等离子体纳米结构，提出了使用外部刺激的蜂窝信号的无线控制。弱磁性和组织的低电导率允许交变磁场（AMF）深入人体， MNP的滞后加热特别有希望用于治疗脑部疾病。这项研究经费将开发一种新的无线药理学脑刺激方法，纳米颗粒（MNP）的加热效应，以从温度敏感的神经细胞释放神经调节化合物。接枝在MNP表面的聚合物。开发的技术将适用于多种药物释放按需剂量，这是神经活动刺激所需的。此外，我们还将定制聚合物用于神经刺激物-抑制剂对的组合释放以允许脑调节的表面化学电路信号初步结果表明：1）MNP在AMF下的散热量足够用于从MNP表面快速和完全释放有效载荷，2）MNP靶向神经元膜，抗体特异性，然后进行磁热药物治疗，允许一次性兴奋神经元，活性，和3）从MNP的表面的聚合物生长的精确控制。这项研究资助推动了新的刺激响应混合纳米颗粒系统的神经活动的药理学调制的进展。从聚合物包覆的MNP无线磁热释放多巴胺和氯丙嗪，兴奋和抑制多巴胺能神经元的活性。该系统将针对按需多个剂量通过AMF触发热反应释放。最后，临床相关的功能特性将通过体外测定来评价通过磁热药物释放的神经调节。磁热调节神经活动显示出相当大的希望，作为一种强大的药理学技术，应用于恢复大脑功能，并在单细胞操作设置为更好地了解神经电路.这项工作的未来方向包括开发一个磁热平台，神经活动的药理学调节。