Neurotoxicity of Magnetic Nanoparticles

磁性纳米颗粒的神经毒性

• 批准号: 7589613
• 负责人: VERONICA SHUBAYEV
• 金额: $ 22.33万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7589613
• 关键词: Antioxidants; Apoptosis; Apoptotic; Applied Research; Area; Axonal Transport; Behavior assessment; Biodegradation; Biodistribution; Biological; Blood - brain barrier anatomy; Blood Circulation; Blood-Nerve Barrier; Brain; Buffers; Cell Death; Cell Separation; Cell Transplantation; Cells; Chemistry; Cytokine Activation; DMSA; DNA Damage; Dextran 70; Dextrans; Diagnostic; Drug Delivery Systems; Drug Formulations; Electrons; Engineering; Ensure; Gelatinase B; Goals; Gold; Hour; Image; Immune; Immune system; In Vitro; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Interleukins; Ligands; Ligature; Light; Macrophage Activation; Magnetism; Magnetometries; Mediating; Medicine; Metalloproteases; Microinjections; Modality; Modeling; Molecular; Motor; Nanotechnology; Nervous system structure; Neurites; Neuroglia; Neurons; Neurosciences; Oxidative Stress; PC12 Cells; Peripheral; Peripheral Nerves; Permeability; Phagocytosis; Procedures; Process; Production; Rattus; Reactive Oxygen Species; Relative (related person); Research; Resistance; Role; Safety; Sensory; Series; Signal Transduction; Spinal Cord; Squid; Structure; Study Section; Surface; System; Technology; Testing; Therapeutic; Therapeutic Human Experimentation; Time; Tissue Engineering; Tissues; Toxic effect; Toxicology; Water; base; biomaterial compatibility; caspase-3; cell injury; clinically relevant; cytotoxic; cytotoxicity; dextran; fluorescein isothiocyanate dextran; heme oxygenase-1; in vitro Assay; in vivo; injured; intravenous administration; intravenous injection; iron oxide; macrophage; magnetic beads; magnetic field; molecular imaging; nanometer; nanoparticle; nanoscale; nanotoxicity; neuropathology; neurotoxic; neurotoxicity; novel therapeutics; programs; public health relevance; receptor; sciatic nerve; tool; ultrafine particle

DESCRIPTION (provided by applicant): Engineered iron oxide superparamagnetic nanoparticles (MNPs) offer targeted cutting- edge diagnostic and therapeutic platforms due to their ability to be guided by an external magnetic field, be functionalized and penetrate cell and tissue barriers. In studying the capacity of MNPs to extend neurite outgrowth in differentiated PC12 cells under magnetic force, we observed MNP-induced de-differentiation, loss of neurites, and cell death with increasing concentration of iron oxide, but not dimercaptosuccinic acid (DMSA) used for MNP coating. Mounting evidence suggests that enhanced reactive area, permeability and resistance to biodegradation of nanoparticles promote their cytotoxic potential relative to molecular or bulk counterparts, implicating oxidative stress (OS) as a key paradigm of nanotoxicity. A 3-tier process, OS manifests in activation of reactive oxygen species (ROS) and antioxidant defense (tier I), pro-inflammatory response (tier II) and DNA damage leading to apoptosis (tier III). Upon their in vivo application, nanoparticles are quickly challenged by macrophages, which both buffer potential nanotoxicity of nanoparticles and reduce circulation time necessary for their therapeutic and diagnostic use. In a series of pilot in vivo studies, we used rat sciatic nerve as a combination model for assessment of direct neurotoxicity and effective intraneuronal macrophage infiltration that is unique to peripheral nerve. Within 48 hours of intrafascicular microinjection of anionic DMSA-coated MNPs (AMNPs) that are highly stable, water soluble and resistant to agglomeration, we observed a robust influx of macrophages, activation of heme oxygenase-1, interleukin-12, matrix metalloproteinase (MMP)-9 and caspase 3, all consistent with the oxidative stress paradigm. In contrast, only mild neurotoxic changes were seen in the corresponding sham procedures, control DMSA and dextran-coated iron oxide MNPs microinjections. Utilizing a combination of engineering and biological in vitro and in vivo approaches, this program aims to determine the mechanisms and target cells of central and peripheral neurotoxicity induced by iron oxide MNPs. Emphasis will be made on studying the role of surface chemistry (DMSA, dextran and gold) on activating oxidative stress signaling and biodistribution in vitro and in vivo. A combination of SQUID magnetometry, light, electron and confocal neuropathology, ROS-mediated pro- inflammatory and pro-apoptotic cell signaling analyses and in vivo sensory and motor behavioral assessments will be used. The overall goal of this proposal is to develop and test the engineering strategies that are safe for MNP use in therapeutic and diagnostic platforms in the nervous system. PUBLIC HEALTH RELEVANCE Magnetic nanoparticles (MNPs) offer cutting-edge drug delivery, molecular imaging and tissue engineering tools for all areas of medicine, including neurosciences. However, their enhanced reactive area, permeability and resistance to biodegradation promote their toxic potential. This proposal aims to determine the mechanisms of MNP neurotoxicity, immune activation of defense macrophage system, and develop advanced MNP formulation that are safe and robust for diagnostic, therapeutic and research use in the nervous system.

描述（由申请人提供）：工程氧化铁超顺磁性纳米粒子（MNP）由于其能够由外部磁场引导、功能化以及穿透细胞和组织屏障的能力，提供了有针对性的尖端诊断和治疗平台。在研究磁力作用下 MNP 在分化的 PC12 细胞中延长神经突生长的能力时，我们观察到随着氧化铁浓度的增加，MNP 诱导的去分化、神经突损失和细胞死亡，但不包括用于MNP 涂层。越来越多的证据表明，纳米粒子的反应面积、渗透性和生物降解抗性的增强，相对于分子或本体对应物，提高了其细胞毒性潜力，这表明氧化应激（OS）是纳米毒性的一个关键范例。 OS 是一个 3 层过程，表现为活性氧 (ROS) 的激活和抗氧化防御（第一层）、促炎症反应（第二层）和导致细胞凋亡的 DNA 损伤（第三层）。在体内应用后，纳米颗粒很快就会受到巨噬细胞的攻击，巨噬细胞既可以缓冲纳米颗粒潜在的纳米毒性，又可以减少其治疗和诊断用途所需的循环时间。在一系列体内试验研究中，我们使用大鼠坐骨神经作为组合模型来评估直接神经毒性和周围神经特有的有效神经元内巨噬细胞浸润。在束内显微注射高度稳定、水溶性且抗团聚的阴离子 DMSA 包被的 MNP (AMNP) 后 48 小时内，我们观察到巨噬细胞大量涌入，血红素加氧酶-1、白细胞介素-12、基质金属蛋白酶 (MMP) 被激活。 )-9 和 caspase 3，均符合氧化应激范式。相比之下，在相应的假手术、对照DMSA和葡聚糖包被的氧化铁MNP显微注射中仅观察到轻微的神经毒性变化。该项目利用工程和生物学的体外和体内方法相结合，旨在确定氧化铁 MNP 诱导的中枢和外周神经毒性的机制和靶细胞。重点将研究表面化学（DMSA、葡聚糖和金）在激活体内外氧化应激信号传导和生物分布方面的作用。将结合使用 SQUID 磁力测量、光、电子和共聚焦神经病理学、ROS 介导的促炎和促凋亡细胞信号分析以及体内感觉和运动行为评估。该提案的总体目标是开发和测试 MNP 在神经系统治疗和诊断平台中安全使用的工程策略。 公共卫生相关性 磁性纳米粒子 (MNP) 为包括神经科学在内的所有医学领域提供尖端的药物输送、分子成像和组织工程工具。然而，它们增强的反应面积、渗透性和抗生物降解性增加了它们的潜在毒性。该提案旨在确定 MNP 神经毒性、防御巨噬细胞系统的免疫激活机制，并开发安全可靠的先进 MNP 制剂，用于神经系统的诊断、治疗和研究。