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）：工程氧化铁超磁磁性纳米颗粒（MNPS）提供有针对性的切割边缘诊断和治疗平台，因为它们能够通过外部磁场进行指导，可以官能化并穿透细胞和组织障碍。在研究MNP在磁力下延伸分化PC12细胞中神经突生长的能力时，我们观察到MNP诱导的脱二分化，神经突的丧失和细胞死亡，氧化铁浓度的增加，而不是DimerCaptosocactoscoccincinic Acid（DMSA）用于MNP涂料。越来越多的证据表明，相对于分子或散装对应物，反应性面积，渗透性和对纳米颗粒的生物降解的抗性促进其细胞毒性潜力，这意味着氧化应激（OS）是纳米毒性的关键范式。 OS的3层过程表现出活性氧（ROS）和抗氧化剂防御（Tier I），促炎反应（II层）和DNA损伤导致细胞凋亡（Tier III）的激活。纳米颗粒在其体内应用后很快受到巨噬细胞的挑战，巨噬细胞既可以缓冲纳米颗粒的潜在纳米毒性，又减少了其治疗和诊断使用所需的循环时间。在一系列试验性体内研究中，我们使用大鼠坐骨神经作为联合模型来评估直接神经毒性和有效的神经内巨噬细胞浸润，这是周围神经独有的。在高度稳定，水溶性和对聚集的抗性的阴离子DMSA涂层的MNP（AMNP）的48小时内，我们观察到巨噬细胞的稳健涌入，血红素氧酶-1，血红素酶-1，Interleukin-12，interleukin-12，of intrix Mellopoteinase（Metallypase）（MMMPase 3和Caspase 3和Caspase 3和Caspase） - 9 范例。相比之下，在相应的假手术中仅观察到轻度的神经毒性变化，对照DMSA和脱氧涂层的氧化铁MNPS微型注射。该程序利用工程和生物学的体外和体内方法的结合，旨在确定由氧化铁MNP诱导的中心和周围神经毒性的机理和靶细胞。将重点放在研究表面化学（DMSA，葡萄糖和黄金）在体外和体内激活氧化应激信号传导和生物分布的作用。鱿鱼磁力测定法，光，电子和共聚焦神经病理学，ROS介导的促炎性和促凋亡细胞信号分析以及体内感觉和运动行为评估的组合。该提案的总体目标是制定和测试在神经系统中在治疗和诊断平台中使用MNP安全的工程策略。 公共卫生相关性 磁性纳米颗粒（MNP）为包括神经科学在内的所有医学领域提供了最先进的药物输送，分子成像和组织工程工具。但是，它们的反应性区域增强，渗透性和对生物降解的抗性促进了它们的毒性潜力。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的机制，并开发高级MNP公式，这些配方可安全，可用于神经系统中的诊断，治疗和研究用途。