Reconciling Nanoceria's Jekyll and Hyde Reputation Toward Safer Nanotherapy

调和 Nanoceria 的 Jekyll 和 Hyde 声誉以实现更安全的纳米疗法

• 批准号: 9303423
• 负责人: Robert Allen Yokel
• 金额: $ 32.85万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303423
• 关键词: 3-Dimensional; Address; Adverse effects; Affect; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Area; Attention; Back; Behavior; Biodistribution; Biological; Biological Availability; Bone Marrow; Breathing; Buffers; Cells; Characteristics; Chemicals; Coculture Techniques; Development; Diesel Fuels; Dose; Employee Strikes; Family; Future; Goals; Granuloma; Health; Industrialization; Inflammasome; Inflammation; Inflammatory; Lipopolysaccharides; Liver; Lung; Mammalian Cell; Mammals; Measures; Mechanics; Mediating; Medical; Metabolic Biotransformation; Modeling; Mononuclear; Morphology; Oral; Organ; Oxidation-Reduction; Oxidative Stress; Phagocytes; Physiological; Pilot Projects; Polishes; Precipitation; Property; Rattus; Reactive Oxygen Species; Recycling; Reporting; Research; Research Personnel; Route; Safety; Spleen; Stress; Surface; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; absorption; base; biological adaptation to stress; biological systems; bioprocess; body system; catalyst; ceric oxide; design; insight; interest; intravenous injection; metal oxide; nanomaterials; nanoscale; nanotherapy; novel; oxidation; particle; public health relevance; response

 DESCRIPTION (provided by applicant): The technological development of nanomaterials has been underway for decades. Only in the past decade has serious attention been paid to their potential unwanted health and environmental effects. Many nanomaterials do not readily dissolve or disintegrate in biological and environmental milieu. As a result, they can persist where they are sequestered (in mammals, mostly in mononuclear phagocyte system organs such as the liver, spleen and bone marrow) for months, possibly years, often associated with inflammatory/oxidative stress responses, including granuloma. These unwanted effects have been seen with nanoceria (nanoscale cerium dioxide). On the other hand, nanoceria has been shown to be an effective anti-inflammatory/antioxidant in numerous cellular, cell, and whole animal models of inflammation/oxidative stress. Nanoceria's pro- and antioxidant effects result from its auto-catalytic redox behavior (oxidation from Ce (III) to Ce (IV) and reduction back to Ce (III)). The first specific aim of this project will determine if nanoceria can produce inflammatory/pro- oxidant effects in the absence of elevated inflammation/oxidative stress and anti-inflammatory/antioxidant effects when inflammation/oxidative stress is elevated, and determine the lowest observed adverse dose and lowest observed beneficial dose. Four nanoceria will be studied: a 5 and a 30 nm nanoceria extensively studied for their distribution, persistence and effects in the rat (preliminary findings) and a third that others have demonstrated produces beneficial inflammatory/pro-oxidant effects. These three will be synthesized and extensively characterized in-house. The fourth will be NM-212, a commercial nanoceria that is being extensively studied by the inhalation route by others. Due to the very low oral and pulmonary absorption of nanomaterials, nanoceria will be delivered by intravenous injection to establish sufficient levels in multiple organs to study its biodistribution, persistene, biotransformation, and effects. Preliminary findings indicate that nanoceria undergoes some bioprocessing in mammalian cells over months to a more stable form. This appears to occur via dissolution and formation of very small nanoceria particles. These very small nanoceria particles have a greater enrichment of Ce (III) on their surface; therefore they are expected to have enhanced anti-inflammatory/antioxidant properties. This biotransformation suggests enhanced benefit over time associated with nanoceria's persistence and bioprocessing. The second specific aim will test the hypothesis that the distribution, form, and effects of nanoceria change over time due to its bioprocessing in the liver to smaller, more antioxidant forms. The third specific aim will identify factors that contribute to nanoceria dissolution and precipitation and mediate its bioprocessing and precipitation in the liver. The proposed studies will identify nanoceria doses that maximize its efficacy relative to its unwanted effects, elucidate nanoceria's long term fate in a model mammal, the rat, and provide the insight into its biotransformation that may enable safer by design nanoceria for use as a therapeutic agent with prolonged anti-inflammatory/antioxidant activity.

 描述（由申请人提供）：纳米材料的技术开发已经进行了几十年。只是在过去十年中，人们才认真注意到它们可能对健康和环境造成的有害影响。许多纳米材料在生物和环境环境中不容易溶解或分解。因此，它们可以在它们被隔离的地方（在哺乳动物中，主要是在单核吞噬细胞系统器官如肝、脾和骨髓中）持续数月，可能数年，通常与炎症/氧化应激反应有关，包括肉芽肿。纳米氧化铈（纳米级二氧化铈）已经看到了这些不必要的影响。另一方面，纳米氧化铈已被证明是一种有效的抗炎/抗氧化剂在许多细胞，细胞，和整个动物模型的炎症/氧化应激。纳米氧化铈的促氧化和抗氧化作用源于其自催化氧化还原行为（从Ce（III）氧化为Ce（IV）并还原回Ce （III））。本项目的第一个具体目标是确定纳米氧化铈在炎症/氧化应激升高的情况下是否可以产生炎症/促氧化作用，以及在炎症/氧化应激升高时是否可以产生抗炎/抗氧化作用，并确定观察到的最低不良剂量和观察到的最低有益剂量。将研究四种纳米氧化铈：一种5和一种30 nm的纳米氧化铈，广泛研究其在大鼠中的分布、持久性和影响（初步发现），另一种纳米氧化铈已被证明产生有益的炎症/促氧化作用。将在内部对这三个方面进行综合和广泛的定性。第四个将是NM-212，这是一种商业纳米氧化铈，其他人正在通过吸入途径进行广泛研究。由于纳米材料的口服和肺部吸收非常低，纳米氧化铈将通过静脉注射递送，以在多个器官中建立足够的水平，以研究其生物分布、持久性、生物转化和影响。初步研究结果表明，纳米铈在哺乳动物细胞中经过数月的生物加工，形成更稳定的形式。这似乎是通过溶解和形成非常小的纳米氧化铈颗粒而发生的。这些非常小的纳米氧化铈颗粒在其表面上具有更大的Ce（III）富集;因此，预期它们具有增强的抗炎/抗氧化特性。这种生物转化表明，随着时间的推移，与纳米氧化铈的持久性和生物加工相关的益处增加。第二个具体目标将测试以下假设：纳米氧化铈的分布、形式和影响随着时间的推移而变化，这是由于其在肝脏中的生物加工成更小、更抗氧化的形式。第三个具体目标将确定有助于纳米氧化铈溶解和沉淀的因素，并介导其在肝脏中的生物加工和沉淀。拟议的研究将确定纳米氧化铈剂量，使其相对于其不必要的影响的功效最大化，阐明纳米氧化铈在模型哺乳动物大鼠中的长期命运，并提供对其生物转化的洞察，这可能通过设计纳米氧化铈作为具有长期抗炎/抗氧化活性的治疗剂而使其更安全。