Reconciling Nanoceria's Jekyll and Hyde Reputation Toward Safer Nanotherapy

 描述(申请人提供)：纳米材料的技术发展已经进行了几十年。只是在过去的十年里，人们才对其潜在的有害健康和环境影响给予了严重关注。许多纳米材料在生物和环境环境中不易溶解或分解。因此，它们可以在隔离的地方(在哺乳动物中，主要是在肝、脾和骨髓等单核巨噬细胞系统器官中)持续几个月，甚至几年，通常与炎症/氧化应激反应有关，包括肉芽肿。这些不想要的影响已经在纳米氧化铈(纳米级二氧化铈)中看到了。另一方面，在许多炎症/氧化应激的细胞、细胞和整个动物模型中，纳米氧化钙已被证明是一种有效的抗炎/抗氧化剂。纳米氧化钙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)，并还原为Ce (Iii))。该项目的第一个具体目标将确定纳米氧化钙在没有增加炎症/氧化应激的情况下是否能产生炎症/促氧化作用，以及当炎症/氧化应激增加时是否能产生抗炎/抗氧化作用，并确定最低观察到的不良剂量和最低观察到的有益剂量。将对四种纳米氧化钙进行研究：5纳米和30纳米纳米氧化钙在大鼠体内的分布、持久性和作用(初步发现)，以及第三种已被证明产生有益的炎症/促氧化作用的纳米氧化钙。这三个将在内部进行合成和广泛的表征。第四个是NM-212，这是一种商业纳米陶瓷，其他人正在通过吸入途径对其进行广泛研究。由于纳米材料的口服和肺部吸收很低，将通过静脉注射的方式给药，以在多个器官建立足够的浓度，以研究其生物分布、持久性、生物转化和效应。初步研究结果表明，纳米氧化钙在哺乳动物细胞中经历了几个月的生物处理，形成了更稳定的形式。这似乎是通过非常小的纳米氧化钙颗粒的溶解和形成而发生的。这些非常小的纳米氧化钙颗粒在其表面具有更大的Ce(III)丰度；因此，它们有望具有增强的抗炎/抗氧化性能。这种生物转化表明，随着时间的推移，与纳米陶瓷的持久性和生物处理相关的好处会增加。第二个具体目标将检验这样一个假设，即纳米氧化钙的分布、形式和影响随着时间的推移而改变，这是由于它在肝脏中的生物处理变成了更小、更具抗氧化性的形式。第三个具体目标将确定有助于纳米氧化钙溶解和沉淀的因素，并调节其在肝脏中的生物处理和沉淀。拟议的研究将确定相对于其有害影响最大化其疗效的纳米氧化钙剂量，阐明纳米氧化钙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，通过设计纳米氧化钙作为具有长期抗炎/抗氧化活性的治疗剂，可能使其更安全。

 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.