Fate and Effects of Nanoparticles: Relationship to Physicochemical Properties

纳米颗粒的命运和影响：与理化性质的关系

• 批准号: 7341306
• 负责人: Alison Elder
• 金额: $ 33.33万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-29 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7341306
• 关键词: Aerosols; Air; Area; Breathing; Cells; Characteristics; Condition; Data; Dependence; Deposition; Development; Diagnostic; Dose; Drug or chemical Tissue Distribution; Elderly; Electronics; Generations; Goals; In Vitro; Inflammation; Inhalation Exposure; Intervention; Lead; Link; Liquid substance; Lung; Metric; Numbers; Occupational; Outcome; Outcome Measure; Oxidants; Oxidative Stress; Particle Size; Phase; Property; Protein Binding; Proteins; Public Health; Rattus; Reactive Oxygen Species; Research Personnel; Respiratory System; Surface; System; Testing; Therapeutic; Time; Tissues; Toxic effect; cell injury; cell type; design; exposed human population; in vivo; insight; nanomaterials; nanoparticle; nanoscale; nanosized; particle; predictive modeling; response; statistics; therapy design; uptake

DESCRIPTION (provided by applicant) Objectives: The unique physicochemical properties of nanoscale (<100 nm) materials results in the potential to revolutionize the electronic, diagnostic, and therapeutic fields. Although some manufactured NPs have been in use for some time, new nanomaterials are rapidly being developed. Existing studies on the effects of ambient air and manufactured nanosized particles have shown that they are more toxic than larger ones and that the observed toxicity is oxidative stress-related. One unique feature of nanosized materials is that the surface area and, therefore the number of reactive molecules at the particle surface, increases as particle size decreases. We hypothesize that the oxidative stress in cells and tissues that has been shown to occur in response to NP is a function of the physicochemical characteristics of the NP surface. To test this hypothesis, we have designed five specific aims to 1) evaluate NP deposition in specific regions of the respiratory tract, translocation, and effects in vivo; 2) assess NP interactions with proteins from tissue and cellular extracts; 3) evaluate NP uptake and mechanistic aspects of cellular responses; 4) fully characterize the physicochemical properties of the NP used for exposures and correlate these characteristics with tissue and cellular responses; and 5) correlate physicochemical NP characteristics with in vivo and in vitro responses. Approach: The hypothesis will be tested using an approach that focuses on the in vivo disposition of and responses to NP. Acellular analyses will assess reactive oxygen species-generating capacity and protein binding. NP uptake and mechanisms of toxicity will be tested in the planned in vitro studies using conventional liquid-phase as well as electrospray aerosol exposures. In vivo studies in rats will focus on inflammation and oxidative stress as well as tissue distribution following respiratory tract exposures. These studies will be accompanied by a thorough physicochemical characterization of the particles used. The final goal will be the development of a much-needed predictive model using correlation statistics that will link NP physicochemical characteristics with outcome measures from the acellular, cellular, and in vivo systems and will also identify the best dose and response metrics. Expected Results: The outcomes of this project that are relevant to public health include determinations of the condition under which NPs move out of the lungs after they are inhaled, if and how they cause tissue and cellular injury, and which people might be the most sensitive to these effects. This information can then be used to predict outcomes of human exposures in various settings and lead to interventions that can protect public health if NPs are found to be injurious.

描述（由申请人提供） 目标：纳米级（<100 nm）材料的独特物理化学特性导致可能彻底改变电子，诊断和治疗领域。尽管一些制造的NP已经使用了一段时间，但新的纳米材料正在迅速开发。 现有关于环境空气和制造纳米颗粒的作用的研究表明，它们比大型毒性更毒性，并且观察到的毒性与氧化应激相关。一个独特的功能 纳米化材料的表面积，因此，颗粒表面的反应性分子的数量随着粒径的减小而增加。我们假设细胞和组织中已显示出对NP的氧化应激是NP表面物理化学特征的函数。为了检验这一假设，我们设计了五个特定目标，以评估体内呼吸道，易位和效应的特定区域的NP沉积； 2）评估NP与组织和细胞提取物的蛋白质相互作用； 3）评估细胞反应的NP摄取和机械方面； 4）完全表征用于暴露的NP的理化特性，并将这些特征与组织和细胞反应相关联； 5）将物理化学NP特征与体内和体外反应相关联。 方法：该假设将使用一种侧重于体内处置和对NP的反应的方法进行检验。细胞分析将评估活性氧的产生能力和蛋白质结合。 NP的摄取和毒性机制将在计划的体外研究中使用常规液相以及电喷雾气溶胶暴露。大鼠体内研究将集中于炎症和氧化应激以及呼吸道暴露后的组织分布。这些 研究将伴随着所用颗粒的彻底物理化学表征。最终目标将是使用相关统计数据的急需的预测模型的开发，该模型将将NP物理化学特征与来自细胞，细胞和体内系统的结果指标联系起来，还将确定最佳剂量和响应指标。 预期结果：该项目与公共卫生相关的结果包括确定NP在吸入后从肺部移出的状况，是否以及如何造成组织和细胞损伤，以及哪些人对这些影响最敏感。然后，这些信息可用于预测各种环境中人类暴露的结果，并导致干预措施，如果发现NP是有害的，可以保护公共卫生。