Fate and Effects of Nanoparticles: Relationship to Physicochemical Properties

描述(由申请人提供) 目的：纳米级(100 Nm)材料独特的物理化学性质使电子、诊断和治疗领域具有革命性的潜力。虽然一些人工制造的纳米粒子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人造纳米颗粒影响的研究表明，它们比更大的颗粒毒性更大，所观察到的毒性与氧化应激有关。一个独特的功能 纳米材料的表面积以及颗粒表面的活性分子的数量随着颗粒尺寸的减小而增加。我们假设，细胞和组织中已被证明对NP的反应发生的氧化应激是NP表面的物理化学特征的函数。为了验证这一假设，我们设计了五个具体目标，以1)评估NP在呼吸道特定区域的沉积、移位和在体内的影响；2)评估NP与组织和细胞提取物蛋白质的相互作用；3)评估NP的摄取和细胞反应的机制方面；4)充分表征用于暴露的NP的物理化学性质，并将这些特征与组织和细胞反应相关联；以及5)将物理化学NP特征与体内和体外反应相关联。 方法：将使用一种侧重于NP在体内的处置和反应的方法来检验该假说。无细胞分析将评估产生活性氧的能力和蛋白质结合。将在计划的体外研究中测试NP的摄取和毒性机制，使用传统的液体和电喷雾气雾剂暴露。在大鼠身上的研究将集中在炎症和氧化应激以及呼吸道暴露后的组织分布上。这些 研究将伴随着对所使用的颗粒进行彻底的物理化学表征。最终目标将是开发一个使用相关统计数据的急需的预测模型，该模型将NP的物理化学特征与非细胞、细胞和体内系统的结果测量联系起来，并将确定最佳剂量和反应度量。 预期结果：该项目与公众健康相关的成果包括确定吸入后NPs从肺部排出的情况，它们是否以及如何造成组织和细胞损伤，以及哪些人可能对这些影响最敏感。然后，这些信息可以用来预测人类在各种环境中暴露的结果，并在发现NPs有害的情况下导致能够保护公共健康的干预措施。

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.