Towards Assessing and Mitigating the Toxicity of Metal Nanoparticles

CBET 1236258本项目旨在推进目前对纳米材料毒性的理解，特别关注金属纳米颗粒（NPs）在“不可扩展的制度”（1 nm - 10 nm）中的尺寸依赖性毒性。该方法是基于精细控制和良好表征的金属纳米颗粒的合成的组合，使用斑马鱼模型进行快速毒理学筛选和机理研究，它建立在一位工程师的专业知识基础上，该工程师是纳米材料合成，表征和应用方面的专家，结合了一位医学研究人员，他是人类疾病斑马鱼模型的专家。这项工作利用了许多独特的试剂和设施，包括匹兹堡大学的斑马鱼设施，这是世界上最大的设施之一。所提出的方法将应用于三种在消费品和工业过程中的纳米材料应用中具有广泛相关性的金属（Ag，Fe和Ni），具体包括以下步骤：-尺寸在1 - 10 nm范围内的金属纳米颗粒的尺寸控制合成（加上30 - 100 nm尺寸范围内的控制），以及在毒理学研究之前对这些材料进行仔细和广泛的表征。通过斑马鱼研究鉴定这些工程化NP的大小和剂量依赖性毒性。器官特异性毒性的机制研究，以识别靶器官，与相应的游离金属盐进行比较，并作为粒度的函数。最后，研究多孔二氧化硅涂层对金属纳米颗粒毒性的影响，作为一种潜在的手段，以减轻NP毒性，而不影响可及性，因此功能的工程NPs.Overall，所提出的方法旨在开发快速和可靠的筛选纳米颗粒毒性的方法，提高对“不可缩放”尺寸制度（10 nm）中纳米毒性的理解，并展示了一种通过多孔涂层减轻纳米颗粒毒性的方法。智力优势该项目直接解决了纳米毒理学研究的多学科性质所带来的根本挑战。通过集中在两个方面的科学意义，以及巨大的实际意义：系统研究的尺寸依赖的纳米毒性在“不可扩展”的制度，这在很大程度上被忽视了迄今为止，和多孔涂层的研究作为一种手段，以减轻金属纳米粒子的毒性，它的目的是使显着的进步，更好地了解在纳米尺度上的金属的毒性。该项目还将把斑马鱼研究作为纳米毒理学研究的快速和强大的筛选工具。通过使用组织特异性启动子下表达报告基因的转基因斑马鱼品系，将首次有可能快速评估（大小特异性）NP毒性的潜在靶器官。这将有助于确定纳米材料的毒性和靶向途径是否会因尺寸而发生根本性变化，类似于在亚纳米颗粒中的金属纳米颗粒的化学反应性的公认的基本变化，展示快速可靠的纳米毒性筛选工具，以及发展对纳米级材料毒性的更好的基本理解，可能会产生深远的影响开发和实施安全的“纳米功能”消费品。快速和具有成本效益的筛选将为在基于纳米材料的消费品和工业产品中稳健和负责任地实施纳米颗粒铺平道路，进一步加速这些材料的市场渗透，对生活质量产生潜在的巨大影响。更好地理解纳米毒性的基本原理将有助于（先发制人地）指导新型纳米材料的设计，并将安全性纳入其设计。最后，这样的理解可以为纳米材料的立法行动提供可靠的准则。

CBET 1236258The present project aims to advance the current understanding of nanomaterials toxicity with a specific focus on size-dependent toxicity of metal nanoparticles (NPs) in the "non-scalable regime" (1 nm - 10 nm). The approach is based on the combination of the synthesis of finely controlled and well-characterized metal nanoparticles, with the use of zebrafish models for fast toxicological screening and mechanistic studies It builds onto the expertise of an engineer who is an expert on nanomaterials synthesis, characterization, and application, combined with that of a medical researcher who is an expert on zebrafish models of human disease. The proposed work exploits a number of unique reagents and facilities, including the University of Pittsburgh's zebrafish facility, one of the largest in the world. The proposed approach will be applied to three metals with broad relevance in nanomaterials application in consumer products and industrial processes (Ag, Fe, and Ni), and comprises specifically the following steps:- Size-controlled synthesis of metal nanoparticles with dimensions in the 1 - 10 nm range (plus controls in the size range of 30 - 100 nm), and careful and extensive characterization of these materials prior to toxicological studies.-Identification of size- and dose- dependent toxicity of these engineered NPs via zebrafish studies.- Mechanistic studies of organ-specific toxicity to identify target organs in comparison to the respective free metal salt and as function of particle size.- Finally, investigation of the impact of porous silica coatings on the toxicity of metal nanoparticles as a potential means to mitigate NP toxicity without impacting accessibility and hence functionality of the engineered NPs.Overall, the proposed approach aims to develop methodology for fast and reliable screening of nanoparticle toxicity, improve understanding of nanotoxicity in the "non-scalable" size regime (10 nm), and demonstrate an approach towards mitigating nanoparticle toxicity via porous coatings.Intellectual Merit The project directly addresses the fundamental challenge posed by the multidisciplinary nature of nanotoxicological studies. By focusing on two aspects of scientific significance as well as great practical importance: the systematic study of size-dependent nanotoxicity in the "non-scalable" regime, which has been largely neglected to-date, and the study of porous coatings as a means towards mitigating the toxicity of metal nanoparticles, it aims to enable significant advances towards a better fundamental understanding of the toxicity of metals at the nanoscale. The project will furthermore establish zebrafish studies as a fast and robust screening tool for nanotoxicological studies. By using transgenic zebrafish lines expressing reporter genes under tissue specific promoters, rapid evaluation of potential target organs for (size-specific) NP toxicity will be possible for the first time. This will enable establishing whether nanomaterials are subject to size-dependent fundamental changes in toxicity and target pathways, similar to the well-established fundamental changes in chemical reactivity for metal NPs in the sub-10 nm range.Broader Impact Demonstration of fast and reliable screening tools for nanotoxicity and development of an improved fundamental understanding of the toxicity of materials in the nanoscale regime could have profound impact on the development and implementation of safe "nano-enabled" consumer products. Fast and cost-efficient screening would pave the way towards robust and responsible implementation of NPs in nanomaterials-based consumer and industrial products, further accelerating the market penetration of these materials with potentially huge impact on quality of life. An improved understanding of the basic principles of nanotoxicity would furthermore help to (pre-emptively) guide the design of novel nanomaterials with safety built into their design. Finally, such an understanding could yield reliable guidelines for legislative action on nanomaterials.