Sytems Analysis of Nanoparticle Biocompatibility

纳米粒子生物相容性的系统分析

基本信息

批准号：
7497144
负责人：
Brian D. Thrall
金额：
$ 46.19万
依托单位：
BATTELLE PACIFIC NORTHWEST LABORATORIES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-17 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7497144
关键词：
Acute Adverse effects Animals Antibodies Attention Bioinformatics Biological Biological Assay Biological Markers Caliber Cell Culture System Cell membrane Cells Cellular Assay Characteristics Charge Chemicals Chemistry Conditioned Culture Media Coupled Data Databases Development Dose Enzyme-Linked Immunosorbent Assay Extracellular Protein Future Genes Goals Histopathology In Vitro Lung Lavage Fluid Mass Spectrum Analysis Measures Messenger RNA Micelles Microarray Analysis Modeling Modification Mus Nature Outcome Particle Size Pathway Analysis Pathway interactions Personal Satisfaction Play Predictive Value Procedures Property Protein Isoforms Proteins Proteomics Proxy Public Health Quantitative Structure-Activity Relationship Range Research Research Personnel Roentgen Rays Role Screening procedure Series Silicon Silicon Dioxide Site Spectrum Analysis Statistical Models Surface Surface Properties System Testing Tissues Translating Work absorption base biomaterial compatibility consumer product design dosimetry expectation functional group human study in vitro Assay in vivo macrophage nanomaterials nanoparticle nanoscale nanotoxicology particle programs prototype response silanol size

项目摘要

DESCRIPTION (provided by applicant) We propose a quantitative structure activity relationship (QSAR) approach to investigate the specific physical and chemical surface properties that influence nanoparticle biocompatibility. Amorphous silica is chosen as an experimental particle due to its widespread use in consumer products, and because it is readily synthesized in a wide range of defined sizes and surface chemistries. Our recent work shows that the bioactivity of amorphous silica is greatly enhanced in particles <50 nm. We hypothesize that this is due to changes in the silanol site surface chemistry as particle diameter is decreased. Our approach involves three aims: 1) A panel of nanoparticle-induced secreted proteins will be identified using advanced mass spectrometry-based proteomic analysis of conditioned medium from macrophages exposed to amorphous silica, coupled with our existing gene microarray data. Bioinformatic pathway analysis will be performed to select ~20 pathway biomarkers, which will be used to modify an antibody sandwich-based protein ELISA microarray platform for multiplexed response analyses. 2) A series of silicabased particles where size and surface chemistry is selectively altered with functional groups will be prepared and characterized for size, charge, aggregation state, dissolution products and silanol types. X-ray absorption near-edge spectroscopy will be used to identify surface silicon isoforms in particles adsorbed to micelles mimicking cell membranes. The biological responses of each particle will be assessed in multiwell cellular assays with macrophages, using the ELISA microarray platform to provide quantitative measures of dose-response for ~20 different pathway markers. QSAR analyses will be performed with the measured physicochemical parameters and biological response data to identify relationships that correlate most strongly. 3) Particles selected from QSAR analysis will be further tested in mice exposed by intratracheal instillation, and biological responses will be determined by histopathology along with ELISA microarray analysis of bronchial lavage fluid. Comparison of QSAR results obtained in aims 2 and 3 will determine how predictive the in vitro assay is, as well as highlight particle characteristics that are most important for dictating biocompatibility in vivo. The results will determine properties of nano-scale amorphous silica that determine its biocompatibility, and reveal general principals relevant to other types of nanomaterial. In addition, the approach and biomarkers developed from this work will provide a screening platform that can be deployed to a variety of nanomaterials in the future.

描述（由申请人提供）我们提出了一种定量结构活性关系（QSAR）方法来研究影响纳米粒子生物相容性的特定物理和化学表面特性。选择无定形二氧化硅作为实验颗粒是因为它在消费产品中广泛使用，并且很容易合成各种规定的尺寸和表面化学性质。我们最近的工作表明，<50 nm 的颗粒中无定形二氧化硅的生物活性大大增强。我们假设这是由于随着粒径减小，硅烷醇位点表面化学发生变化。我们的方法涉及三个目标：1）将使用先进的基于质谱的蛋白质组学分析对暴露于无定形二氧化硅的巨噬细胞的条件培养基进行鉴定，并结合我们现有的基因微阵列数据来鉴定一组纳米颗粒诱导的分泌蛋白。将进行生物信息学途径分析以选择约 20 个途径生物标志物，这些生物标志物将用于修改基于抗体夹心的蛋白质 ELISA 微阵列平台，以进行多重响应分析。 2) 将制备一系列二氧化硅基颗粒，并用官能团选择性地改变其尺寸和表面化学性质，并对其尺寸、电荷、聚集状态、溶解产物和硅烷醇类型进行表征。 X射线吸收近边光谱将用于识别吸附在模拟细胞膜的胶束上的颗粒中的表面硅亚型。每个颗粒的生物反应将在巨噬细胞的多孔细胞测定中进行评估，使用 ELISA 微阵列平台为约 20 种不同途径标记物提供剂量反应的定量测量。将使用测量的物理化学参数和生物反应数据进行 QSAR 分析，以确定相关性最强的关系。 3) 从QSAR分析中选择的颗粒将在气管内滴注暴露的小鼠中进行进一步测试，并且将通过组织病理学以及支气管灌洗液的ELISA微阵列分析来确定生物反应。目标 2 和目标 3 中获得的 QSAR 结果的比较将确定体外测定的预测性，并突出显示对于决定体内生物相容性最重要的颗粒特征。结果将确定纳米级无定形二氧化硅的特性，从而决定其生物相容性，并揭示与其他类型纳米材料相关的一般原理。此外，这项工作开发的方法和生物标志物将提供一个可以在未来部署到各种纳米材料的筛选平台。