Sytems Analysis of Nanoparticle Biocompatibility

纳米粒子生物相容性的系统分析

• 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
• 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

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，以研究影响纳米颗粒生物相容性的特定物理和化学表面特性。由于其在消费产品中的广泛使用，因此选择了无定形二氧化硅作为实验颗粒，并且由于它在各种定义的尺寸和表面化学范围内很容易合成。我们最近的工作表明，在<50 nm的颗粒中，无定形二氧化硅的生物活性大大增强。我们假设这是由于颗粒直径降低时硅烷醇位点表面化学的变化所致。 我们的方法涉及三个目的：1）将使用基于晚期质谱法的蛋白质组学分析来鉴定纳米颗粒诱导的分泌蛋白，对暴露于无定形硅胶的巨噬细胞的条件培养基，并与我们现有的现有基因微阵列数据相结合。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，该标志物将用于修改基于抗体三明治的蛋白质ELISA微阵列平台以进行多重响应分析。 2）一系列硅酸盐的颗粒，其中将准备并以官能组选择大小和表面化学，并以尺寸，电荷，聚合状态，溶解产物和硅烷醇类型来改变并表征。 X射线吸收近边光谱将用于鉴定吸附到模仿细胞膜的胶束上的颗粒中的表面硅同工型。使用ELISA微阵列平台，将在具有巨噬细胞的多韦尔细胞测定中评估每个粒子的生物学反应，以提供约20种不同途径标记的剂量反应的定量测量。 QSAR分析将使用测得的理化参数和生物反应数据进行，以识别最密切相关的关系。 3）从QSAR分析中选择的颗粒将进一步测试通过气管内滴注暴露的小鼠，生物学反应将通过组织病理学以及ELISA微阵列分析的支气管灌洗液分析确定。在AIM 2和3中获得的QSAR结果的比较将决定体外测定的预测性，并突出显示粒子特性对于决定体内生物相容性最重要。结果将确定纳米级非晶二氧化硅的性质，该二氧化硅决定其生物相容性，并揭示与其他类型的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筛选平台，将来可以将其部署到各种纳米材料。