BIOLOGICAL FATE AND BIOCOMPATIBILITY OF SILICA-BASED NANOCONSTRUCTS

二氧化硅基纳米结构的生物命运和生物相容性

• 批准号: 10579946
• 负责人: Hamid Ghandehari
• 金额: $ 50.13万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579946
• 关键词: Acute; Address; Adsorption; Adverse effects; Affect; Animal Model; Animals; Antibodies; Applications Grants; Bacteria; Biodistribution; Biological; Blood; Bone Marrow; Cell Cycle; Cell division; Cessation of life; Characteristics; Chronic; Cues; Dependence; Dose; Drug Carriers; Drug Delivery Systems; Exposure to; Female; Frequencies; Gene Expression; Generations; Genes; Genetic Transcription; Geometry; Health; Hormones; Human; Immune; Immune response; Immune signaling; Immune system; Immunoglobulin G; Immunoglobulin M; Immunologics; In Vitro; Inbred BALB C Mice; Inflammasome; Inflammatory; Inflammatory Response; Intravenous; Investigation; Knowledge; Leukocytes; Liver; Liver Extract; Lung; Lymphocyte; Macrophage; Maximum Tolerated Dose; Mediating; Metabolic Clearance Rate; Metabolism; Modification; Molecular; Mononuclear; Mus; Organ; Phagocytes; Phenotype; Pluripotent Bone Marrow Stem Cell; Porosity; Proliferating; Property; Proteins; Rattus; Recovery; Safety; Signal Pathway; Signal Transduction; Silicon Dioxide; Spleen; Surface; System; Testing; Time; Tissues; Toxic effect; Variant; Whole Blood; biomaterial compatibility; cytotoxicity; density; genotoxicity; granulocyte; immune function; immunotoxicity; in vivo; innovation; intravenous administration; intravenous injection; male; monocyte; nano; nanoparticle; neutrophil; overexpression; particle; patient population; peripheral blood; response; sex; side effect; uptake

PROJECT SUMMARY A major challenge with systemic administration of silica nanoparticles (SNPs) is clearance by and accumulation in organs of mononuclear phagocytic system (MPS), and subsequent immune response. Poor loading capacity of SNPs, their stability and vacuolization in macrophages, and potentially lower metabolism and clearance rates in patient populations may necessitate administration of high and frequent doses of SNPs which could lead to MPS saturation and overload. Detailed investigation of immunotoxicity of SNPs in the MPS is needed to establish their safety profile to choose drug carriers with well-defined immunological properties. The influence of SNPs on the fate and function of phagocytes after uptake and saturation, and on host immune response need further elucidation. The correlation between the physicochemical properties of SNPs and the mechanisms of sex-dependent toxicity is unclear. Also, the immune response alteration upon i.v. administration of SNPs and the mechanisms behind this response are largely unknown. To address these knowledge gaps in this grant application the following Specific Aims are proposed: 1) To investigate the influence of saturation of macrophages with SNPs on their phagocytic activity, survival, proliferation, and immune signaling as a function of nanoparticle physicochemical properties. The underlying hypothesis to be tested in this aim is that saturation of macrophages by SNPs will influence their normal function, molecular signaling, and fate based on nanoparticle characteristics. 2) To investigate bone marrow toxicity and function of tissue-resident macrophages after i.v. administration of SNPs, and assess the number and activation status of circulating phagocytes after in vitro exposure to SNPs. The underlying hypothesis to be tested in this aim is that size, geometry, and porosity of SNPs influence the normal function of bone marrow, tissue-resident macrophages, and peripheral blood phagocytes, a phenomenon which may be reversible and depend on dose and frequency of administration. 3) To investigate the immune side effects and anti-PEG response of systemically administered SNPs as a function of animal sex and particle physicochemical properties. The underlying hypotheses are: i) Anti-PEG IgM and IgG will be generated in a time-dependent manner upon exposure to PEGylated SNPs; ii) variation in immune response in female vs male Th1 and Th2 bias animal models will contribute to SNP toxicity and immune- mediated side effects. This proposal is significant because understanding key physicochemical properties of SNPs with well- defined immunological properties will help establish safer platforms for intravenous drug delivery. It is innovative because for the first time it approaches different SNP interactions with various components of the immune system as a result of animal-sex and different immune-biased in a systematic fashion.

项目摘要 全身施用二氧化硅纳米颗粒（SNP）的一个主要挑战是通过 在单核吞噬细胞系统（MPS）的器官中积累，以及随后的免疫应答。贫困 SNPs的负载能力，它们在巨噬细胞中的稳定性和空泡化，以及潜在的较低的代谢和 患者群体中的清除率可能需要施用高剂量和频繁剂量的SNP， 可能导致MPS饱和和过载。MPS中SNP的免疫毒性的详细研究是 需要确定其安全性，以选择具有明确免疫学特性的药物载体。的 单核苷酸多态性对吞噬细胞在摄取和饱和后的命运和功能以及对宿主免疫的影响 回应需要进一步说明。SNPs的理化性质与基因型之间的相关性 性别依赖性毒性的机制尚不清楚。此外，静脉内给药后的免疫应答改变 SNPs和这种反应背后的机制在很大程度上是未知的。为了弥补这些知识差距， 本赠款申请提出了以下具体目标： 1)为了研究具有SNPs的巨噬细胞饱和对其吞噬活性的影响， 存活、增殖和免疫信号传导作为纳米颗粒物理化学性质的函数。的 在此目的中待检验的基本假设是，巨噬细胞被SNP饱和将影响它们的免疫应答。 正常功能、分子信号传导和基于纳米颗粒特征的命运。 2)目的：研究i. v.后骨髓毒性和组织驻留巨噬细胞的功能。 施用SNP，并评估体外施用后循环吞噬细胞的数量和活化状态。 暴露于SNPs。在这一目标中要测试的基本假设是， SNPs影响骨髓、组织驻留巨噬细胞和外周血的正常功能 吞噬细胞，这种现象可能是可逆的，并取决于给药的剂量和频率。 3)为了研究全身施用SNP的免疫副作用和抗PEG应答， 动物性别和颗粒物理化学性质的函数。基本假设是：i）抗PEG IgM和IgG将在暴露于聚乙二醇化SNP后以时间依赖性方式产生; ii）IgM和IgG的变化， 在雌性与雄性Th 1和Th 2偏向动物模型中免疫应答将导致SNP毒性和免疫- 介导的副作用。 这一建议是重要的，因为理解SNPs的关键理化性质， 确定的免疫学特性将有助于建立更安全的静脉内药物输送平台。它是创新的 因为这是它第一次与免疫系统的各种成分进行不同的SNP相互作用， 由于动物性别和不同的免疫偏向，在一个系统的方式。