BIOLOGICAL FATE AND BIOCOMPATIBILITY OF SILICA-BASED NANOCONSTRUCTS

项目总结 全身给药二氧化硅纳米粒(SNPs)的一个主要挑战是通过和 在单核吞噬系统(MPS)器官中的蓄积，以及随后的免疫反应。穷 SNPs的载量，它们在巨噬细胞中的稳定性和空泡化，以及潜在的低代谢和 患者人群的清除率可能需要使用高剂量和频繁剂量的SNPs， 可能会导致MPS饱和和过载。MPS中SNPs免疫毒性的详细研究 需要建立他们的安全概况，以选择具有明确免疫学特性的药物载体。这个 SNPs对吞噬细胞摄取和饱和后命运和功能的影响及对宿主免疫的影响 对此的反应需要进一步阐明。单核苷酸多态的理化性质与遗传易感性的相关性 性别依赖性毒性的机制尚不清楚。同时观察静脉注射后免疫反应的变化。行政管理 SNPs的数量以及这种反应背后的机制在很大程度上是未知的。要解决这些知识差距， 这项赠款申请的具体目的如下： 1)研究SNPs饱和对巨噬细胞吞噬功能的影响。 存活、增殖和免疫信号作为纳米颗粒物理化学性质的函数。这个 在这一目标中需要检验的基本假设是，SNPs对巨噬细胞的饱和将影响其 基于纳米颗粒特性的正常功能、分子信号和命运。 2)研究静脉注射后组织驻留巨噬细胞的骨髓毒性和功能。 给予SNPs，并评估体外循环吞噬细胞的数量和激活状态 暴露于SNPs。在这一目标中要检验的基本假设是， 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，这一现象可能是可逆的，取决于给药的剂量和频率。 3)研究全身应用SNPs AS的免疫副作用和抗聚乙二醇反应。 动物性别和颗粒物理化学性质的函数。基本的假设是：i)反聚乙二醇化 免疫球蛋白和免疫球蛋白将在接触聚乙二醇单核苷酸的情况下以时间依赖的方式产生；ii)在 雌性与雄性Th1和Th2偏向动物模型的免疫反应将有助于SNP的毒性和免疫- 间接的副作用。 这一建议具有重要意义，因为对SNP的关键物理化学性质有很好的了解- 明确的免疫学特性将有助于建立更安全的静脉给药平台。它是创新的 因为它第一次接近不同的SNP与免疫系统的不同组件的相互作用 由于动物的性别和免疫系统的不同而产生偏差。

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.