BIOLOGICAL FATE AND BIOCOMPATIBILITY OF SILICA-BASED NANOCONSTRUCTS

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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.