Abstract
As pharmaceutical excipients, mesoporous silica nanoparticles (MSNs) have attracted considerable concern based on potential risks to the public. The impact of MSNs on biochemical metabolism is poorly understood, and few studies have compared the effects of MSNs administered via different routes. To evaluate the hepatotoxicity of MSNs, metabolomics, proteomics and transcriptomic analyses were performed in mice after intravenous (20 mg/kg/d) or oral ad-ministration (200 mg/kg/d) of MSNs for 10 days. Intravenous injection induced significant hepatic injury based on pathological inspection and increased the levels of AST/ALT and the inflammatory factors IL-6, IL-1β and TNF-a. Omics data suggested intravenous administration of MSNs perturbed the following metabolites: succinate, hypoxanthine, GSSG, NADP+, NADPH and 6-phosphogluconic acid. In addition, increases in GPX, SOD3, G6PD, HK, and PFK at proteomic and transcriptomic levels suggested elevation of glycolysis and pentose phosphate pathway, synthesis of glutathione and nucleotides, and antioxidative pathway activity, whereas oxidative phosphorylation, TCA and mitochondrial energy metabolism were reduced. On the other hand, oral administration of MSNs disturbed inflammatory factors and metabolites of ribose-5-phosphate, 6-phosphogluconate, GSSG, and NADP+ associated with the pentose phosphate pathway, glutathione synthesis and oxidative stress albeit to a lesser extent than intravenous injection despite the administration of a ten-fold greater dose. Overall, systematic biological data suggested that intravenous injection of nanoparticles of pharmaceutical excipients substantially affected hepatic metabolism function and induced oxidative stress and inflammation, whereas oral administration exhibited milder effects compared with intravenous injection.
Highlights
Mesoporous silica nanoparticles (MSNs) have been widely used in biology (Rosenholm et al, 2016) and medicine (Tang et al, 2012) due to their high pore volume, large specific surface area, easy surface modification, biocompatibility, and degradability features, such as slow drug release (He et al, 2016; Song et al, 2016)
These results indicated that oral administration of mesoporous silica nanoparticles (MSNs) induced a proinflammatory response in the liver and that intravenous injection of MSNs induced significant hepatic injury in mice
Our data showed that intravenous injection of MSNs caused significant changes in parameters related to liver function, histopathological sections, and biological system results based on metabolomics, genomics, and proteomics
Summary
Mesoporous silica nanoparticles (MSNs) have been widely used in biology (Rosenholm et al, 2016) and medicine (Tang et al, 2012) due to their high pore volume, large specific surface area, easy surface modification, biocompatibility, and degradability features, such as slow drug release (He et al, 2016; Song et al, 2016). An increasing number of studies have demonstrated that these tiny nanoparticles can affect the tissues and cells of the body, causing inflammation and histopathological changes (Liu et al, 2012; Peeters et al, 2013; Nemmar et al, 2016; Zhang et al, 2018). Nanomaterials and porous adsorption particles for pharmacies are generally prepared as injections, oral dosage forms or powder sprays, which enter the body through intravenous, gavage or atomization, respectively (Fu et al, 2013). Studies have suggested that after orally administered nanoparticles enter the intestine, these nanoparticles can further pass through the intestinal membrane barrier, enter into the circulation system and subsequently tissues and cells, and impact the body (He et al, 2011; Li et al, 2015; Chen et al, 2019, 2020). Similar to the processes of solid particles in the atmosphere and in sprays, these solid particles mainly enter the lungs through breathing via the respiratory tract, adhere to the oral cavity and nasal cavity, enter the gastrointestinal tract through drinking or eating, or enter the cells in the oral mucosa of the nasal cavity (Griese, 1999; Patton and Byron, 2007; Park et al, 2010; Garbuzenko et al, 2014; Shin et al, 2017; Pietroiusti et al, 2018; Rosário et al, 2021)
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