Li Jing, Sun Runbin, Xu Hui, Wang Guangji
Lab of Nano-Biology Technology, School of Physics and Electronics, Institute of Super-Microstructure and Ultrafast Process in Advanced Materials, Central South University, Changsha, China.
Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2022 Jan 27;13:835359. doi: 10.3389/fphar.2022.835359. eCollection 2022.
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.
作为药物赋形剂，介孔二氧化硅纳米颗粒（MSNs）因其对公众的潜在风险而备受关注。人们对MSNs对生物化学代谢的影响了解甚少，而且很少有研究比较不同给药途径的MSNs的作用。为了评估MSNs的肝毒性，在小鼠静脉注射（20mg/kg/d）或口服（200mg/kg/d）MSNs 10天后进行了代谢组学、蛋白质组学和转录组学分析。病理检查显示静脉注射可引起明显的肝损伤，并增加AST/ALT水平以及炎症因子IL-6、IL-1β和TNF-α的水平。组学数据表明，静脉注射MSNs会干扰以下代谢物：琥珀酸、次黄嘌呤、GSSG、NADP+、NADPH和6-磷酸葡萄糖酸。此外，蛋白质组学和转录组学水平上GPX、SOD3、G6PD、HK和PFK的增加表明糖酵解和磷酸戊糖途径、谷胱甘肽和核苷酸的合成以及抗氧化途径活性增强，而氧化磷酸化、三羧酸循环（TCA）和线粒体能量代谢则降低。另一方面，口服MSNs会干扰与磷酸戊糖途径、谷胱甘肽合成和氧化应激相关的炎症因子以及磷酸核糖-5-磷酸、6-磷酸葡萄糖酸、GSSG和NADP+的代谢物，尽管给药剂量是静脉注射的10倍，但影响程度仍低于静脉注射。总体而言，系统生物学数据表明，静脉注射药物赋形剂纳米颗粒会显著影响肝脏代谢功能并诱导氧化应激和炎症，而口服给药的影响比静脉注射更轻微。
