ABSTRACT
BACKGROUND: Understanding the in vivo size-dependent pharmacokinetics and toxicity of nanoparticles is crucial to determine their successful development. Systematic studies on the size-dependent biological effects of nanoparticles not only help to unravel unknown toxicological mechanism but also contribute to the possible biological applications of nanomaterial. METHODS: In this study, the biodistribution and the size-dependent biological effects of Fe3O4@SiO2-NH2 nanoparticles (Fe@Si-NPs) in three diameters (10, 20 and 40 nm) were investigated by ICP-AES, serum biochemistry analysis and NMR-based metabolomic analysis after intravenous administration in a rat model. RESULTS: Our findings indicated that biodistribution and biological activities of Fe@Si-NPs demonstrated the obvious size-dependent and tissue-specific effects. Spleen and liver are the target tissues of Fe@Si-NPs, and 20 nm of Fe@Si-NPs showed a possible longer blood circulation time. Quantitative biochemical analysis showed that the alterations of lactate dehydrogenase (LDH) and uric acid (UA) were correlated to some extent with the sizes of Fe@Si-NPs. The untargeted metabolomic analyses of tissue metabolomes (kidney, liver, lung, and spleen) indicated that different sizes of Fe@Si-NPs were involved in the different biochemical mechanisms. LDH, formate, uric acid, and GSH related metabolites were suggested as sensitive indicators for the size-dependent toxic effects of Fe@Si-NPs. The findings from serum biochemical analysis and metabolomic analysis corroborate each other. Thus we proposed a toxicity hypothesis that size-dependent NAD depletion may occur in vivo in response to nanoparticle exposure. To our knowledge, this is the first report that links size-dependent biological effects of nanoparticles with in vivo NAD depletion in rats. CONCLUSION: The integrated metabolomic approach is an effective tool to understand physiological responses to the size-specific properties of nanoparticles. Our results can provide a direction for the future biological applications of Fe@Si-NPs.
Subject(s)
Magnetite Nanoparticles/chemistry , Magnetite Nanoparticles/toxicity , Silicon Dioxide/chemistry , Administration, Intravenous , Animals , Kidney/metabolism , L-Lactate Dehydrogenase/metabolism , Liver/metabolism , Lung/metabolism , Male , Metabolome , Metabolomics , Particle Size , Rats , Rats, Sprague-Dawley , Spleen/metabolism , Tissue Distribution , Uric Acid/metabolismABSTRACT
Core-shell structured Fe3O4@SiO2-NH2 nanoparticles (Fe@Si-NPs) demonstrated outstanding potentials in drug targeting and delivery and medical imaging. However, they have limited clinical applications due to unknown chronic bio-effects and potential bio-related risks. In this study, the subchronic biological effects and metabolic fate of 20 nm Fe@Si-NPs in Sprague-Dawley rats in 12 weeks were investigated by the biochemical assay and NMR-based metabonomic analysis using an intravenous model. Biofluids (plasma and urine) analysis provided the transportation, absorption, and excretion information of Fe@Si-NPs. Urine metabonome displayed a metabolic recovery while self-regulation of plasma metabonome leaded to the parallel metabolic trends between dosed and control groups in 12 weeks. And biological tissues (spleen, liver, kidney, and lung) analysis indicated liver and spleen are the targeted-organs of Fe@Si-NPs. The obvious metabolic variations responding to the biodistribution were induced by Fe@Si-NPs although no visible toxic effects were observed in these tissues. Besides the common energy metabolism response to the xenobiotics, Fe@Si-NPs also disturbed the metabolic pathways in glycerophospholipid and sphingolipid metabolism, metabolisms of purine, pyrimidine, and nicotinate. Our results provide preliminary validation for the potential use of Fe@Si-NPs in clinical medicine and give identifiable ground for the dose selection and bio-nanoagent optimization.
Subject(s)
Magnetite Nanoparticles/toxicity , Nanoparticles/toxicity , Silicon Dioxide/toxicity , Animals , Metabolomics/methods , Rats , Rats, Sprague-Dawley , Silicon Dioxide/metabolism , Tissue DistributionABSTRACT
BACKGROUND: Core-shell-structured nanoparticles (NPs) have attracted much scientific attention due to their promising potential in biomedical fields in recent years. However, their underlying mechanisms of action and potential adverse effects following administration remain unknown. METHODS: In the present study, a 1H nuclear magnetic resonance-based metabonomic strategy was applied to investigate the metabolic consequences in rats following the intravenous administration of parent NPs of core-shell-structured nanoparticles, Fe3O4@SiO2-NH2 (Fe@Si) NPs. RESULTS: Alterations reflected in plasma and urinary metabonomes indicated that Fe@Si NPs induced metabolic perturbation in choline, ketone-body, and amino-acid metabolism besides the common metabolic disorders in tricarboxylic acid cycle, lipids, and glycogen metabolism often induced by the exogenous agents. Additionally, intestinal flora metabolism and the urea cycle were also influenced by Fe@Si NP exposure. Time-dependent biological effects revealed obvious metabolic regression, dose-dependent biological effects implied different biochemical mechanisms between low- and high-dose Fe@Si NPs, and size-dependent biological effects provided potential windows for size optimization. CONCLUSION: Nuclear magnetic resonance-based metabonomic analysis helps in understanding the biological mechanisms of Fe@Si NPs, provides an identifiable ground for the selection of view windows, and further serves the clinical translation of Fe@Si NP-derived and -modified bioprobes or bioagents.
