Silver nanoparticles (nanosilver) are broadly used today in textiles, food packaging, household devices and bioapplications, prompting a better understanding of their toxicity and biological interactions. In particular, the cytotoxicity of nanosilver with respect to mammalian cells remains unclear, because such investigations can be biased by the nanosilver coatings and the lack of particle size control. Here, nanosilver of well-defined size (5.7 to 20.4 nm) supported on inert nanostructured silica is produced using flame aerosol technology. The cytotoxicity of the prepared nanosilver with respect to murine macrophages is assessed in vitro because these cells are among the first to confront nanosilver upon its intake by mammals. The silica support facilitates the dispersion and stabilization of the prepared nanosilver in biological suspensions, and no other coating or functionalization is applied that could interfere with the biointeractions of nanosilver. Detailed characterization of the particles by X-ray diffraction and electron microscopy reveals that the size of the nanosilver is well controlled. Smaller nanosilver particles release or leach larger fractions of their mass as Ag⁺ ions upon dispersion in water. This strongly influences the cytotoxicity of the nanosilver when incubated with murine macrophages. The size of the nanosilver dictates its mode of cytotoxicity (Ag⁺ ion-specific and/or particle-specific). The toxicity of small nanosilver (<10 nm) is mostly mediated by the released Ag⁺ ions. The influence of such ions on the toxicity of nanosilver decreases with increasing nanosilver size (>10 nm). Direct silver nanoparticle-macrophage interactions dominate the nanosilver toxicity at sizes larger than 10 nm.
Hydrogen peroxide (HO) is an abundant molecule associated with biological functions and reacts with natural enzymes, such as catalase. Even though direct HO measurement can be used to diagnose pathological conditions, such as infection and inflammation, HO quantification further enables the detection of disease biomarkers in enzyme-linked assays (e.g., ELISA) in which enzymatic reactions may generate or consume HO. Such a quantification is often measured optically with organic dyes in biological media that suffer, however, from poor stability. Currently, the optical HO biosensing without organic-dyes in biological media and at low, submicromolar, concentrations has yet to be achieved. Herein, we rationally design biomimetic artificial enzymes based on antioxidant CeO nanoparticles that become luminescent upon their Eu doping. We vary systematically their diameter from 4 to 16 nm and study their catalase-mimetic antioxidant activity, manifested as catalytic HO decomposition in aqueous solutions, revealing a strong nanoparticle surface area dependency. The interaction with HO influences distinctly the particle luminescence rendering them highly sensitive HO biosensors down to 0.15 μM (5.2 ppb) in solutions for biological assays. Our results link two, so far, unrelated research domains, the CeO nanoparticle antioxidant activity and luminescence by rare-earth doping. When these enzyme-mimetic nanoparticles are coupled with alcohol oxidase, biosensing can be extended to ethanol exemplifying how their detection potential can be broadened to additional biologically relevant metabolites. The enzyme-mimetic nanomaterial developed here could serve as a starting point of sophisticated in vitro assays toward the highly sensitive detection of disease biomarkers.
There is an increasing interest in using the zebrafish (Danio rerio) larva as a vertebrate screening model to study drug disposition. Since the pronephric kidney of zebrafish larvae shares high similarity with the anatomy of nephrons in higher vertebrates including humans, we explored in the present study whether 3 to 4 days old zebrafish larvae have a fully functional pronephron. Intravenous injection of fluorescent polyethylene glycol and dextran derivatives of different molecular weight revealed a cut-off of 4.4 to 7.6 nm in hydrodynamic diameter for passive glomerular filtration, which is in agreement with corresponding values in rodents and humans. Distal tubular reabsorption of a FITC-folate conjugate, covalently modified with PEG2000, via the folate receptor 1 was shown. Transport experiments of fluorescent substrates were assessed in the presence and absence of specific inhibitors in the blood systems. Thereby, functional expression in the proximal tubule of oat/slc22, mrp1/abcc1, mrp2/abcc2, mrp4/abcc4 and the zebrafish larvaes' p-glycoprotein analog abcb4 was shown. In addition, non-renal clearance of fluorescent substrates and plasmaprotein binding characteristics were assessed in vivo. Results of transporter studies were confirmed by extrapolation to ex vivo experiments in killifish (Fundulus heteroclitus) proximal kidney tubules. We conclude that the zebrafish larva has a fully functional pronephron at 96 hours post fertilization and is therefore an attractive translational vertebrate screening model to bridge the gap between cell culture-based test systems and pharmacokinetic experiments in higher vertebrates.
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