The dissolution of citrate-stabilized and poly(vinylpyrrolidone)-stabilized silver nanoparticles in water was studied by dialysis for up to 125 days at 5, 25, and 37 °C. The particles slowly dissolve into ions on a time scale of several days. However, in all cases, a limiting value of the released silver was observed, i.e., the particles did not completely dissolve. In some cases, the nanoparticles released up to 90% of their weight. Formal kinetic data were computed. Rate and degree of dissolution depended on the functionalization as well as on the storage temperature. The release of silver led to a considerably increased toxicity of silver nanoparticles which had been stored in dispersion for several weeks toward human mesenchymal stem cells due to the increased concentration of silver ions. Consequently, "aged" (i.e., immersed) silver nanoparticles are much more toxic to cells than freshly prepared silver nanoparticles.

Silver ions and silver nanoparticles have a well-known biological effect that typically occurs in biological or environmental media of complex composition. Silver nanoparticles release silver ions if oxidizing species like molecular oxygen or hydrogen peroxide are present. The presence of glucose as a model for reducing sugars has only a small effect on the dissolution rate. In the presence of chloride ions, precipitation of silver chloride nanoparticles occurs. At physiological salt concentrations, no precipitation of silver phosphate occurs as the precipitation of silver chloride always occurs first. If the surface of a silver nanoparticle is passivated by cysteine, the dissolution is quantitatively inhibited. Upon immersion of silver nanoparticles in pure water for 8 months, leading to about 50% dissolution, no change in the surface was observed by transmission electron microscopy. A model for the dissolution was derived from immersion and dissolution experiments in different media and from high-resolution transmission electron microscopy. A literature survey on the available data on the dissolution of silver nanoparticles showed that only qualitative trends can be identified as the nature of the nanoparticles and of the immersion medium are practically never comparable. The dissolution effects were confirmed by cell culture experiments (human mesenchymal stem cells and neutrophil granulocytes) where silver nanoparticles that were stored under argon had a clearly lower cytotoxicity than those stored under air.They also led to a less formation of reactive oxygen species (ROS). This underscores that silver ions are the toxic species.

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Silver is commonly used both in ionic form and in nanoparticulate form as a bactericidal agent. This is generally ascribed to a higher toxicity towards prokaryotic cells than towards mammalian cells. Comparative studies with both silver ions (such as silver acetate) and polyvinylpyrrolidone (PVP)stabilized silver nanoparticles (70 nm) showed that the toxic effect of silver occurs in a similar concentration range for Escherichia coli, Staphylococcus aureus, human mesenchymal stem cells (hMSCs), and peripheral blood mononuclear cells (PBMCs), i.e. 0.5 to 5 ppm for silver ions and 12.5 to 50 ppm for silver nanoparticles. For a better comparison, bacteria were cultivated both in Lysogeny broth medium (LB) and in Roswell Park Memorial Institute medium (RPMI)/10% fetal calf serum (FCS) medium, as the state of silver ions and silver nanoparticles may be different due to the presence of salts, and biomolecules like proteins. The effective toxic concentration of silver towards bacteria and human cells is almost the same. Experimental Preparation of silver acetate solutionsSilver acetate (Sigma-Aldrich; ReagentPlus 1 , 99%) was dissolved in ultrapure water, prepared with an ELGA PURELAB Ultra (ELGA Labwater, Germany) instrument.

Spherical silver nanoparticles with a diameter of 50 AE 20 nm and stabilized with either poly(N-vinylpyrrolidone) (PVP) or citrate were dispersed in different cell culture media: (i) pure RPMI, (ii) RPMI containing up to 10% of bovine serum albumin (BSA), and (iii) RPMI containing up to 10% of fetal calf serum (FCS). The agglomeration behavior of the nanoparticles was studied with dynamic light scattering and optical microscopy of individually tracked single particles. Whereas strong agglomeration was observed in pure RPMI and in the RPMI-BSA mixture within a few hours, the particles remained well dispersed in RPMI-FCS. In addition, the biological effect of PVP-stabilized silver nanoparticles and of silver ions on human mesenchymal stem cells (hMSCs) was studied in pure RPMI and also in RPMI-BSA and RPMI-FCS mixtures, respectively. Both proteins considerably increased the cell viability in the presence of silver ions and as well as silver nanoparticles, indicating a binding of silver by these proteins.

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SummaryPVP-capped silver nanoparticles with a diameter of the metallic core of 70 nm, a hydrodynamic diameter of 120 nm and a zeta potential of −20 mV were prepared and investigated with regard to their biological activity. This review summarizes the physicochemical properties (dissolution, protein adsorption, dispersability) of these nanoparticles and the cellular consequences of the exposure of a broad range of biological test systems to this defined type of silver nanoparticles. Silver nanoparticles dissolve in water in the presence of oxygen. In addition, in biological media (i.e., in the presence of proteins) the surface of silver nanoparticles is rapidly coated by a protein corona that influences their physicochemical and biological properties including cellular uptake. Silver nanoparticles are taken up by cell-type specific endocytosis pathways as demonstrated for hMSC, primary T-cells, primary monocytes, and astrocytes. A visualization of particles inside cells is possible by X-ray microscopy, fluorescence microscopy, and combined FIB/SEM analysis. By staining organelles, their localization inside the cell can be additionally determined. While primary brain astrocytes are shown to be fairly tolerant toward silver nanoparticles, silver nanoparticles induce the formation of DNA double-strand-breaks (DSB) and lead to chromosomal aberrations and sister-chromatid exchanges in Chinese hamster fibroblast cell lines (CHO9, K1, V79B). An exposure of rats to silver nanoparticles in vivo induced a moderate pulmonary toxicity, however, only at rather high concentrations. The same was found in precision-cut lung slices of rats in which silver nanoparticles remained mainly at the tissue surface. In a human 3D triple-cell culture model consisting of three cell types (alveolar epithelial cells, macrophages, and dendritic cells), adverse effects were also only found at high silver concentrations. The silver ions that are released from silver nanoparticles may be harmful to skin with disrupted barrier (e.g., wounds) and induce oxidative stress in skin cells (HaCaT). In conclusion, the data obtained on the effects of this well-defined type of silver nanoparticles on various biological systems clearly demonstrate that cell-type specific properties as well as experimental conditions determine the biocompatibility of and the cellular responses to an exposure with silver nanoparticles.