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In vivo human time-exposure study of orally dosed commercial silver nanoparticles.

ABSTRACT: Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receive increasing health assessment. We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content were determined. No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. No morphological changes were detected in the lungs, heart or abdominal organs. No significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation. In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems are warranted to assert human toxicity thresholds.In this study, the effects of commercially available nanoparticles were studied in healthy volunteers, concluding no detectable toxicity with the utilized comprehensive assays and tests. As the authors rightfully state, further studies are definitely warranted. Studies like this are much needed for the more widespread application of nanomedicine.

SUBMITTER: Munger MA

PROVIDER: S-EPMC3877176 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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In vivo human time-exposure study of orally dosed commercial silver nanoparticles.

Munger Mark A MA Radwanski Przemyslaw P Hadlock Greg C GC Stoddard Greg G Shaaban Akram A Falconer Jonathan J Grainger David W DW Deering-Rice Cassandra E CE

Nanomedicine : nanotechnology, biology, and medicine 20130628 1

Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receive increasing health assessment. We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content were determined. No clinically important changes in metabo ...[more]

PMID: 23811290

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Project description:Attaching affinity ligands to nanoparticles (NPs) increases selectivity for targeting cells and tissues, and can result in improved sensitivity and reduced off-target toxicity in diagnostic and therapeutic systems. The decision over key features - NP size, shape, coating strategies and targeting ligands for clinical translation is often hampered by a lack of quantitative in vivo NP homing assays. Sensitive, internally controlled assays are needed which allow for quantitative comparisons (auditions) among various formulations of targeted NPs. We recently reported the development of peptide-functionalized, isotopically-barcoded silver NPs (AgNPs) for ultrasensitive studies centered on measuring relative ratios of NP internalization into cultured cells. Here we evaluated the application of this technology for NP homing studies in live mice using peptides with previously described tissue tropism; one peptide that favors vascular beds of the normal lungs (RPARPAR; receptor neuropilin-1, or NRP-1) and another that is selective for central nervous system vessels (CAGALCY). Equimolar mixtures of the peptide-targeted Ag107-NPs and Ag109 control particles were mixed and injected intravenously. Distribution profiles of Ag107 and Ag109 in tissue extracts were determined simultaneously through inductively coupled plasma mass spectrometry (ICP-MS). Compared to non-targeted particles up to ?9-fold increased lung accumulation was seen for RPARPAR-OH AgNPs (but not for AgNPs functionalized with RPARPAR-NH2, which does not bind to NRP-1). Similarly, AgNPs functionalized with the brain-homing CAGALCY peptide were overrepresented in brain extracts. Spatial distribution (mapping) analysis by laser ablation ICP-MS (LA-ICP-MS) was used to determine the ratio Ag107/Ag109 in tissue cryosections. The mapping demonstrated preferential accumulation of the RPARPAR-AgNPs in the perivascular areas around pulmonary veins, and CAGALCY AgNPs accumulated in discrete areas of the brain (e.g. in the vessels of cerebellar fibrillary tracts). Based on these results, the internally controlled ratiometric AgNP system is suitable for quantitative studies of the effect of targeting ligands on NP biodistribution, at average tissue concentration and distribution at the microscopic level. The platform might be particularly relevant for target sites with high local variability in uptake, such as tumors.

Project description:BackgroundThe study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials.ResultsAgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver.ConclusionsThe results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules containing selenium and sulfur in the intestinal wall of rats exposed to either of the silver forms suggests a common mechanism of their formation. Additional studies however, are needed to gain further insight into the underlying mechanisms of the granule formation, and to clarify whether AgNPs dissolve in the gastrointestinal system and/or become absorbed and translocate as intact nanoparticles to organs and tissues.

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In vivo human time-exposure study of orally dosed commercial silver nanoparticles.

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In vivo human time-exposure study of orally dosed commercial silver nanoparticles.

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