title: Tissue distribution and acute toxicity of silver after single intravenous administration in mice: nano-specific and size-dependent effects.
abstract: BACKGROUND
  Silver nanoparticles (AgNPs) are an important class of nanomaterials used as antimicrobial agents for a wide range of medical and industrial applications. However toxicity of AgNPs and impact of their physicochemical characteristics in in vivo models still need to be comprehensively characterized. The aim of this study was to investigate the effect of size and coating on tissue distribution and toxicity of AgNPs after intravenous administration in mice, and compare the results with those obtained after silver acetate administration.
  
  
  METHODS
  Male CD-1(ICR) mice were intravenously injected with AgNPs of different sizes (10 nm, 40 nm, 100 nm), citrate-or polyvinylpyrrolidone-coated, at a single dose of 10 mg/kg bw. An equivalent dose of silver ions was administered as silver acetate. Mice were euthanized 24 h after the treatment, and silver quantification by ICP-MS and histopathology were performed on spleen, liver, lungs, kidneys, brain, and blood.
  
  
  RESULTS
  For all particle sizes, regardless of their coating, the highest silver concentrations were found in the spleen and liver, followed by lung, kidney, and brain. Silver concentrations were significantly higher in the spleen, lung, kidney, brain, and blood of mice treated with 10 nm AgNPs than those treated with larger particles. Relevant toxic effects (midzonal hepatocellular necrosis, gall bladder hemorrhage) were found in mice treated with 10 nm AgNPs, while in mice treated with 40 nm and 100 nm AgNPs lesions were milder or negligible, respectively. In mice treated with silver acetate, silver concentrations were significantly lower in the spleen and lung, and higher in the kidney than in mice treated with 10 nm AgNPs, and a different target organ of toxicity was identified (kidney).
  
  
  CONCLUSIONS
  Administration of the smallest (10 nm) nanoparticles resulted in enhanced silver tissue distribution and overt hepatobiliary toxicity compared to larger ones (40 and 100 nm), while coating had no relevant impact. Distinct patterns of tissue distribution and toxicity were observed after silver acetate administration. It is concluded that if AgNPs become systemically available, they behave differently from ionic silver, exerting distinct and size-dependent effects, strictly related to the nanoparticulate form.
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. camilla.recordati@gmail.com.
authors.forename: Camilla
authors.initials: C
authors.lastname: Recordati
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. marcella.demaglie@unimi.it.|Dipartimento di Scienze Veterinarie e Sanità Pubblica (DIVET), Università degli Studi di Milano, 20133, Milan, Italy. marcella.demaglie@unimi.it.
authors.forename: Marcella
authors.initials: M
authors.lastname: De Maglie
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. bianchessi.silvia@hsr.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bianchessi
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. simona.argentiere@fondazionefilarete.com.
authors.forename: Simona
authors.initials: S
authors.lastname: Argentiere
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. claudia.cella@unimi.it.|Dipartimento di Fisica, Università degli Studi di Milano, 20133, Milan, Italy. claudia.cella@unimi.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cella
authors.affiliation: Dipartimento di Scienze Veterinarie e Sanità Pubblica (DIVET), Università degli Studi di Milano, 20133, Milan, Italy. silvana.mattiello@unimi.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Mattiello
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità - National Health Institute, 00161, Rome, Italy. francesco.cubadda@iss.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cubadda
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità - National Health Institute, 00161, Rome, Italy. federica.aureli@iss.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Aureli
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità - National Health Institute, 00161, Rome, Italy. marilena.damato@iss.it.
authors.forename: Marilena
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Department of Food Safety and Veterinary Public Health, Istituto Superiore di Sanità - National Health Institute, 00161, Rome, Italy. andrea.raggi@iss.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Raggi
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. cristina.lenardi@mi.infn.it.|Dipartimento di Fisica, Università degli Studi di Milano, 20133, Milan, Italy. cristina.lenardi@mi.infn.it.|Centro Interdisciplinare Materiali e Interfacce Nanostrutturati (CIMAINA), Università degli Studi di Milano, 20133, Milan, Italy. cristina.lenardi@mi.infn.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Lenardi
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. paolo.milani@mi.infn.it.|Dipartimento di Fisica, Università degli Studi di Milano, 20133, Milan, Italy. paolo.milani@mi.infn.it.|Centro Interdisciplinare Materiali e Interfacce Nanostrutturati (CIMAINA), Università degli Studi di Milano, 20133, Milan, Italy. paolo.milani@mi.infn.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Milani
authors.affiliation: Fondazione Filarete, 20139, Milan, Italy. eugenio.scanziani@unimi.it.|Dipartimento di Scienze Veterinarie e Sanità Pubblica (DIVET), Università degli Studi di Milano, 20133, Milan, Italy. eugenio.scanziani@unimi.it.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Scanziani
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D019343:Citric Acid / Q000737:chemistry; D005705:Gallbladder Diseases / Q000139:chemically induced / Q000473:pathology; D006470:Hemorrhage / Q000139:chemically induced / Q000473:pathology; D007275:Injections, Intravenous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D053758:Nanoparticles; D009336:Necrosis; D010316:Particle Size; D011205:Povidone / Q000737:chemistry; D018570:Risk Assessment; D012834:Silver / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D018030:Silver Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity; D013154:Spleen / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D000085:Acetates; D018030:Silver Compounds; C103100:silver acetate; D019343:Citric Acid; D012834:Silver; D011205:Povidone