title: Negligible particle-specific toxicity mechanism of silver nanoparticles: the role of Ag+ ion release in the cytosol.
abstract: Toxicity of silver nanoparticles (AgNPs) is supported by many observations in literature, but no mechanism details have been proved yet. Here we confirm and quantify the toxic potential of fully characterized AgNPs in HeLa and A549 cells. Notably, through a specific fluorescent probe, we demonstrate the intracellular release of Ag(+) ions in living cells after nanoparticle internalization, showing that in-situ particle degradation is promoted by the acidic lysosomal environment. The activation of metallothioneins in response to AgNPs and the possibility to reverse the main toxic pathway by Ag(+) chelating agents demonstrate a cause/effect relationship between ions and cell death. We propose that endocytosed AgNPs are degraded in the lysosomes and the release of Ag(+) ions in the cytosol induces cell damages, while ions released in the cell culture medium play a negligible effect. These findings will be useful to develop safer-by-design nanoparticles and proper regulatory guidelines of AgNPs. From the clinical editor: The authors describe the toxic potential of silver nanoparticles (AgNP) in human cancer cell lines. Cell death following the application of AgNPs is dose-dependent, and it is mostly due to Ag+ ions. Further in vivo studies should be performed to gain a comprehensive picture of AgNP-toxicity in mammals.
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: De Matteis
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Maria Ada
authors.initials: MA
authors.lastname: Malvindi
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Galeone
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Virgilio
authors.initials: V
authors.lastname: Brunetti
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: De Luca
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Sachin
authors.initials: S
authors.lastname: Kote
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Prakash
authors.initials: P
authors.lastname: Kshirsagar
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Sabella
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bardi
authors.affiliation: Istituto Italiano di Tecnologia, Center for Bio-Molecular Nanotechnologies@Unile, Arnesano (Lecce), Italy. Electronic address: pierpaolo.pompa@iit.it.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pompa
mesh_terms: D002414:Cations, Monovalent / Q000493:pharmacokinetics; D003600:Cytosol / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D053768:Metal Nanoparticles / Q000737:chemistry*; D012834:Silver / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D002414:Cations, Monovalent; D012834:Silver
keywords: Ion release; Nanoparticles; Silver; Toxicity