5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Toxicity Mechanism of Low Doses of NaGdF 4:Yb 3+,Er 3+ Upconverting Nanoparticles in Activated Macrophage Cell Lines

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Gadolinium-doped nanoparticles (NPs) are regarded as promising luminescent probes. In this report, we studied details of toxicity mechanism of low doses of NaGdF 4-based fluorescent nanoparticles in activated RAW264.7, J774A.1 macrophages. These cell lines were specifically sensitive to the treatment with nanoparticles. Using nanoparticles of three different sizes, but with a uniform zeta potential (about −11 mV), we observed rapid uptake of NPs by the cells, resulting in the increased lysosomal compartment and subsequent superoxide induction along with a decrease in mitochondrial potential, indicating the impairment of mitochondrial homeostasis. At the molecular level, this led to upregulation of proapoptotic Bax and downregulation of anti-apoptotic Bcl-2, which triggered the apoptosis with phosphatidylserine externalization, caspase-3 activation and DNA fragmentation. We provide a time frame of the toxicity process by presenting data from different time points. These effects were present regardless of the size of nanoparticles. Moreover, despite the stability of NaGdF 4 nanoparticles at low pH, we identified cell acidification as an essential prerequisite of cytotoxic reaction using acidification inhibitors (NH 4Cl or Bafilomycin A1). Therefore, approaching the evaluation of the biocompatibility of such materials, one should keep in mind that toxicity could be revealed only in specific cells. On the other hand, designing gadolinium-doped NPs with increased resistance to harsh conditions of activated macrophage phagolysosomes should prevent NP decomposition, concurrent gadolinium release, and thus the elimination of its toxicity.

          Related collections

          Most cited references42

          • Record: found
          • Abstract: found
          • Article: not found

          Gadolinium-based Contrast Agent Accumulates in the Brain Even in Subjects without Severe Renal Dysfunction: Evaluation of Autopsy Brain Specimens with Inductively Coupled Plasma Mass Spectroscopy.

          To use inductively coupled plasma mass spectroscopy (ICP-MS) to evaluate gadolinium accumulation in brain tissues, including the dentate nucleus (DN) and globus pallidus (GP), in subjects who received a gadolinium-based contrast agent (GBCA).
            Bookmark
            • Record: found
            • Abstract: found
            • Article: found
            Is Open Access

            Different endocytotic uptake mechanisms for nanoparticles in epithelial cells and macrophages

            Summary Precise knowledge regarding cellular uptake of nanoparticles is of great importance for future biomedical applications. Four different endocytotic uptake mechanisms, that is, phagocytosis, macropinocytosis, clathrin- and caveolin-mediated endocytosis, were investigated using a mouse macrophage (J774A.1) and a human alveolar epithelial type II cell line (A549). In order to deduce the involved pathway in nanoparticle uptake, selected inhibitors specific for one of the endocytotic pathways were optimized regarding concentration and incubation time in combination with fluorescently tagged marker proteins. Qualitative immunolocalization showed that J774A.1 cells highly expressed the lipid raft-related protein flotillin-1 and clathrin heavy chain, however, no caveolin-1. A549 cells expressed clathrin heavy chain and caveolin-1, but no flotillin-1 uptake-related proteins. Our data revealed an impeded uptake of 40 nm polystyrene nanoparticles by J774A.1 macrophages when actin polymerization and clathrin-coated pit formation was blocked. From this result, it is suggested that macropinocytosis and phagocytosis, as well as clathrin-mediated endocytosis, play a crucial role. The uptake of 40 nm nanoparticles in alveolar epithelial A549 cells was inhibited after depletion of cholesterol in the plasma membrane (preventing caveolin-mediated endocytosis) and inhibition of clathrin-coated vesicles (preventing clathrin-mediated endocytosis). Our data showed that a combination of several distinguishable endocytotic uptake mechanisms are involved in the uptake of 40 nm polystyrene nanoparticles in both the macrophage and epithelial cell line.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Nanomaterial cytotoxicity is composition, size, and cell type dependent

              Background Despite intensive research efforts, reports of cellular responses to nanomaterials are often inconsistent and even contradictory. Additionally, relationships between the responding cell type and nanomaterial properties are not well understood. Using three model cell lines representing different physiological compartments and nanomaterials of different compositions and sizes, we have systematically investigated the influence of nanomaterial properties on the degrees and pathways of cytotoxicity. In this study, we selected nanomaterials of different compositions (TiO2 and SiO2 nanoparticles, and multi-wall carbon nanotubes [MWCNTs]) with differing size (MWCNTs of different diameters 50 nm; but same length 0.5-2 μm) to analyze the effects of composition and size on toxicity to 3T3 fibroblasts, RAW 264.7 macrophages, and telomerase-immortalized (hT) bronchiolar epithelial cells. Results Following characterization of nanomaterial properties in PBS and serum containing solutions, cells were exposed to nanomaterials of differing compositions and sizes, with cytotoxicity monitored through reduction in mitochondrial activity. In addition to cytotoxicity, the cellular response to nanomaterials was characterized by quantifying generation of reactive oxygen species, lysosomal membrane destabilization and mitochondrial permeability. The effect of these responses on cellular fate - apoptosis or necrosis - was then analyzed. Nanomaterial toxicity was variable based on exposed cell type and dependent on nanomaterial composition and size. In addition, nanomaterial exposure led to cell type dependent intracellular responses resulting in unique breakdown of cellular functions for each nanomaterial: cell combination. Conclusions Nanomaterials induce cell specific responses resulting in variable toxicity and subsequent cell fate based on the type of exposed cell. Our results indicate that the composition and size of nanomaterials as well as the target cell type are critical determinants of intracellular responses, degree of cytotoxicity and potential mechanisms of toxicity.
                Bookmark

                Author and article information

                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                03 January 2019
                January 2019
                : 9
                : 1
                : 14
                Affiliations
                [1 ]Hirszfeld Institute of Immunology and Experimental Therapy, PAS, 53-114 Wroclaw, Poland; edyta.wysokinska@ 123456iitd.pan.wroc.pl (E.W.); strzadal@ 123456iitd.pan.wroc.pl (L.S.)
                [2 ]Faculty of Chemistry, University of Wroclaw, 50-383 Wroclaw, Poland; jakub.cichos@ 123456chem.uni.wroc.pl (J.C.); miroslaw.karbowiak@ 123456chem.uni.wroc.pl (M.K.)
                [3 ]PORT Polish Center for Technology Development, 54-066 Wroclaw, Poland; Agnieszka.Kowalczyk@ 123456eitplus.pl (A.K.); Artur.Bednarkiewicz@ 123456eitplus.pl (A.B.)
                Author notes
                [* ]Correspondence: kalas@ 123456iitd.pan.wroc.pl ; Tel.: +48-071-3709939
                Author information
                https://orcid.org/0000-0003-0202-5271
                Article
                biomolecules-09-00014
                10.3390/biom9010014
                6359000
                30609856
                e23681eb-47d6-480e-b8a5-523a81c681e4
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 November 2018
                : 21 December 2018
                Categories
                Article

                gadolinium,nanoparticles,upconversion,macrophages,lanthanides,fluorescent,toxicity,cytotoxicity,mitochondria,contrast agents

                Comments

                Comment on this article