© 2016 Principi et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). International Journal of Nanomedicine 2016:11 4299–4316 International Journal of Nanomedicine Dovepress submit your manuscript | www.dovepress.com Dovepress 4299 OrIgINal research open access to scientific and medical research Open access Full Text article http://dx.doi.org/10.2147/IJN.S109950 systemic distribution of single-walled carbon nanotubes in a novel model: alteration of biochemical parameters, metabolic functions, liver accumulation, and infammation in vivo elisa Principi, 1, * rossana girardello, 2, * antonino Bruno, 1, * Isabella Manni, 3 elisabetta gini, 2 ari anna Pagani, 1 annalisa grimaldi, 2 Federico Ivaldi, 4 Terenzio congiu, 5 Daniela De stefano, 1 giulia Pia ggio, 3 Magda de eguil eor, 2 Douglas M Noonan, 1,2 adri ana albini 1 1 Vascular Biology and angiogenesis, scientific and Technology Pole, Irccs MultiMedi ca, Milano, 2 Department of Biotechnology and life sciences, University of Insubria, Varese, 3 Department of research, advanced Diagnosis and Innovation, regina el ena National cancer Institute, rome, 4 Department of Neuroscience, Ophthalmology and genetics, University of genoa, genoa, 5 Department of surgical and Morphological sciences, University of Insubria, Varese, Italy *These authors contributed equally to this work Abstract: The increasing use of carbon nanotubes (CNTs) in several industrial applications raises concerns on their potential toxicity due to factors such as tissue penetrance, small dimen- sions, and biopersistence. Using an in vivo model for CNT environmental exposure, mimicking CNT exposition at the workplace, we previously found that CNTs rapidly enter and disseminate in the organism, initially accumulating in the lungs and brain and later reaching the liver and kidneys via the bloodstream in CD1 mice. Here, we monitored and traced the accumulation of single-walled CNTs (SWCNTs), administered systemically in mice, in different organs and the subsequent biological responses. Using the novel in vivo model, MITO-Luc bioluminescence reporter mice, we found that SWCNTs induce systemic cell proliferation, indicating a dynamic response of cells of both bone marrow and the immune system. We then examined metabolic (water/food consumption and dejections), functional (serum enzymes), and morphological (organs and tissues) alterations in CD1 mice treated with SWCNTs, using metabolic cages, performing serum analyses, and applying histological, immunohistochemical, and ultrastruc- tural (transmission electron microscopy) methods. We observed a transient accumulation of SWCNTs in the lungs, spleen, and kidneys of CD1 mice exposed to SWCNTs. A dose- and time-dependent accumulation was found in the liver, associated with increases in levels of aspartate aminotransferase, alanine aminotransferase and bilirubinemia, which are metabolic markers associated with liver damage. Our data suggest that hepatic accumulation of SWCNTs associated with liver damage results in an M1 macrophage-driven inflammation. Keywords: single-walled carbon nanotubes, nanotoxicity, metabolism, hepatic function, inflammation, Kupffer cells, mouse models Introduction Given their unique chemical and physical properties, carbon nanotubes (CNTs) represent a class of nanoparticles widely used in several industrial settings. Single- walled CNTs (SWCNTs) are also of interest for their potential medical applications, 1 including in vivo delivery 2–4 of drugs, 5 proteins, peptides, 6–8 and nucleic acids 8 for gene transfer 9 or gene silencing. 6 In oncology, experimental studies have been focused on SWCNTs as a new tool to target tumor cells 10 for antineoplastic treatment of tumor angiogenesis and in vivo tumor imaging. 11 The small diameter, the relatively long length, and the biopersistence of CNTs have been linked to the structure of asbestos, suggesting extensive concerns on potential pulmonary health hazards. 12–17 CNT tissue accumulation, stability over long periods, final fate, and toxicological impact on health correspondence: Douglas M Noonan Scientifc and Technology Pole, IRCCS Multimedica, Via g. Fantoli 16/15, Milano 20138, Italy Tel +39 025 540 6532 Fax +39 332 21 7609 email douglas.noonan@uninsubria.it International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 3.236.55.199 on 18-Jun-2020 For personal use only. 1 / 1