RESUMEN
Gold (Au) can be deposited as nanoparticles (NPs) smaller than 10 nm in diameter on a variety of metal oxide (MOx) NPs. Au/MOx have high catalytic performance and selective oxidation capacity which could have implications in terms of biological activity, and more specifically in modulation of the inflammatory reaction. Therefore, the aim of this study was to examine the effect of Au/TiO2, Au/ZrO2 and Au/CeO2 on viability, phagocytic capacity and inflammatory profile (TNF-α and IL-1ß secretion) of murine macrophages. The most important result of this study is an anti-inflammatory effect of Au/MOx depending on the MOx nature with particle internalization and no alteration of cell viability and phagocytosis. The effect was dependent on the MOx NPs chemical nature (Au/TiO2 > Au/ZrO2 > Au/CeO2 if we consider the number of cytokines whose concentration was reduced by the NPs), and on the inflammatory mediator considered. The effect of Au/TiO2 NPs was not related to Au NPs size (at least in the case of Au/TiO2 NPs in the range of 3-8 nm). To the best of our knowledge, this is the first demonstration of an anti-inflammatory effect of Au/MOx.
Asunto(s)
Antiinflamatorios/farmacología , Oro , Macrófagos/efectos de los fármacos , Nanopartículas del Metal/química , Óxidos/química , Adsorción , Animales , Biotecnología , Supervivencia Celular , Inflamación , Lipopolisacáridos , Macrófagos Peritoneales , Metales , Ratones , Ratones Endogámicos C57BL , Nanomedicina , Nanotecnología , Oxígeno/química , Tamaño de la Partícula , Fagocitosis , Células RAW 264.7 , Titanio/químicaRESUMEN
The in vivo fate and biodegradability of carbon nanotubes is still a matter of debate despite tremendous applications. In this paper we describe a molecular pathway by which macrophages degrade functionalized multi-walled carbon nanotubes (CNTs) designed for biomedical applications and containing, or not, iron oxide nanoparticles in their inner cavity. Electron microscopy and Raman spectroscopy show that intracellularly-induced structural damages appear more rapidly for iron-free CNTs in comparison to iron-loaded ones, suggesting a role of iron in the degradation mechanism. By comparing the molecular responses of macrophages derived from THP1 monocytes to both types of CNTs, we highlight a molecular mechanism regulated by Nrf2/Bach1 signaling pathways to induce CNT degradation via NOX2 complex activation and O2â¢-, H2O2 and OH⢠production. CNT exposure activates an oxidative stress-dependent production of iron via Nrf2 nuclear translocation, Ferritin H and Heme oxygenase 1 translation. Conversely, Bach1 was translocated to the nucleus of cells exposed to iron-loaded CNTs to recycle embedded iron. Our results provide new information on the role of oxidative stress, iron metabolism and Nrf2-mediated host defence for regulating CNT fate in macrophages.
RESUMEN
Despite numerous applications, the cellular-clearance mechanism of multiwalled carbon nanotubes (MWCNTs) has not been clearly established yet. Previous in vitro studies showed the ability of oxidative enzymes to induce nanotube degradation. Interestingly, these enzymes have the common capacity to produce reactive oxygen species (ROS). Here, we combined material and life science approaches for revealing an intracellular way taken by macrophages to degrade carbon nanotubes. We report the in situ monitoring of ROS-mediated MWCNT degradation by liquid-cell transmission electron microscopy. Two degradation mechanisms induced by hydroxyl radicals were extracted from these unseen dynamic nanoscale investigations: a non-site-specific thinning process of the walls and a site-specific transversal drilling process on pre-existing defects of nanotubes. Remarkably, similar ROS-induced structural injuries were observed on MWCNTs after aging into macrophages from 1 to 7 days. Beside unraveling oxidative transformations of MWCNT structure, we elucidated an important, albeit not exclusive, biological pathway for MWCNT degradation in macrophages, involving NOX2 complex activation, superoxide production, and hydroxyl radical attack, which highlights the critical role of oxidative stress in cellular processing of MWCNTs.
Asunto(s)
Macrófagos/metabolismo , Nanotubos de Carbono/análisis , Especies Reactivas de Oxígeno/metabolismo , Animales , Línea Celular , Humanos , Macrófagos/efectos de los fármacos , Masculino , Glicoproteínas de Membrana/metabolismo , NADPH Oxidasa 2 , NADPH Oxidasas/metabolismo , Nanotubos de Carbono/toxicidad , Nanotubos de Carbono/ultraestructura , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
Safe implementation of nanotechnology and nanomedicine requires an in-depth understanding of the life cycle of nanoparticles in the body. Here, we investigate the long-term fate of gold/iron oxide heterostructures after intravenous injection in mice. We show these heterostructures degrade in vivo and that the magnetic and optical properties change during the degradation process. These particles eventually eliminate from the body. The comparison of two different coating shells for heterostructures, amphiphilic polymer or polyethylene glycol, reveals the long lasting impact of initial surface properties on the nanocrystal degradability and on the kinetics of elimination of magnetic iron and gold from liver and spleen. Modulation of nanoparticles reactivity to the biological environment by the choice of materials and surface functionalization may provide new directions in the design of multifunctional nanomedicines with predictable fate.
Asunto(s)
Envejecimiento/fisiología , Materiales Biocompatibles Revestidos/farmacocinética , Portadores de Fármacos/farmacocinética , Compuestos Férricos/farmacocinética , Oro/farmacocinética , Nanopartículas de Magnetita/análisis , Alquenos/química , Animales , Materiales Biocompatibles Revestidos/química , Portadores de Fármacos/química , Compuestos Férricos/química , Oro/química , Inyecciones Intravenosas , Hígado/metabolismo , Hígado/ultraestructura , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/ultraestructura , Anhídridos Maleicos/química , Ratones , Ratones Endogámicos C57BL , Nanomedicina/instrumentación , Nanomedicina/métodos , Polietilenglicoles/química , Polímeros/química , Bazo/metabolismo , Bazo/ultraestructura , Electricidad Estática , Propiedades de SuperficieRESUMEN
Titanium dioxide (TiO2) nanoparticles are used in many applications. Due to their small size, easy body penetration and toxicological adverse effects have been suspected. Numerous studies have tried to characterize TiO2 translocation after oral, dermal or respiratory exposure. In this study, we focused on TiO2 nanoparticle biodistribution, clearance and toxicological effects after intravenous injection, considering TiO2 translocation in the blood occurs. Using ICP-OES, transmission electron microscopy, and histological methods, we found TiO2 accumulation in liver, lungs and spleen. We estimated TiO2 nanoparticles' half life in the body to about 10 days. Clinical biomarkers were also quantified for 56 days to identify potential toxicological impact on lungs, blood, liver, spleen and kidneys. Results showed absence of toxicological effects after TiO2 intravenous injection at concentrations of 7.7 to 9.4 mg/kg.
Asunto(s)
Nanopartículas del Metal/administración & dosificación , Titanio/administración & dosificación , Titanio/farmacocinética , Animales , Microanálisis por Sonda Electrónica , Semivida , Inyecciones Intravenosas , Masculino , Nanopartículas del Metal/toxicidad , Nanopartículas del Metal/ultraestructura , Microscopía Electrónica de Transmisión , Modelos Biológicos , Tamaño de la Partícula , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Titanio/toxicidadRESUMEN
With the fast development of noninvasive diagnosis, the design of multimodal imaging probes has become a promising challenge. If many monofunctional nanocarriers have already proven their efficiency, only few multifunctional nanoprobes have been able to combine the advantages of diverse imaging modalities. An innovative nanoprobe called mesoporous persistent luminescence magnetic nanohybrids (MPNHs) is described that shows both optical and magnetic resonance imaging (MRI) properties intended for in vivo multimodal imaging in small animals. MPNHs are based on the assembly of chromium-doped zinc gallate oxide and ultrasmall superparamagnetic iron oxide nanoparticles embedded in a mesoporous silica shell. MPNHs combine the optical advantages of persistent luminescence, such as real time imaging with highly sensitive and photostable detection, and MRI negative contrast properties that ensure in vivo imaging with rather high spatial resolution. In addition to their imaging capabilities, these MPNHs can be motioned in vitro with a magnet, which opens multiple perspectives in magnetic vectorization and cell therapy research.
Asunto(s)
Medios de Contraste/síntesis química , Mediciones Luminiscentes/métodos , Imagen por Resonancia Magnética/métodos , Nanopartículas de Magnetita/química , Imagen Multimodal/métodos , Imagen de Cuerpo Entero/métodos , Animales , Diseño de Fármacos , Nanopartículas de Magnetita/ultraestructura , Ratones , Ratones Endogámicos BALB C , Especificidad de Órganos , Tamaño de la Partícula , Distribución TisularRESUMEN
Structure and composition at the nanoscale determine the behavior of biological systems and engineered materials. The drive to understand and control this behavior has placed strong demands on developing methods for high resolution imaging. In general, the improvement of three-dimensional (3D) resolution is accomplished by tightening constraints: reduced manageable specimen sizes, decreasing analyzable volumes, degrading contrasts, and increasing sample preparation efforts. Aiming to overcome these limitations, we present a non-destructive and multiple-contrast imaging technique, using principles of X-ray laminography, thus generalizing tomography towards laterally extended objects. We retain advantages that are usually restricted to 2D microscopic imaging, such as scanning of large areas and subsequent zooming-in towards a region of interest at the highest possible resolution. Our technique permits correlating the 3D structure and the elemental distribution yielding a high sensitivity to variations of the electron density via coherent imaging and to local trace element quantification through X-ray fluorescence. We demonstrate the method by imaging a lithographic nanostructure and an aluminum alloy. Analyzing a biological system, we visualize in lung tissue the subcellular response to toxic stress after exposure to nanotubes. We show that most of the nanotubes are trapped inside alveolar macrophages, while a small portion of the nanotubes has crossed the barrier to the cellular space of the alveolar wall. In general, our method is non-destructive and can be combined with different sample environmental or loading conditions. We therefore anticipate that correlative X-ray nano-laminography will enable a variety of in situ and in operando 3D studies.
Asunto(s)
Electrones , Imagenología Tridimensional/métodos , Macrófagos Alveolares/ultraestructura , Imagen Molecular/métodos , Nanotubos de Carbono/ultraestructura , Alveolos Pulmonares/ultraestructura , Tomografía Computarizada por Rayos X/métodos , Aleaciones , Animales , Bovinos , Fluorescencia , Imagenología Tridimensional/instrumentación , Imagen Molecular/instrumentación , Nanotecnología , Ratas , Tomografía Computarizada por Rayos X/instrumentación , Rayos XRESUMEN
The long term outcome of nanoparticles in the organism is one of the most important concerns raised by the development of nanotechnology and nanomedicine. Little is known on the way taken by cells to process and degrade nanoparticles over time. In this context, iron oxide superparamagnetic nanoparticles benefit from a privileged status, because they show a very good tolerance profile, allowing their clinical use for MRI diagnosis. It is generally assumed that the specialized metabolism which regulates iron in the organism can also handle iron oxide nanoparticles. However the biotransformation of iron oxide nanoparticles is still not elucidated. Here we propose a multiscale approach to study the fate of nanomagnets in the organism. Ferromagnetic resonance and SQUID magnetization measurements are used to quantify iron oxide nanoparticles and follow the evolution of their magnetic properties. A nanoscale structural analysis by electron microscopy complements the magnetic follow-up of nanoparticles injected to mice. We evidence the biotransformation of superparamagnetic maghemite nanoparticles into poorly-magnetic iron species probably stored into ferritin proteins over a period of three months. A putative mechanism is proposed for the biotransformation of iron-oxide nanoparticles.
Asunto(s)
Compuestos Férricos/química , Compuestos Férricos/metabolismo , Nanopartículas/química , Animales , Espectroscopía de Resonancia por Spin del Electrón , Masculino , Ratones , Microscopía Electrónica de Transmisión , Nanopartículas/ultraestructuraRESUMEN
BACKGROUND: Constituted only by carbon atoms, CNT are hydrophobic and hardly detectable in biological tissues. These properties make biokinetics and toxicology studies more complex. METHODS: We propose here a method to investigate the biopersistence of CNT in organism, based on detection of nickel, a metal present in the MWCNT we investigated. RESULTS AND CONCLUSION: Our results in rats that received MWCNT by intratracheal instillation, reveal that MWCNT can be eliminated and do not significantly cross the pulmonary barrier but are still present in lungs 6 months after a unique instillation. MWCNT structure was also showed to be chemically modified and cleaved in the lung. These results provide the first data of CNT biopersistence and clearance at 6 months after respiratory administration.