Günter Schmid

Gold Nanoparticles of Diameter 1.4 nm Trigger Necrosis by Oxidative Stress and Mitochondrial Damage

Gold nanoparticles (AuNPs) are generally considered nontoxic, similar to bulk gold, which is inert and biocompatible. AuNPs of diameter 1.4 nm capped with triphenylphosphine monosulfonate (TPPMS), Au1.4MS, are much more cytotoxic than 15-nm nanoparticles (Au15MS) of similar chemical composition. Here, major cell-death pathways are studied and it is determined that the cytotoxicity is caused by oxidative stress. Indicators of oxidative stress, reactive oxygen species (ROS), mitochondrial potential and integrity, and mitochondrial substrate reduction are all compromised. Genome-wide expression profiling using DNA gene arrays indicates robust upregulation of stress-related genes after 6 and 12 h of incubation with a 2 x IC50 concentration of Au1.4MS but not with Au15MS nanoparticles. The caspase inhibitor Z-VAD-fmk does not rescue the cells, which suggests that necrosis, not apoptosis, is the predominant pathway at this concentration. Pretreatment of the nanoparticles with reducing agents/antioxidants N-acetylcysteine, glutathione, and TPPMS reduces the toxicity of Au1.4MS. AuNPs of similar size but capped with glutathione (Au1.1GSH) likewise do not induce oxidative stress. Besides the size dependency of AuNP toxicity, ligand chemistry is a critical parameter determining the degree of cytotoxicity. AuNP exposure most likely causes oxidative stress that is amplified by mitochondrial damage. Au1.4MS nanoparticle cytotoxicity is associated with oxidative stress, endogenous ROS production, and depletion of the intracellular antioxidant pool.

Particle size-dependent and surface charge-dependent biodistribution of gold nanoparticles after intravenous administration

Gold nanoparticles (GNP) provide many opportunities in imaging, diagnostics, and therapies of nanomedicine. Hence, their biokinetics in the body are prerequisites for specific tailoring of nanomedicinal applications and for a comprehensive risk assessment. We administered (198)Au-radio-labelled monodisperse, negatively charged GNP of five different sizes (1.4, 5, 18, 80, and 200 nm) and 2.8 nm GNP with opposite surface charges by intravenous injection into rats. After 24h, the biodistribution of the GNP was quantitatively measured by gamma-spectrometry. The size and surface charge of GNP strongly determine the biodistribution. Most GNP accumulated in the liver increased from 50% of 1.4 nm GNP to >99% of 200 nm GNP. In contrast, there was little size-dependent accumulation of 18-200 nm GNP in most other organs. However, for GNP between 1.4 nm and 5 nm, the accumulation increased sharply with decreasing size; i.e. a linear increase with the volumetric specific surface area. The differently charged 2.8 nm GNP led to significantly different accumulations in several organs. We conclude that the alterations of accumulation in the various organs and tissues, depending on GNP size and surface charge, are mediated by dynamic protein binding and exchange. A better understanding of these mechanisms will improve drug delivery and dose estimates used in risk assessment.

Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration

Abstract It is of urgent need to identify the exact physico-chemical characteristics which allow maximum uptake and accumulation in secondary target organs of nanoparticulate drug delivery systems after oral ingestion. We administered radiolabelled gold nanoparticles in different sizes (1.4–200 nm) with negative surface charge and 2.8 nm nanoparticles with opposite surface charges by intra-oesophageal instillation into healthy adult female rats. The quantitative amount of the particles in organs, tissues and excrements was measured after 24 h by gamma-spectroscopy. The highest accumulation in secondary organs was mostly found for 1.4 nm particles; the negatively charged particles were accumulated mostly more than positively charged particles. Importantly, 18 nm particles show a higher accumulation in brain and heart compared to other sized particles. No general rule accumulation can be made so far. Therefore, specialized drug delivery systems via the oral route have to be individually designed, depending on the respective target organ.

Air-blood barrier translocation of tracheally instilled gold nanoparticles inversely depends on particle size.

Gold nanoparticles (AuNP) provide many opportunities in imaging, diagnostics, and therapy in nanomedicine. For the assessment of AuNP biokinetics, we intratracheally instilled into rats a suite of (198)Au-radio-labeled monodisperse, well-characterized, negatively charged AuNP of five different sizes (1.4, 2.8, 5, 18, 80, 200 nm) and 2.8 nm AuNP with positive surface charges. At 1, 3, and 24 h, the biodistribution of the AuNP was quantitatively measured by gamma-spectrometry to be used for comprehensive risk assessment. Our study shows that as AuNP get smaller, they are more likely to cross the air-blood barrier (ABB) depending strongly on the inverse diameter d(-1) of their gold core, i.e., their specific surface area (SSA). So, 1.4 nm AuNP (highest SSA) translocated most, while 80 nm AuNP (lowest SSA) translocated least, but 200 nm particles did not follow the d(-1) relation translocating significantly higher than 80 nm AuNP. However, relative to the AuNP that had crossed the ABB, their retention in most of the secondary organs and tissues was SSA-independent. Only renal filtration, retention in blood, and excretion via urine further declined with d(-1) of AuNP core. Translocation of 5, 18, and 80 nm AuNP is virtually complete after 1 h, while 1.4 nm AuNP continue to translocate until 3 h. Translocation of negatively charged 2.8 nm AuNP was significantly higher than for positively charged 2.8 nm AuNP. Our study shows that translocation across the ABB and accumulation and retention in secondary organs and tissues are two distinct processes, both depending specifically on particle characteristics such as SSA and surface charge.

Size dependent translocation and fetal accumulation of gold nanoparticles from maternal blood in the rat

BackgroundThere is evidence that nanoparticles (NP) cross epithelial and endothelial body barriers. We hypothesized that gold (Au) NP, once in the blood circulation of pregnant rats, will cross the placental barrier during pregnancy size-dependently and accumulate in the fetal organism by 1. transcellular transport across the hemochorial placenta, 2. transcellular transport across amniotic membranes 3. transport through ~20xa0nm wide transtrophoblastic channels in a size dependent manner. The three AuNP sizes used to test this hypothesis are either well below, or of similar size or well above the diameters of the transtrophoblastic channels.MethodsWe intravenously injected monodisperse, negatively charged, radio-labelled 1.4xa0nm, 18xa0nm and 80xa0nm 198AuNP at a mass dose of 5, 3 and 27xa0?g/rat, respectively, into pregnant rats on day 18 of gestation and in non-pregnant control rats and studied the biodistribution in a quantitative manner based on the radio-analysis of the stably labelled 198AuNP after 24xa0hours.ResultsWe observed significant biokinetic differences between pregnant and non-pregnant rats. AuNP fractions in the uterus of pregnant rats were at least one order of magnitude higher for each particle size roughly proportional to the enlarged size and weight of the pregnant uterus. All three sizes of 198AuNP were found in the placentas and amniotic fluids with 1.4xa0nm AuNP fractions being two orders of magnitude higher than those of the larger AuNP on a mass base. In the fetuses, only fractions of 0.0006 (30xa0ng) and 0.00004 (0.1xa0ng) of 1.4xa0nm and 18xa0nm AuNP, respectively, were detected, but no 80xa0nm AuNP (<0.000004 (<0.1xa0ng)). These data show that no AuNP entered the fetuses from amniotic fluids within 24xa0hours but indicate that AuNP translocation occurs across the placental tissues either through transtrophoblastic channels and/or via transcellular processes.ConclusionOur data suggest that the translocation of AuNP from maternal blood into the fetus is NP-size dependent which is due to mechanisms involving (1) transport through transtrophoblastic channels ¿ also present in the human placenta ¿ and/or (2) endocytotic and diffusive processes across the placental barrier.

ALUMINA MEMBRANES : TEMPLATES FOR NOVEL NANOCOMPOSITES

Three different examples have shown that nanoporous alumina membranes serve as ideal templates for the formation of nanostructured materials and also as a support of those materials in composites. The unique properties of such membranes (transparency, chemical resistivity, thermal stability, adjustable pore sizes etc.) and the very simple mode of generating these composites are the benefits of using this inorganic template material.

Differential hERG ion channel activity of ultrasmall gold nanoparticles

Understanding the mechanism of toxicity of nanomaterials remains a challenge with respect to both mechanisms involved and product regulation. Here we show toxicity of ultrasmall gold nanoparticles (AuNPs). Depending on the ligand chemistry, 1.4-nm-diameter AuNPs failed electrophysiology-based safety testing using human embryonic kidney cell line 293 cells expressing human ether-á-go-go-Related gene (hERG), a Food and Drug Administration-established drug safety test. In patch-clamp experiments, phosphine-stabilized AuNPs irreversibly blocked hERG channels, whereas thiol-stabilized AuNPs of similar size had no effect in vitro, and neither particle blocked the channel in vivo. We conclude that safety regulations may need to be reevaluated and adapted to reflect the fact that the binding modality of surface functional groups becomes a relevant parameter for the design of nanoscale bioactive compounds.

Chemical tailoring of the charging energy in metal cluster arrangements by use of bifunctional spacer molecules

The insertion of bifunctional spacer molecules into a three-dimensional arrangement of Pd561phen36O200 clusters leads to an increase of the charging energy from 0.02 eV to 0.05 eV, which was determined from the temperature dependence of the conductivity.

The diode behavior of asymmetrically ordered Au55 clusters.

Future nanoelectronic devices may well be based on an assembled monolayer of ligand-stabilized metal clusters, Au55 in this case: Irradiation of the monolayer with an electon beam generates diodic behavior. While the clusters themselves resist decomposition, the system exhibits interesting time-dependant electrical characteristics, as shown by the current-voltage curve.

Physical and Chemical Consequences of Size-Reduction of Gold: Bioresponse and Biodistribution

The article is dealing with the dependency of physical and chemical properties on size and coating of gold nanoparticles (Au NPs) and their potential in medicine. Full-shell clusters of the type Au55(PR3)12Cl6 are in the focal point due to their special properties. They act as quantum dots at room temperature and their stability is based on the perfect cuboctahedral structure. The bioresponse of the 1.4xa0nm Au55 clusters is, compared with smaller and larger Au NPs, very special, indicated by high cytotoxicity. It is caused by oxidative stress in cells accompanied by direct interactions with DNA. Biodistribution in Wistar–Kyoto rats differs also characteristically from larger Au NPs. Larger Au NPs, intravenously injected, assemble almost quantitatively in the liver, whereas Au55 clusters distribute over numerous other organs. All comparisons have been carried out by Au species with identical ligand molecules in order to have the same conditions concerning surface behaviour.