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, 200nm) and 2.8nm GNP with opposite surface charges by intravenous injection into rats. After 24 h 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 1.4nm GNP to > 99% of 200nm GNP. In contrast, there was little size dependent accumulation of 18nm to 200nm GNP in most other organs. However, for GNP between 1.4nm and 5nm the accumulation increased sharply with decreasing size; i.e. a linear increase with the volumetric specific surface area. The differently charged 2.8nm 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.

1.4‐nm gold nanoparticles (NPs) are observed to cross the air/blood barrier of the lungs much more efficiently than 18‐nm gold NPs (see figure). The NP accumulation pattern in the secondary‐target organs differs strongly from those seen after direct intravenous injection. From this, it is hypothesized that NPs interact dynamically with proteins and cells, which determines their accumulation in the various organs.

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Inorganic nanoparticles are frequently engineered with an organic surface coating to improve their physicochemical properties, and it is well known that their colloidal properties may change upon internalization by cells. While the stability of such nanoparticles is typically assayed in simple in vitro tests, their stability in a mammalian organism remains unknown. Here, we show that firmly grafted polymer shells around gold nanoparticles may degrade when injected into rats. We synthesized monodisperse radioactively labelled gold nanoparticles ((198)Au) and engineered an (111)In-labelled polymer shell around them. Upon intravenous injection into rats, quantitative biodistribution analyses performed independently for (198)Au and (111)In showed partial removal of the polymer shell in vivo. While (198)Au accumulates mostly in the liver, part of the (111)In shows a non-particulate biodistribution similar to intravenous injection of chelated (111)In. Further in vitro studies suggest that degradation of the polymer shell is caused by proteolytic enzymes in the liver. Our results show that even nanoparticles with high colloidal stability can change their physicochemical properties in vivo.

Currently, translocation of inhaled insoluble nanoparticles (NP) across membranes like the air-blood barrier into secondary target organs (STOs) is debated. Of key interest are the involved biological mechanisms and NP parameters that determine the efficiency of translocation. We performed NP inhalation studies with rats to derive quantitative biodistribution data on the translocation of NP from lungs to blood circulation and STOs. The inhaled NP were chain aggregates (and agglomerates) of either iridium or carbon, with primary particle sizes of 2-4 nm (Ir) and 5-10 nm (C) and aggregate sizes (mean mobility diameters) between 20 and 80 nm. The carbon aggregates contained a small fraction ( < 1%) of Ir primary particles. The insoluble aggregates were radiolabeled with (192)Ir. During 1 h of inhalation, rats were intubated and ventilated to avoid extrathoracic NP deposition and to optimize deep lung NP deposition. After 24 h, (192)Ir fractions in the range between 0.001 and 0.01 were found in liver, spleen, kidneys, heart, and brain, and an even higher fraction (between 0.01 and 0.05) in the remaining carcass consisting of soft tissue and bone. The fractions of (192)Ir carried with the carbon NP retained in STOs, the skeleton, and soft tissue were significantly lower than with NP made from pure Ir. Furthermore, there was significantly less translocation and accumulation with 80-nm than with 20-nm NP aggregates of Ir. These studies show that both NP characteristics--the material and the size of the chain-type aggregates--determine translocation and accumulation in STOs, skeleton, and soft tissue.

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.

BackgroundThere is ongoing discussion that inhaled nanoparticles (NPs, < 100 nm) may translocate from epithelial deposition sites of the lungs to systemic circulation.Objectives and MethodsWe studied the disappearance of NPs from the epithelium by sequential lung retention and clearance and bronchoalveolar lavage (BAL) measurements in healthy adult Wistar Kyoto (WKY) rats at various times over 6 months after administration of a single 60- to 100-min intratracheal inhalation of iridium-192 (192Ir)–radiolabeled NPs. A complete 192Ir balance of all organs, tissues, excretion, remaining carcass, and BAL was performed at each time point.ResultsDirectly after inhalation we found free NPs in the BAL; later, NPs were predominantly associated with alveolar macropages (AMs). After 3 weeks, lavageable NP fractions decreased to 0.06 of the actual NP lung burden. This is in stark contrast to the AM-associated fraction of micron-sized particles reported in the literature. These particles remained constant at about 0.8 throughout a 6-month period. Three weeks after inhalation, 80% of the retained Ir NPs was translocated into epithelium and interstitium.ConclusionThere is a strong size-selective difference in particle immobilization. Furthermore, AM-mediated NP transport to the larynx originates not only from the NP fraction retained on the epithelium but also from NPs being reentrained from the interstitium to the luminal side of epithelium. We conclude that NPs are much less phagocytized by AMs than large particles but are effectively removed from the lung surface into the interstitium. Even from these interstitial sites, they undergo AM-mediated long-term NP clearance to the larynx.

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 198Au-radio-labelled 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-h, 3-h, and 24-h the biodistribution of the AuNP was quantitatively measured by gamma-spectrometry to be used for comprehensive risk assessment. Our study shows, 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 which 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.