We measured the viscoelastic properties of the cytoplasm of J774 macrophages with a recently developed microrheometer. Ferromagnetic beads (1.3 microm in diameter) were used to determine the local viscoelastic moduli. Step-force pulses were applied to the magnetic beads and the displacement was observed by single particle tracking. By analyzing the creep response curves in terms of a triphasic mechanical equivalent circuit, we measured the shear elastic modulus, the effective viscosities, and the strain relaxation time. The values of the shear modulus vary by more than an order of magnitude within the cell population (range, 20-735 Pa; average, 343 Pa) and by a factor of 2 within single cells. The effective viscosity of the cytoplasm exhibits a relatively sharp distribution about an average of eta = 210 Pa s (+/- 143 Pa s). We measured the displacement field generated by the local forces by observing the induced motion of nonmagnetic beads. Even at distances of the order of 1 microm, no induced motion was seen, suggesting that the cytoplasm is composed of clusters of densely packed and cross-linked filaments separated by soft regions. In another series of experiments we analyzed the magnetophoretic motion of the ferromagnetic beads at a constant magnetic force. Measuring the bead velocity parallel and perpendicular to the applied force showed that local active forces on the beads varied from 50 to 900 pN.

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.

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.

Epidemiological studies continue to indicate associations between exposure to increased concentrations of ambient fine and ultrafine particles and adverse health effects in susceptible individuals. The ultrafine particle fraction in the ambient atmosphere seems to play a specific role. Yet, the dosimetry (including deposition patterns in the respiratory tract and, particularly, the biokinetic fate of ultrafine particles) is not fully understood. In contrast to fine particles, inhaled ultrafine particles seem to follow different routes in the organism. Cardiovascular effects observed in epidemiological studies triggered the discussion on enhanced translocation of ultrafine particles from the respiratory epithelium towards circulation and subsequent target organs, such as heart, liver, and brain, eventually causing adverse effects on cardiac function and blood coagulation, as well as on functions of the central nervous system. Current knowledge on systemic translocation of ultrafine particles in humans and animal models is reviewed. Additionally, an estimate of accumulating particle numbers in secondary target organs during chronic exposure is extrapolated from long-term translocation data obtained from rats. Toxicological studies aim to provide the biological plausibility of health effects of ultrafine particles and to identify cascades of mechanisms that are causal for the gradual transition from the physiological status towards pathophysiologcal alterations and eventually chronic disease. Considering the interaction between insoluble ultrafine particles and biological systems (such as body fluids, proteins, and cells), there still are gaps in the current knowledge on how ultrafine particles may cause adverse reactions. This paper reviews the current concept of interactions between insoluble ultrafine particles and biological systems.