ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies

Abstract

BackgroundThe difficulty of directly measuring cellular dose is a significant obstacle to application of target tissue dosimetry for nanoparticle and microparticle toxicity assessment, particularly for in vitro systems. As a consequence, the target tissue paradigm for dosimetry and hazard assessment of nanoparticles has largely been ignored in favor of using metrics of exposure (e.g. μg particle/mL culture medium, particle surface area/mL, particle number/mL). We have developed a computational model of solution particokinetics (sedimentation, diffusion) and dosimetry for non-interacting spherical particles and their agglomerates in monolayer cell culture systems. Particle transport to cells is calculated by simultaneous solution of Stokes Law (sedimentation) and the Stokes-Einstein equation (diffusion).ResultsThe In vitro Sedimentation, Diffusion and Dosimetry model (ISDD) was tested against measured transport rates or cellular doses for multiple sizes of polystyrene spheres (20-1100 nm), 35 nm amorphous silica, and large agglomerates of 30 nm iron oxide particles. Overall, without adjusting any parameters, model predicted cellular doses were in close agreement with the experimental data, differing from as little as 5% to as much as three-fold, but in most cases approximately two-fold, within the limits of the accuracy of the measurement systems. Applying the model, we generalize the effects of particle size, particle density, agglomeration state and agglomerate characteristics on target cell dosimetry in vitro.ConclusionsOur results confirm our hypothesis that for liquid-based in vitro systems, the dose-rates and target cell doses for all particles are not equal; they can vary significantly, in direct contrast to the assumption of dose-equivalency implicit in the use of mass-based media concentrations as metrics of exposure for dose-response assessment. The difference between equivalent nominal media concentration exposures on a μg/mL basis and target cell doses on a particle surface area or number basis can be as high as three to six orders of magnitude. As a consequence, in vitro hazard assessments utilizing mass-based exposure metrics have inherently high errors where particle number or surface areas target cells doses are believed to drive response. The gold standard for particle dosimetry for in vitro nanotoxicology studies should be direct experimental measurement of the cellular content of the studied particle. However, where such measurements are impractical, unfeasible, and before such measurements become common, particle dosimetry models such as ISDD provide a valuable, immediately useful alternative, and eventually, an adjunct to such measurements.

Preliminary protein corona formation stabilizes gold nanoparticles and improves deposition efficiency

“…We hypothesize that this alteration to AuNP dosimetry is due to the increased particle stability and observed alteration to the protein corona. As smaller agglomerates allow for increased diffusion and NP transport, a greater fraction of AuNPs will reach the HaCaT surface (Cho et al 2011;Hinderliter et al 2010); thus increasing the deposition efficiency. This theory is further supported by the dynamic results, which introduced a new mode of NP transport and interfered in deposition.…”

Assessing nanoparticle toxicity in cell-based assays: influence of cell culture parameters and optimized models for bridging the in vitro–in vivo gap

“…Therefore the concept of dose is more complex and dynamic for NP as it is for chemicals. To address this issue Teeguarden et al developed the concept of particokinetics to model the NP behaviour in dispersion based on its likelihood to diffuse, sediment and agglomerate in dispersion 116,131 . Since both diffusion and sedimentation are influenced by agglomeration, the latter is expected to have a major impact on the NP uptake and toxicity 169 .…”

Different responses of Caco-2 and MCF-7 cells to silver nanoparticles are based on highly similar mechanisms of action

“…The size and electro density of the AgNPs shows degradation, which appeared to be more severe in the lysosomes when comparing (N) versus (O). Zhu et al, 2013), others report it the other way around (Cho et al, 2011;Hinderliter et al, 2010), and also maximal uptake in a privileged size gap was reported (Chithrani et al, 2006;Varela et al, 2012). Higher uptake of larger NPs could be explained by sedimentation of the larger NPs onto the cells (Hinderliter et al, 2010), leading to increased cellular uptake (Cho et al, 2011).…”