ISD3: a particokinetic model for predicting the combined effects of particle sedimentation, diffusion and dissolution on cellular dosimetry for in vitro systems

Abstract

BackgroundThe development of particokinetic models describing the delivery of insoluble or poorly soluble nanoparticles to cells in liquid cell culture systems has improved the basis for dose-response analysis, hazard ranking from high-throughput systems, and now allows for translation of exposures across in vitro and in vivo test systems. Complimentary particokinetic models that address processes controlling delivery of both particles and released ions to cells, and the influence of particle size changes from dissolution on particle delivery for cell-culture systems would help advance our understanding of the role of particles and ion dosimetry on cellular toxicology. We developed ISD3, an extension of our previously published model for insoluble particles, by deriving a specific formulation of the Population Balance Equation for soluble particles.ResultsISD3 describes the time, concentration and particle size dependent dissolution of particles, their delivery to cells, and the delivery and uptake of ions to cells in in vitro liquid test systems. We applied the model to calculate the particle and ion dosimetry of nanosilver and silver ions in vitro after calibration of two empirical models, one for particle dissolution and one for ion uptake. Total media ion concentration, particle concentration and total cell-associated silver time-courses were well described by the model, across 2 concentrations of 20 and 110 nm particles. ISD3 was calibrated to dissolution data for 20 nm particles as a function of serum protein concentration, but successfully described the media and cell dosimetry time-course for both particles at all concentrations and time points. We also report the finding that protein content in media affects the initial rate of dissolution and the resulting near-steady state ion concentration in solution for the systems we have studied.ConclusionsBy combining experiments and modeling, we were able to quantify the influence of proteins on silver particle solubility, determine the relative amounts of silver ions and particles in exposed cells, and demonstrate the influence of particle size changes resulting from dissolution on particle delivery to cells in culture. ISD3 is modular and can be adapted to new applications by replacing descriptions of dissolution, sedimentation and boundary conditions with those appropriate for particles other than silver.Electronic supplementary materialThe online version of this article (10.1186/s12989-018-0243-7) contains supplementary material, which is available to authorized users.

An Integrated In Vitro–In Silico Approach for Silver Nanoparticle Dosimetry in Cell Cultures

“…Experimentally, we first tracked the Ag NP dissolution and sedimentation process in static-cuvette experiments as a function of the initial administered concentrations (nominal media concentrations). The rationale was to validate the particokinetic model ISD3 provided by Thomas et al (2018) quantifying how the nano-particle concentrations computationally predicted by the model fit with those measured at half height of the cuvette (Fig. 3; grey bars).…”

“…Finally, it would be interesting to quantify the cell viability affected by absorbed nanoparticles of different materials and diameter sizes. These features, included the protein corona on the surface of the nanoparticles (in this work protein layer equal to (120-17.5) / 2 = 51.25 nm), model the primary particle structure and specifically influence the induced nanotoxicity effects 3,41 .…”

“…1) Liquid media characteristics; 2) protein-coated particle characteristics; 3) initial particle size distribution; 4) grid specification and boundary conditions; 5) time integration inputs. The input values used in 41 correspond to those for a nominal 20 nm silver nanomaterial in 10% serum. Hence, they are also suitable for Ag NMP300 in 10% FBS in the concentration range used in our studies (5-80 µg mL -1 ) and only a few values (shown in bold in Table 3) were modified for modelling the dissolution process involved in our static-cuvette and 96-well micro-plates.…”

“…The MATLAB code of ISD3 model is available from Thomas et al (2018) and can be downloaded at https://nanodose.pnnl.gov. The boundary conditions of the experimental system can be easily updated by modifying the input data defined and discussed within the MATLAB script named "inputdata.m".…”

“…Ag NPs and dissolved Ag + in cells) affecting the measured viability of a cell monolayer. Ag NP sedimentation measured in static-cuvette experiments was compared with theoretical values computed by the particokinetic model (ISD3) proposed by Thomas and colleagues 41 .…”