Nanoparticle Polydispersity Can Strongly Affect In Vitro Dose

Abstract

When nanomaterials meet the biological world, the cellular interaction of nanoparticles is routinely assessed in in vitro systems. Establishing doseresponse relationships requires that the dose of nanoparticles delivered to the cell is accurate and precise. Nanoparticles as such or coated with high molecular-weight compounds are rarely uniform and the infl uence of heterogeneity, including polydispersity both in size and mass density, on the delivered dose is never studied before. Furthermore, a probabilistic term describing particle adherence to cells is introduced and the importance is discussed. By tracing the movement of discrete particles via modeling, it is found that the infl uence of heterogeneity cannot be neglected when the average particle size promotes settling over diffusion. However, the infl uence of polydispersity on the delivered cellular dose is less critical for particulate systems whose mean size promotes diffusion. The infl uence of a non-instantaneous particle association to the cell is negligible for particles whose motion is dominated by settling, but it is relevant for small particles whose motion is governed by diffusion.at least three elementary processes that are relevant for in vitro dose: (i) delivery of NPs to the cell, (ii) adherence to the cell membrane, and (iii) internalization. Any of these processes can be a rate-limiting factor. Awareness concerning the peculiarities of NP transport in fl uids and the relevance to liquid-based in vitro assays is on the rise, as shown by the steadily increasing number of research papers adopting the concept of particokinetics proposed by Teeguarden et al. [ 20,25 ] for interpreting dose-response curves. The concept of particokinetics, describing uniform particles, [ 20,25 ] challenges the still-reigning paradigm that the dose to which adherent cells are exposed to at the bottom of the cell-culture dish is proportional to the concentration of NPs in the suspension. However, the concentration of NPs in suspension defi nes only the administered dose, and the above paradigm is strictly valid only when all NPs in the suspension have completely settled, in which case the delivered dose is equal to the administered dose. The ultimate fate of NPs in a fl uid is eventually dictated by its mass density, i.e., NPs will settle if their mass density is greater than that of the fl uid. The impact of NP size and mass density on transport has been known for a long time [26][27][28][29] : in general, sedimentation is dominant for large NPs of "higher" mass density, while diffusion dominates the transport for small NPs of "lower" mass density. The kinetics of a particle is quantifi ed by the diffusion coeffi cient (the Stokes-Einstein equation and the settling velocity, Stokes' law). [ 26 ] Depending on (i) the hydrodynamic radius of the NPs, (ii) the mass density difference between the particle and the fl uid, (iii) the concentration of NPs in the colloidal suspension, (iv) the total volume of the colloidal suspension administrated to the cell culture, and (v...

Formula-Driven, Size-Tunable Synthesis of PMMA Nanoparticles by Varying Surfactant Concentration

“…The low dispersity is beneficial for biological studies, where size dispersity affects the cytotoxicity of nanoparticle therapies [25][26][27].…”

Combination of thresholding and fitting methods for measuring nanoparticle sizes and size distributions in (S)TEM

“…They are very reactive or catalytic. High diffusion rate, enhanced chemical and biological activity associated with penetrating capabilities through cell membranes are characteristics of nanoparticles less than a few 10 nm in diameter and less owing to their large area to volume ratio (Guzman, Dille, & Godet, 2012;Marambio-Jones & Hoek, 2010;Park et al, 2011;Rodriguez-Lorenzo, Rothen-Rutishauser, Petri-Fink, & Balog, 2014). At present the total market for composites with nanoparticles is expected to grow.…”

In vitro-ex vivo model systems for nanosafety assessment

“…Even at the early stage of any advanced models, the calculation of the proper dosing of the investigated nanomaterials is examined and potential scenarios have been outlined. The model has been extended by RodriguezLorenzo and colleagues, who included heterogeneity, including polydispersity both in size and mass density to study the influence of heterogeneity on the particokinetics of nanoparticles and on the corresponding delivered dose (79). Therefore it will be essential that at least a full set of dosing-relevant characteristics is given in a publication so that in the future a direct comparisons of results of the different approaches is feasible.…”