The origin of heterogeneous nanoparticle uptake by cells

Abstract

Understanding nanoparticle uptake by biological cells is fundamentally important to wide-ranging fields from nanotoxicology to drug delivery. It is now accepted that the arrival of nanoparticles at the cell is an extremely complicated process, shaped by many factors including unique nanoparticle physico-chemical characteristics, protein-particle interactions and subsequent agglomeration, diffusion and sedimentation. Sequentially, the nanoparticle internalisation process itself is also complex, and controlled by multiple aspects of a cell’s state. Despite this multitude of factors, here we demonstrate that the statistical distribution of the nanoparticle dose per endosome is independent of the initial administered dose and exposure duration. Rather, it is the number of nanoparticle containing endosomes that are dependent on these initial dosing conditions. These observations explain the heterogeneity of nanoparticle delivery at the cellular level and allow the derivation of simple, yet powerful probabilistic distributions that accurately predict the nanoparticle dose delivered to individual cells across a population.

Isolating the sources of heterogeneity in nanoparticle-cell interactions

“…S1). This indicates that the cell populations exhibit heterogeneity, and is consistent with previous observations (9)(10)(11)(12)(13).…”

“…The exact influence of these properties is unclear, as the impact is obscured by both the influence of transport phenomena, such as sedimentation, diffusion and aggregation, and cell-type specific interactions between cells and nanoparticles (4,(6)(7)(8). The inherent variation in cell characteristics within a population further obscures the roles of individual processes, and results in heterogeneous experimental data (9)(10)(11)(12)(13).…”

“…Even if such cell subpopulations are rare, they can nevertheless have a substantial impact on disease progression (14,18,19). Identifying whether a cell population does, in fact, contain heterogeneity in relevant cell characteristics or whether variation in experimental data is merely a by-product of the stochastic nature of nanoparticle transport is therefore critical for therapeutic success (9)(10)(11)(12)(13). Furthermore, understanding how heterogeneity in cell characteristics, such as receptor numbers or vesicle formation rates, manifests itself in commonly-measured experimental data is crucial for isolating and quantifying sources of heterogeneity.…”

“…ever, such models describe the average nanoparticle behavior and dose, and are not suitable for predicting dosage distributions or cell heterogeneity. Statistical approaches allow for the quantification of heterogeneity from experimental data (9,10,13), but do not provide mechanistic understanding about how heterogeneity in experimental data arises from heterogeneity in multiple cell characteristics. Further, as we will demonstrate, conclusions obtained from previous statistical approaches are incapable of explaining heterogeneity observed in our time course experiments.…”

Analyse quantitativer Partikelaufnahme von Zellen über verschiedene Messmethoden

“…Eine klare Verbesserung der theoretischen Modelle ist notwendig, welche dafür sorgen würden, dass experimentelle Daten sporadisch zu quantitativen Parametern führen . Außerdem sollten Data‐Mining‐Ansätze für z.…”