title: Analysis of the influence of cell heterogeneity on nanoparticle dose response.
abstract: Understanding the effect of variability in the interaction of individual cells with nanoparticles on the overall response of the cell population to a nanoagent is a fundamental challenge in bionanotechnology. Here, we show that the technique of time-resolved, high-throughput microscopy can be used in this endeavor. Mass measurement with single-cell resolution provides statistically robust assessments of cell heterogeneity, while the addition of a temporal element allows assessment of separate processes leading to deconvolution of the effects of particle supply and biological response. We provide a specific demonstration of the approach, in vitro, through time-resolved measurement of fibroblast cell (HFF-1) death caused by exposure to cationic nanoparticles. The results show that heterogeneity in cell area is the major source of variability with area-dependent nanoparticle capture rates determining the time of cell death and hence the form of the exposure–response characteristic. Moreover, due to the particulate nature of the nanoparticle suspension, there is a reduction in the particle concentration over the course of the experiment, eventually causing saturation in the level of measured biological outcome. A generalized mathematical description of the system is proposed, based on a simple model of particle depletion from a finite supply reservoir. This captures the essential aspects of the nanoparticle–cell interaction dynamics and accurately predicts the population exposure–response curves from individual cell heterogeneity distributions.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ware
authors.forename: Biana
authors.initials: B
authors.lastname: Godin
authors.forename: Neenu
authors.initials: N
authors.lastname: Singh
authors.forename: Ravish
authors.initials: R
authors.lastname: Majithia
authors.forename: Sabeel
authors.initials: S
authors.lastname: Shamsudeen
authors.forename: Rita E
authors.initials: RE
authors.lastname: Serda
authors.forename: Kenith E
authors.initials: KE
authors.lastname: Meissner
authors.forename: Paul
authors.initials: P
authors.lastname: Rees
authors.forename: Huw D
authors.initials: HD
authors.lastname: Summers
mesh_terms: D001692:Biological Transport; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D053758:Nanoparticles / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors