title: The effect of particle agglomeration on the formation of a surface-connected compartment induced by hydroxyapatite nanoparticles in human monocyte-derived macrophages.
abstract: Agglomeration dramatically affects many aspects of nanoparticle-cell interactions. Here we show that hydroxyapatite nanoparticles formed large agglomerates in biological medium resulting in extensive particle uptake and dose-dependent cytotoxicity in human macrophages. Particle citration and/or the addition of the dispersant Darvan 7 dramatically reduced mean agglomerate sizes, the amount of particle uptake and concomitantly cytotoxicity. More surprisingly, agglomeration governed the mode of particle uptake. Agglomerates were sequestered within an extensive, interconnected membrane labyrinth open to the extracellular space. In spite of not being truly intracellular, imaging studies suggest particle degradation occurred within this surface-connected compartment (SCC). Agglomerate dispersion prevented the SCC from forming, but did not completely inhibit nanoparticle uptake by other mechanisms. The results of this study could be relevant to understanding particle-cell interactions during developmental mineral deposition, in ectopic calcification in disease, and during application of hydroxyapatite nanoparticle vectors in biomedicine.
authors.affiliation: Cambridge Advanced Imaging Centre, Dept. of Physiology, Development and Neuroscience, Anatomy Building, Cambridge University, Downing Street, Cambridge CB2 3DY, UK.
authors.forename: Karin H
authors.initials: KH
authors.lastname: Müller
authors.forename: Michael
authors.initials: M
authors.lastname: Motskin
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Philpott
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Routh
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Shanahan
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Duer
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Skepper
mesh_terms: D002478:Cells, Cultured; D017886:Durapatite / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects*; D009000:Monocytes / Q000166:cytology; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D010316:Particle Size; D013499:Surface Properties
chemical_list: D017886:Durapatite
keywords: Agglomeration; Aggregation; Cytotoxicity; Hydroxyapatite nanoparticles; Macrophages; Surface-connected compartment