We applied high resolution
laser ablation inductively coupled plasma
time-of-flight mass spectrometry (LA-ICP-TOF-MS) with cellular spatial
resolution for bioimaging of nanoparticles uptaken by fibroblast multicellular
spheroids (MCS). This was used to quantitatively investigate interactions
of silver nanoparticles (Ag NPs) and the distributions of intrinsic
minerals and biologically relevant elements within thin sections of
a fibroblast MCS as a three-dimensional in vitro tissue
model. We designed matrix-matched calibration standards for this purpose
and printed them using a noncontact piezo-driven array spotter with
a Ag NP suspension and multielement standards. The limits of detection
for Ag, Mg, P, K, Mn, Fe, Co, Cu, and Zn were at the femtogram (10–15 g) level, which is sufficient to investigate intrinsic
minerals in thin MCS sections (20 μm thick). After incubation
for 48 h, Ag NPs were enriched in the outer rim of the MCS but not
detected in the core. The localization of Ag NPs was inhomogeneous
in the outer rim, and they were colocalized with a single-cell-like
structure visualized by Fe distribution (pixel size of elemental images:
5 × 0.5 μm). The quantitative value for the total mass
of Ag NPs in a thin section by the present method agreed with that
obtained by ICP-sector field (SF)-MS with a liquid mode after acid
digestion.