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Laser Ablation-Inductively Coupled Plasma Time-of-Flight Mass Spectrometry Imaging of Trace Elements at the Single-Cell Level for Clinical Practice.

In this work, a combination of routine clinical practice and state-of-the-art laser ablation-inductively coupled plasma time-of-flight mass spectrometry (LA-ICP-TOFMS) imaging is presented for multielement analysis of single cells on clinical samples. More specifically, routinely drawn blood thin films of a patient undergoing treatment with the anticancer drug cisplatin were studied. The presented label-free approach enabled rapid analysis of hundreds of cells at the single-cell level within a few minutes without additional tailored sample preparation. The employed low-dispersion LA setup is based on the tube-type COBALT ablation cell in combination with the aerosol rapid introduction system (ARIS) providing pixel-resolved imaging at 250-500 Hz for biological sample material. In order to cope with the short transient signals of only a few milliseconds delivered by the laser ablation setup, an icpTOF 2R TOF-based ICP-MS instrument was used for analysis, which has a mass coverage of m/ z = 14-256. Leukocytes and erythrocytes, imaged with a laser beam of 4 μm and pixel interspacing of 2 μm, were differentiated on the basis of their intrinsic trace-elemental pattern. Overall, red blood cells displayed high iron intensities, whereas individual white blood cells were characterized by their high phosphorus content and increased sulfur signal. Unsupervised multivariate statistical analysis was applied to the data set. Principal component plots showed a clear clustering of leukocytes versus erythrocytes. The approach allowed studying not only the drug distribution between plasma and cells but also, for the first time, the preferential accumulation of platinum in different blood cell types without the need of cell fixation and labeling. Extracellular hotspots of platinum were observed, whereas only a small fraction of platinum was associated with erythrocytes. The investigation demonstrates the potential of low-dispersion LA-ICP-TOFMS as a rapid and powerful tool for label-free single-cell imaging in the clinical context.