Subcellular capillary sampling coupled to laser ablation – Inductively coupled plasma – Mass spectrometry (LA-ICP-MS) allows targeted analysis of thallium in a radiopharmaceutical model

Abstract

Background: The detection of trace elements in sub-cellular compartments is essential for understanding the biological function of metals and for optimising drug delivery treatments, including radionuclides used for cancer therapies. Laser ablation – inductively coupled plasma – mass spectrometry (LA-ICP-MS) offers excellent sensitivity to metals but is typically limited to chemically fixed samples. Furthermore, spatial resolution (≤ 1–5 μm) achievable with current LA-ICP-MS systems is insufficient to resolve sub-cellular features. This study addresses the challenge of detecting metals in live single cells and sub-cellular compartments through a novel integration of capillary sampling with LA-ICP-MS. Results: We present a novel workflow that enables the detection of metals in live cells and sub-cellular compartments by integrating capillary sampling with laser ablation – inductively coupled plasma – mass spectrometry (LA-ICP-MS). The methodology involves collecting single cells or sub-cellular contents into a sampling capillary under confocal microscopy, followed by deposition onto a flat surface for analysis by LA-ICP-MS. The deposition substrate (Si wafer), internal standard (bismuth), analyte transfer and analysis protocols were optimised using standards and confocal microscopy to maximise precision and sensitivity. The methodology was then applied to PANC-1 cancer cells incubated with thallium chloride as a model for thallium-201, a therapeutic radionuclide candidate. Thallium was detected in the single cells and mitochondria-enriched samples, both in media and after phosphate-buffered saline (PBS) washing, but not in controls, confirming successful sub-cellular metal detection. Significance: This methodology enables precise measurement of trace elements in living single cells and subcellular compartments, overcoming key limitations of current metal imaging techniques. By combining capillary sampling with LA-ICP-MS for the first time, it provides a robust platform for investigating the kinetics and localisation of exogenous elements or metal-based drugs at the subcellular level, with strong potential to advance targeted radionuclide therapy and cellular metal biology.