Here, we report on the use of human serum albumin (HSA)-modified Fe
3O
4 nanoparticles (NPs) (HSA-Fe
3O
4 NPs) for affinity-SALDI-MS of small drugs in human biological liquids. We demonstrated that HSA-Fe
3O
4 NPs effectively captured small drugs from human urine and serum
via the interactions between HSA and these drugs. The drugs adsorbed on HSA could then be identified by directly introducing the HSA-Fe
3O
4 NPs into a mass spectrometer for SALDI-MS analysis. The ability of HSA to interact with multiple small drugs facilitated the simultaneous detection of a 4-drug-mixture in serum,
viz., phenytoin, ibuprofen, camptothecin, and warfarin sodium, by affinity-SALDI-MS using HSA-Fe
3O
4 NPs. In contrast, matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) with an organic matrix could detect only warfarin sodium. We also demonstrated the capacity of affinity-SALDI-MS to quantify warfarin sodium in urine samples across a range of 50 – 1000 μM (
R2 = 0.998) when using HSA-Fe
3O
4 NPs. The detection sensitivity was further improved to a range of 5 – 100 μM (
R2 = 0.999) by using denatured HSA. The open structure of denatured HSA may enhance the effective extraction of small drugs from biological liquids, and increase the detection-sensitivity of affinity-SALDI-MS. Affinity-SALDI-MS using protein-modified Fe
3O
4 NPs can open up new approaches to the analytical detection of small drugs in biological liquids by SALDI-MS.
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