Large-scale assembly and pattern transfer of SERS-active nanoparticles for application in drug monitoring of methotrexate in blood serum

Self-assembly of plasmonic gold nanoparticles (AuNPs) in periodic arrays with nanometric gaps results in the optimization of near- and far-field effects, which provides excellent surface-enhanced Raman spectroscopy (SERS) sensitivity. Herein, we report the assembly of ∼30 nm AuNPs on electron beam lithography (EBL) substrates using an inexpensive and simple method of stamping. This method yields a highly regular arrangement of AuNPs in the nanochannels of EBL substrates. An experimental approach reveals that, when using the stamping method, the groove width of the gratings plays an important role in linearly arranging the AuNPs on the EBL substrates and is a result of unidirectional flow of AuNPs due to the capillary effect. For assessment of the substrate's SERS efficiency, rhodamine 6 G and brilliant blue were tested with a limit of detection (LOD) of 10.2 nM. To practically test the clinical-based translation of SERS substrates, detection of the chemotherapy drug methotrexate (MTX) was performed with an LOD of 13.7 nM in human blood serum to illustrate its potential in therapeutic drug monitoring (TDM) and its translation into clinics.