Cavitands Endow All-Dielectric Beads with Selectivity for Plasmon-Free Enhanced Raman Detection of Nϵ-Methylated Lysine

SiO2/TiO2 microbeads (T-rex) are promising materials for plasmon-free surface-enhanced Raman scattering (SERS), offering several key advantages in biodiagnostics. In this paper we report the combination of T-rex beads with tetraphosphonate cavitands (Tiiii), which imparts selectivity toward Nϵ-methylated lysine. SERS experiments demonstrated the efficiency and selectivity of the T-rex-Tiiii assays in detecting methylated lysine hydrochloride (Nϵ-Me-Lys-Fmoc) from aqueous solutions, even in the presence of the parent Lys-Fmoc hydrochloride as interferent. The negative results obtained in control experiments using TSiiii ruled out any other form of surface recognition or preferential physisorption. MALDI-TOF analyses on the beads exposed to Nϵ-Me-Lys-Fmoc revealed the presence of the Tiiii•Nϵ-Me-Lys-Fmoc complex. Raman analyses based on the intensity ratio of Nϵ-Me-Lys-Fmoc and cavitand-specific modes resulted in a dose-response plot, which allowed for estimating the concentration of Nϵ-methylated lysine from initial solutions in the 1 × 10-3 to 1 × 10-5 M range. These results can set the basis for the development of new Raman assays for epigenetic diagnostics.