The widespread use of gold nanoparticles (AuNPs) in biomedical and analytical applications arises from their versatile surface functionalization with clinically relevant compounds. Investigating their binding behavior using simple model compounds of clinical interest is essential for gaining fundamental insight into more complex interaction systems. Herein, single particle inductively coupled plasma mass spectrometry (SP-ICP-MS) and flow field-flow fractionation (FlFFF) coupled with an inductively coupled plasma mass spectrometry (ICP-MS) were employed to investigate the binding and aggregation behavior of AuNPs upon conjugation with simple model compounds. Proteins were first examined as macromolecular model systems to provide a baseline understanding of how the two techniques reflect core size changes from SP-ICP-MS and hydrodynamic size changes from FlFFF-ICP-MS. D-Penicillamine (DPA) was subsequently employed as a clinically relevant small-molecule model in a Cu 2+ -induced aggregation system with fixed Cu 2+ concentration. A distinct two-step sigmoidal aggregation behavior was observed from AuNP core size evolution, with corresponding hydrodynamic size increases. The results indicate that Cu 2+ promotes aggregation by mediating interactions between AuNP–DPA conjugates, thereby facilitating interparticle association. Moreover, the rapid growth region of the sigmoidal aggregation profile exhibited a linear relationship with DPA concentration, suggesting its potential applicability for quantitative analysis with approximately 13-fold higher sensitivity than conventional UV–Vis spectrometry. Overall, the combined use of these two ICP-MS-based techniques provides fundamental insight into AuNP–compound binding interactions and offers a foundation for studying more complex conjugated systems. • SP-ICP-MS and FlFFF-ICP-MS were combined to probe AuNP binding and aggregation. • D-Penicillamine caused two-step sigmoidal AuNP aggregation in a Cu 2+ system. • Rapid aggregation growth showed linear response to DPA with ∼13× higher sensitivity than UV–Vis.
Karanasophonphun et al. (Sun,) studied this question.