Liquid chromatography-based metallomics and transmission electron microscopy reveal gold nanoparticle surface treatment with vicinal dithiols to abolish protein corona formation

While gold nanoparticles (AuNPs) should allow the delivery of surface immobilized drugs to intended target tissues via the bloodstream, their interactions with plasma proteins may induce their aggregation and thus impede an effective delivery of chemotherapeutic agents to target tissues. The deliberate surface treatment of AuNPs has the potential to overcome this inherent limitation. To probe interactions between surface treated AuNPs in blood plasma, we employed a size-exclusion chromatography (SEC)-based metallomics tool together with transmission electron microscopy (TEM). After the addition of citrate capped AuNPs to plasma, its metallomics analysis revealed a >670 kDa Au species, which TEM analysis identified as AuNP-plasma protein aggregates. To ameliorate the formation of the latter, the surface of citrate capped AuNPs was modified with dithiothreitol (DTT), meso 2,3-dimercaptosuccinic acid (DMSA), or 2,3 dimercapto-1-propionesulfonic acid (DMPS) and the effect of this surface treatment was probed after the addition of these modified AuNPs to rabbit plasma. The results for DMSA/DMPS-treated AuNPs revealed that the tight binding of these dithiols more significantly reduced protein corona formation compared to DTT-AuNPs implying that the surface treatment of AuNPs with DMSA or DMPS is a feasible strategy to control protein corona formation and thus their aggregation in plasma. The AuNP-based delivery of immobilized drugs using targeting sequences to cancer tissues can be enhanced by their surface treatment with DMSA or DMPS. Since dithiols left over after the AuNP surface treatment mobilized iron from plasma metalloproteins, excess dithiols must be removed before injecting patients.