Surface Chemistry and Specific Surface Area Rule the Efficiency of Gold Nanoparticle Sensitizers in Proton Therapy

Gold nanoparticles (AuNPs) are currently the most studied radiosensitizers in proton therapy (PT) applicable for the treatment of solid tumors, where they amplify production of reactive oxygen species (ROS). However, it is underexplored how this amplification is correlated with the AuNPs' surface chemistry. To clarify this issue, we fabricated ligand-free AuNPs of different mean diameters by laser ablation in liquids (LAL) and laser fragmentation in liquids (LFL) and irradiated them with clinically relevant proton fields by using water phantoms. ROS generation was monitored by the fluorescent dye 7-OH-coumarin. Our findings reveal an enhancement of ROS production driven by I) increased total particle surface area, II) utilization of ligand-free AuNPs avoiding sodium citrate as a radical quencher ligands, and III) a higher density of structural defects generated by LFL synthesis, indicated by surface charge density. Based on these findings it may be concluded that the surface chemistry is a major and underexplored contributor to ROS generation and sensitizing effects of AuNPs in PT. We further highlight the applicability of AuNPs in vitro in human medulloblastoma cells.