Synergetic Enhancing Effects Between Platinum Nanosensitizers and Clinically Approved Stabilizing Ligands in Proton Therapy, Causing High‐Yield Double‐Strand Breaks of Plasmid DNA at Relevant Dose

Proton therapy is used to eradicate tumors in sensitive areas by targeted delivery of energy. Its effectiveness can be amplified using nanoparticles (NPs) as sensitizers, due to the production of reactive oxygen species at the NP's catalytically active surface, causing the cleavage of DNA. However, the impact of stabilizing macromolecular ligands capping the particles, needed for nanosensitizer dispersion in physiological fluids, is underexplored. Herein, ligand‐free colloidal platinum NPs (PtNPs) fabricated by scalable laser synthesis in liquids are used, which allows studying particle and ligand effects separately. PtNPs are incubated with stabilizing concentrations of the clinically approved ligands albumin, Tween, and polyethylene glycol, and irradiated with proton beams at clinically relevant doses (2 and 5 Gy). At these doses, plasmid DNA cleavage larger than 55% of clustered DNA damage is achieved. Bovine serum albumin, Tween, and polyethylene glycol on the NP surface work as double‐strand breaks (DSB) enhancers and synergetic effects occur even at low and clinically relevant particle concentrations and irradiation doses. Here, DSB enhancement by ligand‐capped PtNP even exceeds the sum of the individual ligand and particle effects. The presented fundamental correlations provide selection rules for nanosensitizer design in proton therapy.