Resolving the contradiction between simulation and experimental results of using gold nanoparticles in proton therapy.

While gold nanoparticles (GNP)s in proton therapy are widely assumed to exert radio-sensitization via mechanism of secondary electron emission, the discrepancies between simulations and experimental outcomes shows that, in some cases, the secondary electron hypothesis fails to explain the experimental observations particularly distant DNA damage beyond the range of low-energy electrons. These persistent discrepancies show weaknesses of this mechanism, as noted by multiple studies. Resolving the long-standing discrepancy is the main purpose of present research. We predict the survival fractions and sensitization enhancement by Geant4 to bridge the gap between simulation and in-vitro data. Through Geant4 Monte Carlo simulations we demonstrate that proton stopping – not electron emission- by GNPs is the dominant mechanism, driving the GNP enhanced proton therapy via amplification of proton’s linear energy transfer (LET). For the first time, our model successfully reconciles simulation with experimental data by quantifying the key radiobiological parameters: dose enhancement ratio (DER) and sensitization enhancement ratio (SER). These findings redefine GNPs as proton energy modulators rather than electron emitters, resolving the long-standing simulation-experiment discrepancies. However, it is emphasized that, the secondary electron emission from metallic NPs in the range of nano-scale have remarkable impact. Furthermore, we derive a mathematical relationship between DER and cell survival fraction (SF) in the linear-quadratic (LQ) model with predicted survival curves showing strong agreement with in-vitro data.