Title:Simulation of complex DNA damage enhancement and biological effect validation for Proton-CAT

Abstract:Proton therapy has been rapidly advancing due to its excellent conformal index, but its relatively low relative biological effect (RBE) has somewhat limited its therapeutic efficacy for certain tumors. To address this, we previously proposed a nitrogen-targeting Proton-Carbon-Alpha-Therapy (Proton-CAT) enhancement method. In this letter, we present combined multi-scale DNA damage simulations and in vitro cell experiments, further investigating the mechanism of the Proton-CAT. It has been show that $^{15}$N enrichment significantly enhances complex DNA damage induced by high linear energy transfer(LET) particles within tumor regions. Under 30\% $^{15}$N conditions, $\alpha$ and $^{12}$C particle induced DSB++ increased by 175.19\% and 52.94\%, respectively. Furthermore, in vitro cell experiments using $^{15}$N-glutamine ($^{15}$N-Glu) as the $^{15}$N carrier indicated that high concentrations of $^{15}$N-Glu did not bring about significant cytotoxicity. Following 2 Gy irradiation, the cell viability in the 500 $\mu$g/mL $^{15}$N-Glu treated group exhibited a net reduction of about 15.41\% compared to the control this http URL indicates that the enhanced effect of Proton-CAT primarily stems from increased complex DNA damage. This work provides a theoretical basis and multi-scale research framework for the development of the Proton-CAT.