Mechanistic insights into radiosensitization by high atomic number nanoparticles during 177Lu targeted radionuclide therapy using Monte Carlo simulation

Abstract

Background High-Z nanoparticles have emerged as promising radiosensitizers for targeted radionuclide therapy by increasing nanoscale energy deposition and secondary electron production. Although Monte Carlo studies have extensively investigated photon-induced radiosensitization, the mechanisms underlying nanoparticle-enhanced beta-emitting radionuclide therapy remain insufficiently understood. This study evaluated the influence of nanoparticle composition and surrounding medium on radiation interactions, reactive species generation, and DNA damage during 177Lu irradiation. Objective To investigate the dosimetry and radiobiological effects of high-Z nanoparticles combined with the beta-emitting radionuclide 177Lu using Geant4-DNA Monte Carlo simulations. Methods Two complementary simulation models were developed. First, 25 nm nanoparticles (Au, Ag, Pt, Ta, Pd, Gd, Fe, Ti, and their oxides) were simulated in spherical water and polyethylene glycol (PEG)-based phantoms to evaluate dose enhancement factors (DEFs), secondary particle production, and radiation interactions using Livermore, Penelope, and Geant4-DNA physics models. Second, a fibroblast cell model containing distributed nanoparticles and intracellular 177Lu sources was used to assess reactive species production and radiation-induced DNA damage, including single- and double-strand breaks. Results High-Z nanoparticles significantly increased local energy deposition and secondary electron production compared with nanoparticle-free media. Tantalum nanoparticles exhibited the highest dose enhancement, followed by platinum and gold. Dose enhancement reached approximately 1200% (DEF ≈ 13) in the immediate vicinity of the nanoparticle surface and gradually decreased with increasing distance. PEG-based media produced moderately higher energy deposition than water. Nanoparticle incorporation also increased reactive species generation and enhanced both direct and hydroxyl radical-mediated indirect DNA damage. Penelope and Livermore models showed consistent material-dependent trends with only minor differences in secondary particle yields. Conclusion High-Z nanoparticles substantially enhance 177Lu-induced radiation effects by increasing local dose deposition, secondary electron production, reactive species generation, and simulated DNA damage. Tantalum demonstrated the greatest radio sensitizing potential, highlighting its promise as a nanoparticle enhancer for targeted radionuclide therapy.

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