AbstractBackgroundGold NanoParticle (GNP) dose‐enhanced radiation therapy (GNPT) requires consideration of physics across macro‐ to microscopic length scales, however, this presents computational challenges that have limited previous investigations.PurposeTo develop and apply multiscale Monte Carlo (MC) simulations to assess variations in nucleus and cytoplasm dose enhancement factors (n,cDEFs) over tumor‐scale volumes.MethodsThe intrinsic variation of n,cDEFs (due to fluctuations in local gold concentration and cell/nucleus size variation) are estimated via MC modeling of varied cellular GNP uptake and cell/nucleus sizes. Then, the Heterogeneous MultiScale (HetMS) model is implemented in MC simulations by combining detailed models of populations of cells containing GNPs within simplified macroscopic tissue models to evaluate n,cDEFs. Simulations of tumors with spatially uniform gold concentrations (5, 10, or 20 mgAu/gtissue) and spatially varying gold concentrations eluted from a point are performed to determine n,cDEFs as a function of distance from the source for 10 to 370 keV photons. All simulations are performed for three different intracellular GNP configurations: GNPs distributed on the surface of the nucleus (perinuclear) and GNPs packed into one or four endosome(s).ResultsIntrinsic variations in n,cDEFs can be substantial, for example, if GNP uptake and cell/nucleus radii are varied by 20%, variations of up to 52% in nDEF and 25% in cDEF are observed compared to the nominal values for uniform cell/nucleus size and GNP concentration. In HetMS models of macroscopic tumors, subunity n,cDEFs (i.e., dose decreases) can occur for low energies and high gold concentrations due to attenuation of primary photons through the gold‐filled volumes, for example, n,cDEF<1 is observed 3 mm from a 20 keV source for the four endosome configuration. In HetMS simulations of tumors with spatially uniform gold concentrations, n,cDEFs decrease with depth into the tumor as photons are attenuated, with relative differences between GNP models remaining approximately constant with depth in the tumor. Similar initial n,cDEF decreases with radius are seen in the tumors with spatially varying gold concentrations, but the n,cDEFs for all of the GNP configurations converge to a single value for each energy as gold concentration reaches zero.ConclusionsThe HetMS framework has been implemented for multiscale MC simulations of GNPT to compute n,cDEFs over tumor‐scale volumes, with results demonstrating that cellular doses are highly sensitive to cell/nucleus size, GNP intracellular distribution, gold concentration, and cell position in tumor. This work demonstrates the importance of proper choice of computational model when simulating GNPT scenarios and the need to account for intrinsic variations in n,cDEFs due to variations in cell/nucleus size and gold concentration.