Gadolinium oxide nanoparticles as a multimodal contrast enhancement agent for pre-clinical proton imaging

Orthotopic tumor models in pre-clinical translational research are becoming increasingly popular, raising the demands on accurate tumor localization prior to irradiation. This task remains challenging both in x-ray and proton computed tomography (xCT and pCT, respectively), due to the limited contrast of tumor tissue compared to the surrounding tissue. We investigate the feasibility of gadolinium oxide nanoparticles as a multimodal contrast enhancement agent for both imaging modalities. We performed proton radiographies at the experimental room of the Trento Proton Therapy Center using a MiniPIX-Timepix detector and dispersions of gadolinium oxide nanoparticles in sunflower oil with mass fractions up to 8wt%. To determine the minimum nanoparticle concentration required for the detectability of small structures, pCT images of a cylindrical water phantom with cavities of varying gadolinium oxide concentration were simulated using a dedicated FLUKA Monte Carlo framework. These findings are complemented by simulating pCT at dose levels from 80 mGy to 320 mGy of artificially modified murine xCT data, mimicking different levels of gadolinium oxide accumulation inside a fictitious tumor volume. To compare the results obtained for proton imaging to x-ray imaging, cone-beam CT images of a cylindrical PMMA phantom with cavities of dispersions of oil and gadolinium oxide nanoparticles with mass fractions up to 8wt% were acquired at a commercial pre-clinical irradiation setup. For proton radiography, considerable contrast enhancement was found for a mass fraction of 4wt%. Slightly lower values were found for the simulated pCT images at imaging doses below 200 mGy. In contrast, full detectability of small gadolinium oxide loaded structures in xCT at comparable imaging dose is already achieved for 0.5wt%. Achieving such concentrations required for pCT imaging inside a tumor volume inin-vivoexperiments may be challenging, yet it might be feasible using different targeting and/or injection strategies.