Evaluation of dose enhancement due to CuATSM uptake in hypoxic environments with external radiation

Abstract

Most solid tumors contain areas of chronic hypoxia caused by limited diffusion of oxygen from tumor microvasculature. Hypoxic regions have been found to be radioresistant and their presence results in a worse prognosis for tumor control. Metal radiosensitizers have been employed to alleviate the radioresistance in hypoxic tumors by increasing dose through additional photoelectrons and Auger cascades. In recent years, gold nanoparticles (GNP) have been explored for their potential as an enhancer of external beam radiation and become the standard-bearer for the treatment modality; however, GNP have lower cellular uptake in anoxic and hypoxic conditions than under normoxic conditions. Additionally, the large size of nanoparticles decreases their diffusivity, reducing their ability to penetrate into tumor tissue distant from vasculature. The chelator diacetylbis (N(4)-methylthiosemicarbazonato) copper II (CuATSM) provides the potential to overcome the hypoxic barrier by preferentially depositing copper into tumor regions previously inaccessible to treatment. The characteristics of CuATSM have led to its utilization in positron emission tomography (PET) imaging of hypoxic regions. These PET images have also been investigated as a method for dose painting, amplification of intensity modulated radiation therapy (IMRT) dose to hypoxic regions. Additionally, radioactive ⁶⁴CuATSM has been investigated for implementation in brachytherapy for hypoxic tumors. The Auger electrons ejected upon decay of the radioisotope have been shown to be highly damaging to DNA. The intention of this study is to evaluate the potential of CuATSM as an external beam radiosensitizer. This project investigates radiosensitization of CuATSM by Monte Carlo (MC) modeling of different energy external beam spectra available clinically with Electron Gamma Shower (EGSnrc) and Geometry and Tracking (Geant4) and evaluating dose enhancement with CuATSM. These MC models are informed by and evaluated against cell models. Research indicates that CuATSM at high concentrations with low energy photons has efficacy for enhancing dose in hypoxic tumor regions.