Thesis

Modeling the radiobiological effects of gold nanoparticles in proton therapy of glioblastomas

• Call:

  ProtoTera Call 2020

• Academic Year:

  2020/2021

• Supervisor:

  Jorge Sampaio

• Co-Supervisor:

  Filipa Mendes

• Host Institution:

  LIP - Laboratório de Instrumentação e Física Experimental de Partículas

• Granting Degree Institution:

  FCUL (Universidade de Lisboa)

• Typology:

  National

• Abstract:

  Several studies show that the combination of high-Z nanoparticles and external radiotherapy leads to an increased radiation effect in tumoral cells without an increase of the patient dose. However, it is not yet clear how the sequence of physical, chemical, and biological mechanisms contributes to the observed synergic effect. The objective of this Ph.D. research project is to develop simulation tools that allow the analysis and interpretation of radiobiology studies with multifunctional nanoparticles (NPs). The student will develop realistic simulations of the irradiation of monolayer (2D) and spheroid (3D) human glioblastomas multiforme (GBM) cell cultures and xenograft animal models, taking into consideration different concentrations and cellular and subcellular distributions of the Au NPs. The simulations will be implemented based on the Geant4 toolkit and in particular with the extension Geant4-DNA that includes models of the physical and chemical processes induced by radiation at the DNA scale. These must describe the laboratory experimental conditions of irradiation with X-rays and Co-60 sources and with proton beams taking into account the cell lines morphology and 2D and 3D cell culture scenarios. The construction of the computational cell models will be developed based on confocal microscopy images of the biological samples. At a later stage, the simulations will be extended to computational models of mice bearing subcutaneous GBM xenografts. The student will also investigate feasible ways of simulating irradiations of biological systems with different levels of oxygenation (e.g. normoxia vs hypoxia). Based on the simulations, the dose distributions at the subcellular scale will be obtained, as well as the temporal distribution of the reactive oxygen species (ROS) induced by the different irradiation conditions, AuNPs distribution, and concentrations. The microdosimetric distributions in cells and tissues will be used to predict cell survival fractions, and single and double-strand breaks of the DNA, using standard mathematical models of the biological effects of radiation. The results obtained in the simulations will be compared with the biological in vitro and in vivo experimental results, which will include evaluation of cell viability and survival, as well as cell apoptosis and DNA damage (gamma-H2AX) studies. Moreover, the simulated ROS yields will be also compared with the experimentally determined values. The Ph.D. research activities will be developed at LIP (Laboratório de Instrumentação e Física Experimental de Partículas) in close collaboration with C2TN-IST (Centro de Ciência e Tecnologias Nucleares-Instituto Superior Técnico) and ICNAS (Instituto de Ciências Nucleares Aplicadas à Saúde) groups involved in the tasks of AuNPs synthesis, irradiation, and biological studies related to the TOF-PET project. A stay at the UT-MDACC (The University of Texas-MD Anderson Cancer Center) is foreseen to participate in the clinical proton irradiations and characterize the beam to be implemented in the simulations.