Thesis

Proton therapy for glioblastoma multiforme: preclinical radiobiological studies and evaluation of gold nanoparticles as radiosensitizers

• Call:

  ProtoTera Call 2023/2

• Academic Year:

  2023

• Supervisor:

  Francisco Alves

• Co-Supervisor:

  Filipa Mendes

• Host Institution:

  ICNAS - Instituto de Ciências Nucleares Aplicadas à Saúde

• Granting Degree Institution:

  Universidade de Coimbra

• Typology:

  Mixed

• Abroad Institution:

  Universidade de Coimbra

• Abroad Supervisor:

  David Grosshans

• Abstract:

  Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, still being associated with a poor prognosis. Hence, there is an urgent need to develop more effective therapeutic strategies. Proton therapy has been presented as a radiotherapy alternative for this condition, as the proton beam can deliver a higher dose to the lesion while sparing the surrounding healthy tissues, thus reducing neuro-cognitive toxicity. In parallel, the application of gold nanoparticles (AuNPs) in glioma theranostics has been intensifying, since AuNPs can act as local radiosensitizers due to the release of short-range Auger electrons. They are easily functionalized to allow specific binding to the target and radiolabeling with PET imaging isotopes for treatment monitoring. In the case of GBM, AuNPs are expected to overcome the compromised blood-brain-barrier into the tumor site when compared to other chemotherapeutic agents, making them a promising tool to include in radiation therapies. This project aims to compare the radiobiological effects of photons and protons in GBM treatment and to evaluate the potential of using AuNPs as radiosensitizers in photon and proton therapy by preclinical studies. U87 and U373 cells will be exposed to X-rays at UC Biotech, to γ-rays at C2TN and to protons in PET cyclotron-based irradiation set-up at ICNAS in the presence and absence of the AuNPs. Post-irradiation assays will be performed to quantify viability, survival, ROS production and DNA damage. Additionally, GBM xenografts will be developed and administrated with 64Cu-labelled AuNPs, whose biodistribution will be evaluated by PET/MRI imaging and ex-vivo dissection to assess gold content by ICP-MS. These animals will also be exposed to X-ray treatment and proton treatment to evaluate the radiosensitizing effect of the AuNPs. In collaboration with MDACC, these preclinical studies will be reproduced with a clinical proton and photon beams during a 1-year internship.