Nanodosimetric Properties of Very High Energy Electrons through pBR322 Plasmid DNA Studies

  • Kristina Small

Student thesis: Phd

Abstract

1 in 2 people will suffer from cancer during their lifetime and, in the UK, around a third of patients will be treated with radiotherapy, primarily with X-rays. Three decades of research and development into high-gradient linear accelerator technology has resulted in Very High Energy Electrons (VHEE) in the range 100-250 MeV being a potentially viable radiotherapy modality. Advantageous characteristics of VHEE include sufficient penetrative range to treat deep-seated tumours, measured relative insensitivity to inhomogeneities, reduced lateral penumbra and improved dose distribution. VHEE beams can be delivered and controlled rapidly using scanning magnets, making it a candidate for FLASH radiotherapy, a technique involving treatment at ultra-high dose rates - in vitro and in vivo studies present strong evidence of a normal tissue sparing effect. For successful translation of VHEE theory to the clinic, we must understand the effects of VHEE on fundamental biological structures and how these effects compare with well-established modalities. To achieve this, a dose conversion known as Relative Biological Effectiveness (RBE) is required. The primary aim of this project was to quantify the characteristics of VHEE RBE and to compare with other radiotherapy modalities. Traditionally, cell survival is used to measure RBE in vitro, however survival is the end-point of a damage and repair process. To gain fundamental understanding of the biological difference between VHEE and other modalities, it is necessary to separate the nanodosimetric physics qualities of VHEE by looking directly at how damage is induced. DSB yield was therefore selected as the endpoint for RBE calculation, determined following a series of pBR322 plasmid irradiation experiments, the first of their kind for VHEE, at the CLEAR user facility (CERN, 100-200 MeV) and the Christie NHS Foundation Trust (6-15 MeV). 60Co X-ray irradiation provided a reference point for RBE calculations. VHEE RBE varied from 1.1-1.2 over 100-200 MeV, indicating that physical effects of VHEE are similar to that of established modalities. This provides confidence that biological effects including cell death will also be similar - a key step on the road to clinical implementation. Experimental DSB yields were compared with GEANT4-DNA plasmid irradiation simulations of electron track structure, with the aim of producing an accurate Monte Carlo model of VHEE-induced DNA damage. This involved the adaptation of GEANT4-DNA physics constructors to allow modelling of electron track structure above 1 MeV. Parameter optimisation resulted in good agreement between GEANT4-DNA and experimental DSB yields. These damage mechanisms could then be applied to the modelling of biological effects such as DNA damage repair and cell death, with predictions informing treatment planning for clinical cases. As VHEE has been highlighted as a compatible modality for FLASH, a dose-rate variation study was carried out at the CLEAR facility to determine whether a FLASH effect could be observed when irradiating pBR322 DNA at ultra-high dose rates, presenting as a significant decrease in DSB yield. As plasmid irradiation experiments lack many key features causing a FLASH effect (primarily well-oxygenated water), variation between Conventional and FLASH-irradiated samples was not expected. No statistically significant difference between DNA damage yields was observed, it can be suggested that a FLASH effect is not present at the nanoscale under these conditions. A secondary aim of the research was to investigate the range of VHEE beams in various tissues. As part of the steps towards clinical implementation of VHEE, an understanding of the behaviour of treatment beams inside the patient is vital from a treatment planning point of view. As part of this research, a semi-empirical expression for VHEE beam range was produced, dependent on beam energy and the composition of the material through which it travels, using data from simulations of VHEE beams travelling through different media using TOPAS.
Date of Award1 Aug 2021
Original languageEnglish
Awarding Institution
  • The University of Manchester
SupervisorRoger Jones (Supervisor) & Mike Merchant (Supervisor)

Keywords

  • electrons
  • plasmid
  • cancer
  • DNA
  • radiotherapy
  • RBE

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