MR-Linacs provide a unique opportunity for MRI contrast agents to be investigated, not only for the ability to enhance contrast, but for their potential radiosensitising properties to improve radiotherapy treatments. Metal-based nanoparticle contrast agents have a preferential uptake into tumours, allowing for a more targeted approach, and therefore the potential for contrast agents to perform as theranostic agents, both for diagnostic and therapeutic purposes.
Dosimetry was performed to account for the impact of a magnetic field on the dose delivered, using a bespoke setup combining a 6 MV linac and static magnetic field at NPL, which was used to correct for the number of monitor units needed to provide a certain dose to cancer cells in vitro. The radiosensitising impact of both conventional and nanoparticle contrast agents was determined primarily through clonogenic survival assays and DNA damage immunofluorescence assays, at both 225 kVp and 6 MV energies, with and without the presence of a 1.5 T static magnetic field. The contrast enhancement was determined for several different CT and MRI scanners before being compared with patient brain scans to determine clinical relevance of concentrations used in vitro, and combinations of clinical and radiomics features were evaluated using Kaplan-Meier Curves and Hazard Ratios to design a predictive model of overall survival for brain metastases patients treated with SRS. SPIONs were then tested in an in vivo mouse model with H460 xenograft tumours to detect any decrease in the rate of tumour growth caused by radiosensitisation.
Dosimetry measurements validated Alanine, Gafchromic Film and ionisation chambers to be reliable dosimeters in the presence of a magnetic field. SPIONs were found to have the lowest contrast enhancement, particularly at higher concentrations, yet at clinically relevant concentrations they were comparable to AGuIX. Variability was found between 2 different MRI scanners, which is likely due to differences in protocols, caused by varying T1 and T2 relaxation times. In vitro experimentation revealed that SPIONs significantly increased DNA damage to 5 cancer cell lines as well as a significant decrease in clonogenic cell survival in 3 cell lines, which was then determined to be independent of the levels of uptake into the cells, shown via ICP-MS. Finally, an in vivo study with H460 cells treated with 12 Gy radiation and 1 mM SPIONs found a significant decrease in the rate of tumour growth, validating the previous in vitro studies.
This Thesis reports, for the first time, a radiosensitisation from SPIONs in vivo. 3 potential MRI contrast agents were investigated in vitro as potential theranostic agents with the aim of improving both the accuracy of radiotherapy, through greater tumour delineation, and an enhanced dose to tumours through preferential uptake and radiosensitisation. Alongside this, a proof-of-concept model has been established for predicting overall survival in SRS patients with brain metastases, using a combination of clinical and radiomics features. This Thesis forms the basis for further in vitro and in vivo experimentation alongside clinical evidence so that the optimum treatment options with an MR-Linac can be delivered for every cancer patient.
|Date of Award||Jul 2021|
|Sponsors||Medical Research Council & National Physical Laboratory|
|Supervisor||Kevin Prise (Supervisor), Conor McGarry (Supervisor) & Giuseppe Schettino (Supervisor)|