In recent years, many studies investigated biophysical models to predict TAT-related biological effects (from in vitro cell survival, to in vivo tumour control and healthy tissue toxicity) based on dosimetric quantities, but only a few of these studies used microdosimetric analyses. Moreover, the models investigated in these studies are based on very simple scenarios, e.g. one cell type and homogeneous alpha distributions. Thus, they usually fail to predict the biological outcome of more complicated (realistic) scenarios.
As TAT is gaining a lot of interest and more candidate radionuclides, vectors and (pre)clinical applications come into the scene, there is an important need to further elaborate models that are more representative for the realistic TAT applications. The research of this PhD will focus on investigating how microdosimetric quantities can be correlated with the biological response associated to TAT.
Specific TAT scenarios can be identified in which the heterogeneous exposure situations, as mentioned in the introduction, could occur and that need investigation, such as e.g.:
Internalization of the radionuclide in the cell: e.g. receptor agonist vs. antagonist peptides. Especially the agonists can also be internalized by the cell, thus alpha particles can also be emitted directly from the cell cytoplasm or other specific cell substructures.
The choice of isotope, e.g. Bi-213 and Ac-225. Different isotopes will have different decay chains. Some of them can produce alpha-emitting daughters, which will have different biokinetics than the parent nuclide.
The high energy of the alpha decay compromises the stability of the chemical bound with the vector. In such situation the alpha-emitter will not target tumour cells. The radiolysis process by the high dose rates within the radiolabeled peptide solution needs further investigation to improve methods for protecting both the peptide and the chelator.
It is needed to investigate how this heterogeneous exposure configuration affects the biological response (such as cell survival, DNA damage, and oxidative stress) and how a biophysical model based on microdosimetry can help to assess this quantitatively for a range of more relevant scenarios. Dosimetry models need to be developed that link the microdosimetry to small scale dosimetry for in vitro and in vivo irradiation experiments.
The different steps within the research are:
Defining the TAT scenarios, which will set the parameters that influence the models;
Radiobiological experiments with cancer cell lines, including colony survival assays to determine RBE, assessing the number of DNA double strand breaks (DSB) and total cellular amount of reactive oxygen species (ROS) formed;
The calculation of DNA damage with the Monte Carlo code GEANT4-DNA;
The calculation of microdosimetric spectra with Monte Carlo codes (GEANT4-DNA or others).
GEANT4-DNA is a MC code used for modelling biological entities, in which physics models are available in liquid water. It can be used to calculate the absorbed dose (macrodosimetry), the microscopic pattern of the energy deposition (microdosimetry) and cluster size distributions (number of ionizations) in a DNA segment. Data calculated in step 3 will be validated against data obtained in step 2.
The final objective would be to develop a model that predicts biological response (obtained from step 2 and 3) from microdosimetric quantities (obtained from step 4) suitable for different source-geometry scenario's. For each exposure scenario both the biological tests and the microdosimetry will be performed. So if the model is robust enough (i.e. it involves many parameters that are relevant for describing the biological + physical conditions of the scenario), it is hypothesised that it could be applied not only to simple scenarios but also to more complex scenarios (in-vitro and to be investigated also in-vivo).