Medical alpha emitting radionuclides: how to correlate microdosimetry with biological effects?

Tamborino Giulia

Promoter

De Jong Marion, (EURotterdam), m.hendriks-dejong@erasmusmc.nl

SCK•CEN Mentor

De Saint-Hubert Marijke
marijke.de.saint-hubert@sckcen.be
+32 14 33 21 40

SCK•CEN Co-mentor

Struelens Lara
lara.struelens@sckcen.be
+32 14 33 28 85

Expert group

Research in Dosimetric Applications

PhD started

2017-10-01

Short project description

The potential of targeted alpha therapy (TAT) for cancer treatment has been widely acknowledged. Alpha particles are particularly attractive for targeted radionuclide therapy (TRNT) because of (i) their short range (< 100µm), which makes the irradiation specific with the right targeting moiety, and (ii) their high linear energy transfer (LET), which makes them highly cytotoxic. Thus, the same energy transferred to tissue is more toxic for alpha particles than for beta particles, which have a low LET. In this context, the relative biological effectiveness (RBE) has to be taken into account when treatments with different radiation types are being compared.

However, the same characteristics that make alphas attractive also render a number of challenges for the dosimetry of alpha particle-emitting radiopharmaceuticals.  A non-uniform distribution of the radionuclides (e.g. due to heterogeneous target expression among cancer cells and the diversity of structures in the actual tumour tissue) in combination with the short path length and high-LET of alpha radiation might result in a non-uniform dose distribution even at cellular level. This may lead to localized toxicities that affect the tissue as a whole. This toxicity is inconsistent with radiotoxicity predicted by estimations of the average (uniform) absorbed dose. It is therefore inappropriate to investigate the therapeutic efficacy of TAT by macrodosimetry. The microdosimetry approach is more suitable to study TAT from physics point-of-view because it takes into account the stochastic nature of energy deposition at the cellular level. This approach has also been highlighted by the Medical Internal Radiation Dose (MIRD) Committee1 and by the IAEA2.

Because of the short range of alpha particles, the spatial bio-distribution of the alpha emitter at cellular and even sub-cellular level starts to play a role on how effectively tumour cells are irradiated and therefore killed. It is clear that if the distance between the point of emission of the alpha particle and a cancerous cell (and its biological target) is greater than the maximum range of the alpha, no irradiation of that cell will be likely to occur. On the other hand, if the cell is hit by the alpha particle, energy deposition events in the cell and its substructures (like cell nucleus) might show great variations depending on the specific trajectory of the alpha particle, as energy deposition of alpha radiation follows a Bragg peak pattern.

Microdosimetry studies the probability distribution of specific energies (deposited energy per unit mass), i.e. the microdosimetric spectrum. While two different microdosimetric spectra may have the same mean specific energy (proportional to the absorbed dose), they can result in significantly different levels of cell killing. The microdosimetric spectrum is dependent on the size and shape of the target region (the site where the specific energy is evaluated) and source-target geometry (i.e. the position of the point of emission of the alpha particle with respect to the target). The spatial biodistribution of the radionuclide depends on many factors, including the biokinetics of the therapeutic compound, targeting specificity and stability of the radiolabelled vector, level of expression of target molecule in tissues, availability of radiolabelled vector in malignant tissues, etc.

References

  1. G. Sgouros, et al. MIRD Pamphlet No. 22 – Radiobiology and Dosimetry of Alpha-Particle emitters for Targeted Radionuclide Therapy

  2. IAEA report on Technical meeting on "Alpha emitting radionuclides and radiopharmaceuticals for therapy", June 24-28, 2013

Objective

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:

  1. Defining the TAT scenarios, which will set the parameters that influence the models;

  2. 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;

  3. The calculation of DNA damage with the Monte Carlo code GEANT4-DNA;

  4. 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).