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 (< 100 µm), which makes the irradiation specific with the right targeting moiety, and (ii) their high linear energy transfer (LET), which makes them highly cytotoxic. However during Targeted Alpha Therapy (TAT) the recoil energy of recoiling daughters is so high that the chemical bonds of the daughter molecule with the targeting vehicle will be lost. The released daughter molecule can be retained inside the tumor, when internalized inside the cell, which will enhance the cytotoxic effect, but it can as well diffuse or be transported to various organs where it can accumulate and cause radiotoxicity of healthy organs.
225-Actinium (225Ac, half-life 10 days) decays via a cascade of six daughters to 209-Bismuth (209Bi). In its decay chain, 225Ac emits 4 alpha-particles with maximum energies ranging from 5.8 MeV to 8.4 MeV and 2 beta-disintegrations with a maximum energy of 1.6 and 0.6 MeV (see figure 1). This makes 225Ac very promising as therapeutric radioligand, but caution is required on the radiotoxicity of systemically released daughter radionuclides. 217-Astatine (217At) has the shortest half-life (32 miliseconds) and almost instantly decays to 213Bi. Both 221Fr and 213Bi have relatively longer half-lives (45.6 and 4.9 minutes) and therefore can diffuse inside the body and cause severe radiation damage to healthy tissue. Interestingly 221Fr and 213Bi emit gamma-rays with distinct energies of 218 (abundance 11.6%) and 440 keV (abundance 26.1%) respectively, which can be used to image the drug distribution. Nevertheless the high potency of 225Ac requires small activities to be administered for pre-clinical and clinical therapeutic studies, which renders quantification through Single Photon Emission Computed Tomography (SPECT) challenging. Moreover the released daughter molecules may have a different biodistribution and therefore images based on gamma-emitting daughter molecules may fail to reflect the 225Ac distribution, which is an important concern hampering accurate dosimetry. Theranostic approaches may help to overcome this and depict the distribution of 225Ac-labeled compounds by labeling the compound with another radionuclide such as 68-Gallium that allow Position Emission Tomography (PET). For example the first, very promising clinical data on 225Ac-PSMA treatment used 68Ga-PSMA for diagnosis and therapeutic follow-up [2017 Marie Curie Award of the European Association of Nuclear Medicine (EANM)]. Nevertheless, reliable dosimetry is challenging on the basis of 68Ga, because the shorter half-life (68 minutes) will not allow to cover the long half-life of 225Ac (10 days) and dosimetry based on such theranostic approaches assume exactly the same pharmacokinetic between diagnostic and therapeutic radionuclides. On the other hand, the theranostic approach will not give any information on the recoiling daughters which can have altered distribution and important radiotoxicity which needs to be concerned for dosimetry.
Although the treatment capacities of 225Ac are remarkable and research and clinical trials with this radionuclide are nowadays flourishing, an accurate dosimetry and knowledge on the drug distribution and related radiotoxicity effects are lacking behind for optimal patient care. This PhD proposal will focus on the characterization and quantification of the biodistribution of 225Ac and its decay progeny and the resulting absorbed dose calculations on preclinical level, i.e. experiments will be performed in tumour-bearing mice in which radionuclide analysis will be performed on several time points after injection of the 225Ac-compound. Data from pre-clinical studies play an important role in the prediction of human radiation dosimetry for phase I clinical trials, as absorbed doses delivered to organs at risk of radiotoxicity can limit the amount of activity that can be administered into patients.
Ideally, all the radionuclides involved should be individually monitored and quantified in time allowing to have a radionuclide-specific pharmacokinetic profile. As existing and emerging activity determination techniques (gamma counter, µSPECT, alpha autoradiography, alpha spectroscopy and more) each have their specific advantages and limitations for activity quantification, the challenge of the PhD will be to investigate how these methods and protocols need to be optimised and combined to obtain the most optimal result. An important part of the PhD work will be dedicated to setting up reliable quantification methods and protocols for the most important radionuclides in the decay scheme of 225Ac.
The pharmacokinetic profiles of the different radionuclides will serve as an input for organ dose calculations using a Monte Carlo radiation transport code. Finally, organ dose estimates will be compared between a dosimetry approach, relying only on in vivo imaging of the gamma emitting daughter radionuclides, with a more exhaustive dosimetry approach, relying on detailed ex vivo analyses of a larger range of daughter molecules. These results will allow to evaluate the impact of the radiotoxicity of the daughter molecules and suggest appropriate dosimetry approaches or protocols.