"Dosimetry aspects of recoiling daughter nuclides of 225-Actinium in Targeted Alpha Therapy"

Targeted Radionuclide Therapy (TRNT) is a promising treatment for disseminated and metastatic diseases using a targeting agent labeled with a radionuclide delivering a toxic level of radiation to a specific site. DOTATATE labeled with beta-emitter radionuclides has been widely used in the clinic for peptide receptor radionuclide therapy (PRRT), mostly in the form of 177Lu-DOTATATE to treat neuroendocrine tumors. In this context, 68Ga-DOTATATE has been extensively used as theranostic approach to diagnose and personalize radionuclide therapy. TRNT based on alpha-emitting radionuclides, named Targeted Alpha Therapy (TAT), is considered promising because of their short range within tissue and their high linear energy transfer, leading to high cytotoxicity[1]. Specifically, Actinium-225 (225Ac) is considered a promising candidate for TAT because of its relatively long half-life (10.0 days)[2], its high alpha particle emission energies (total of 28 MeV) and it yields a total of four alpha particles during its decay chain together with two gamma-emissions (218 keV and 440 keV), interesting for imaging. Nevertheless, despite the potential cytotoxic effect caused by the alpha decay within the target site, the energy of the recoiling daughters is so high that the chemical bonds between daughter molecules and targeting agents can be broken (i.e. recoiled daughters effect), giving rise to radiotoxicity in healthy tissues or organs. Moreover, quantitative imaging techniques and dosimetry in humans are challenging because (1) alpha-emissions cannot be directly imaged using conventional nuclear medicine imaging methods and (2) the low injected activity, used in clinical studies, makes it challenging to image it using Single Photon Emission Computed Tomography (SPECT)[3]. Therefore, a dosimetry approach for 225Ac in the clinic will most likely be based on theranostic approaches, by extrapolating time–activity curves from scans of analogue radionuclides (e.g. 177Lu or 68Ga). However, these theranostic agents can be characterized by different pharmacokinetic properties and will not give any information on the recoiling daughters which can have altered distribution and important radiotoxicity making the dosimetry of 225Ac, based on such theranostic approaches, a constraint. Due to the difficulty to obtain human data for dosimetry the emphasis lies on pre-clinical studies and extrapolation of results from such studies to human. 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 pre-clinical level. On the one hand extensive longitudinal studies will be performed, using µSPECT systems to visualize tracer biodistribution during in-vivo studies; on the other hand, during ex-vivo experiments, we will quantify the activity concentration in several organs using both gamma- and alpha- emissions (gamma counter/spectrometry or alpha spectrometry) with the possibility of clearly distinguishing between and amongst them. Furthermore, the optimization and combination of protocols and techniques will allow us to obtain accurate quantitative information and pharmacokinetic profiles for each progeny. Moreover, the obtained time activity curves will serve as an input for organ dose calculations using Monte Carlo simulations and it will allow us to calculate absorbed doses to healthy tissues or organs. Finally, organ dose estimations can be compared on one hand, with a dosimetric approach, relying only on in-vivo imaging of the gamma emitting daughter radionuclides (i.e. imaging 213Bi with μSPECT/CT systems using high energy collimator, [4]) as well as theranostic approaches currently used in the clinic (68Ga-DOTATATE); and on the other hand, with a more extensive dosimetric approach, relying on detailed ex-vivo analyses of the daughter molecules. These results will allow to evaluate the impact of the radiotoxicity of each daughter molecules for 225Ac-DOTATATE and to determine the most appropriate dosimetry approaches and protocols for pre-clinical studies, with a potential translation to its clinical applications. [1] G. Sgouros et al., “MIRD Pamphlet No. 22 - Radiobiology and Dosimetry of Alpha- Particle Emitters for Targeted Radionuclide Therapy,” J Nucl Med, vol. 51, no. 2, pp. 311–328, 2010. [2] J. Elgqvist, S. Frost, J. Pouget, and P. Albertsson, “The potential and hurdles of targeted alpha therapy – clinical trials and beyond,” Fontiers Oncol., vol. 3, no. Article 324, pp. 1–9, 2014. [3] G. Sgouros et al., “Pharmacokinetics and Dosimetry of an a-Particle Emitter Labeled Antibody : 213Bi-HuM195 (Anti-CD33) in Patients with Leukemia,” vol. 195, pp. 1935–1946, 1999. [4] A. K. H. Robertson, C. F. Ramogida, C. Rodriguez-rodriguez, and S. Blinder, “Multi-isotope SPECT imaging of the 225Ac decay chain: feasibility studies,” Phys. Med. Biol. 62, vol. 62, no. 2019, pp. 4406–4420, 2017.