APHRODITE-155 - Accelerator-based Production of tHeranostic radionuclides: Investigations on TErbium-155

The production of the theranostic radionuclide (RN) ¹⁵⁵Tb, currently not available on the international market, has gained the attention of the researchers working in the field of radiopharmaceuticals (RPs) as Auger-and Conversion Electrons (ACEs) emitter with a suitable gamma for SPECT (Single Photon Emission Computed Tomography) imaging. ¹⁵⁵Tb can also be coupled to other Tb-isotopes, composing emerging theranostic pairs and innovative tools for fighting cancer with personalized treatments in Nuclear Medicine (NM). The study of ¹⁵⁵Tb therapeutic properties can also shed much light on the true cytotoxic power of ACEs for targeted radionuclide therapy (TRT), since ¹⁵⁵Tb does not emit additional alpha or beta particles. However, the production of significant amounts of ¹⁵⁵Tb is still an open issue. Recently, it was shown that among the low-energy routes only the ¹⁵⁵Gd(p,n) reaction can provide ¹⁵⁵Tb with a suitable radionuclidic purity (RNP) for medical applications. On the other hand, the ¹⁵⁹Tb(p,5n)¹⁵⁵Dy reaction, feasible at intermediate-energy proton cyclotron as the one installed at the INFN-LNL, provides ¹⁵⁵Dy, the precursor of ¹⁵⁵Tb, and can be suitable for a generator-system supply.

APHRODITE-155 aims to assess the best ¹⁵⁵Tb production route by using cyclotrons, comparing low and intermediate routes, considering the Thick Target Yield (TTY), isotopic purity (IP) and RNP of the final ¹⁵⁵Tb. Both experimental and theoretical data will be used to assess the optimal ¹⁵⁵Tb production, also considering the dose increase due to the presence of eventual contaminant RNs for specific ¹⁵⁵Tb-labelled RPs. In-house ¹⁵⁵Tb production at the Sacro Cuore Don Calabria Hospital (SCDCH, Negrar, VR) and at INFN-LNL will be performed, including thick target (TT) manufacture, irradiation runs, optimization of a suitable radiochemical process and quality controls (QC). For the low-energy route, isotopically-enriched [¹⁵⁵Gd]Gd₂O₃ TT and the optimization of a suitable radiochemical process for Tb/Gd will be developed; this radiochemical procedure needs to be automatized to guarantee maximum reproducibility and radiation-protection of the operator. For the intermediate-energy ¹⁵⁹Tb(p,5n)¹⁵⁵Dy reaction, the monoisotopic TT will be irradiated at INFN-LNL and transported to UNIMI unit for Dy/Tb radiochemical separation and subsequently elute the ¹⁵⁵Tb produced from electron capture decay (ec) of ¹⁵⁵Dy. In both cases, gamma-spectrometry measurements are essential to accurately evaluate ¹⁵⁵Tb quality to properly define its future use in preclinical and clinical studies. To test the feasibility of ¹⁵⁵Tb-labelled RPs, dosimetric analysis will be also carried out, paving the way for further in vitro and in vivo tests. The fundamental expertise of the INFN, UNIFE and UNIMI units, in collaboration with the SCDCH, the Istituto Oncologico Veneto (IOV, PD), and the Physics Departments of Padova and Pavia Universities are the ground of this project.

Risultati attesi: 

The APHRODITE-155 project is set to achieve significant advancements across several scientific domains, contributing to both fundamental research and applied nuclear medicine:

•  Experimental and Applied Nuclear Physics: We aim to precisely determine the optimal irradiation parameters for producing 155Tb using proton beams, thoroughly comparing both low- and intermediate-energy routes. This research will not only establish the most efficient production method but also contribute to fundamental nuclear physics by providing new data that can refine the theoretical description of excitation functions in this mass range. This, in turn, will optimize nuclear model parameters (such as level densities, pre- equilibrium, and thermalization aspects), leading to more accurate predictions for thick- target yields, impurities, and radionuclide purity.
• Material’s Science and Engineering - Targetry: The project will advance Spark Plasma Sintering (SPS) technology for Gd2O3 targets. This versatile technology has the potential to be adapted for producing other medically relevant Terbium isotopes by strategically selecting the isotopically enriched target material, nuclear reaction, beam type, and energy range.
• Radiochemistry: A key outcome will be the development of novel radiochemical separation protocols. This includes new methods for separating Terbium from Gadolinium oxide targets, as well as the creation of an automatic module for this process—technologies currently unavailable on the market. Furthermore, new radiochemical separation protocols for Dysprosium from Terbium targets will also emerge thanks to specific expertise in radiochemistry and nuclear physics.
• Medical Physics - Dosimetry: Given that the Auger and Internal Conversion (IC) electrons emitted by 155Tb have low energies and are absorbed at a subcellular level, understanding their distribution and impact on radiation dose is critical. Currently, data on 155Tb cellular absorbed fractions or S-values (absorbed dose per unit of cumulated activity) needed for precise cell dose calculations are absent in existing literature. To address this, the project will develop a specific cellular dosimetry model for 155Tb, enabling a thorough evaluation of the therapeutic potential of its Auger and IC electrons.