Pharmaceutical development of the ISOL technique for the production of radionuclides and their applications in targeted radionuclide therapy

Radiopharmaceuticals are the fundamental tool for nuclear medicine procedures, enabling imaging and therapy of cancer after administration of a radioligand. Imaging or therapy are performed with radionuclides that are bound to a ligand, which selectively accumulates into cancer tissues. The discovery of new radionuclides on one side and the optimization of ligands on the other are fundamental parts of the research in the radiopharmaceutical field. In the first part of this thesis work we aimed at the development of a new technique for the production of pure radionuclides. The study was born from the collaboration between the Department of Pharmaceutical and Pharmacological Sciences (DSF) of the University of Padua (UniPD) and the Legnaro National Laboratories (LNL) of the National Institute for Nuclear Physics (INFN), where the Selective Production of Exotic Species (SPES) project is under development. This project aims at the production of Radioactive Ion Beams (RIBs) by means of the Isotope Separation On-Line technique (ISOL), which can be exploited for radionuclides production. Thanks to mass separation, a feature of the ISOL technique, radionuclides can be produced at high purity because isotopic contaminants can be cleared away easily. Suitable secondary targets (chapter 2) were developed to allow ion beams collection, depending on the accelerated ions. To verify the suitability of the method for radionuclides production, tests with accelerated stable ion beams were carried out and are described in chapter 3. The SPES test bench was used for the elements ionization and acceleration. The beams were collected on the produced secondary targets and quantified. The tests were carried out for yttrium, iodine and copper, elements interesting for the production of 90Y, 125/127/131I and 64/67Cu. The ISOL method guarantees the purification of the radionuclides from the isotopic contaminants, but isobaric and pseudo-isobaric contaminants can be present in the beam and thus in the final solution. For this reason chemical purification methods have to be developed for radionuclides purification. In chapter 4 the synthesis of an inorganic material (sodium nonatitanate) and its use for strontium and yttrium purification is described. The second part of this thesis, chapters 5 and 6, was developed in collaboration with the group of PD Dr. Cristina Müller at the Center for Radiopharmaceutical Sciences (CRS) of Paul Scherrer Institute (PSI). Targeted radionuclide therapy (TRT) represents one of the most promising therapeutic strategies for cancer therapy ; it is based on the use of energetic particles (alpha, beta- or Auger electrons) selectively delivered in proximity of tumors thanks to specific biologic features. Small molecules are an attractive strategy for active targeted delivery because they are amenable for chemical synthesis and have some advantages if compared with high molecular weight vehicles, such as antibodies. A potential challenge of small molecular radiotherapeutics is their fast elimination from the body preventing sufficient accumulation of radioactivity in the malignancies due to glomerular filtration and fast renal clearance; high accumulation of radioactivity in the kidneys increases at the same time the risk of nephrotoxicity. For this reason, new strategies to allow a higher translation from preclinical to clinical phase of small molecule-based radiopharmaceuticals should be developed. In this thesis project two strategies to improve TRT with small molecules were developed. The first relies on the development of radioligands with a serum protein-binding domain. This strategy is based on the consideration that serum proteins have high molecular weight, and for this reason do not undergo glomerular filtration (filtration cut-off 30-50 kDa). In particular, three serum proteins-binding compounds were radiolabeled and characterized in vitro and in vivo (chapter 5). Another strategy to improve TRT efficacy while decreasing side effects is the use of combined-modality regimens. This approach is very popular in cancer therapy since targeting the cancer cell on diverse molecular path mechanisms makes the cell less prone to developing resistance to the therapy. At the same time, the use of multimodality therapies allows to decrease the dosage of single therapies, thus reducing side-effects. In the last chapter of this thesis (chapter 6) a preliminary study combining radionuclide therapy (177Lu-cm10) with two tyrosine kinases inhibitors is described, based on the assumptions of a possible synergistic effect of the two agents