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Abstract
The development of peptide based radiopharmaceuticals has rapidly expanded the role of nuclear medicine in the oncology space to include synergistic diagnostic and therapeutic components. The current rendition of this theranostic approach is built upon the idea that, by utilizing diagnostic and therapeutic radiopharmaceuticals with similar pharmacokinetics, the diagnostic agent can be used as a screening tool in treatment planning. Under this context, uptake patterns observed on PET or SPECT imaging can probe treatment effectiveness prior to the actual administration of any therapeutic, thus mitigating ineffective and burdensome treatments. The most convincing evidence for the utility of theranostics can be seen in the increasingly widespread clinical implementation of 68Ga-PSMA-11 (LOCAMETZ) and 177Lu-PSMA-617 (PLUVICTO) for the visualization and treatment of metastatic castration resistant prostate cancer (mCRPC). This combination of prostate-specific membrane antigen (PSMA) targeting agents have been instrumental in increasing progression-free survival and overall survival times in cases of mCRPC; however, as pseudo theranostics, 68Ga-PSMA-11 and 177Lu-PSMA-617 do not embody a full realization of the potential of theranostics. Because 68Ga-PSMA-11 and 177Lu-PSMA-617 utilize different targeting ligands and radioactive elements, they only share similar rather than identical pharmacokinetics. While this is sufficient for the theranostic implementation described above, pseudo theranostics are unsuitable for the application of diagnostic imaging as a predictor of therapeutic dosimetry in treatment planning, often considered to be the penultimate goal of nuclear medicine theranostics. The development of predictive dosimetry would instead require a true theranostic pair, two radiopharmaceuticals which utilize the same targeting ligand and two different radioisotopes of the same element for diagnostic imaging and targeted radionuclide therapy. In this regard, the radioscandiums are optimal for true theranostic use as they consist of two potential PET imaging agents, 43Sc and 44Sc, as well as a beta electron emitting isotope well suited for therapy, 47Sc. As a group 3 trivalent cation, the radioscandiums can also conjugate with DOTA, the chelator which connects the radionuclide to the targeting ligand in PSMA-617. Consequently, radioscandium PSMA-617 has the potential to have applications in mCRPC which overlap with 68Ga-PSMA-11 and 177Lu-PSMA-617 in addition to the potential for predictive dosimetry as a true theranostic pair. Before these potential applications can be tested, however, significant strides need to be made in the development of radioscandium pharmaceuticals with regards to accelerator-based production, radiochemistry, pre-clinical evaluation, and dosimetric simulation. These aspects of radioscandium development are therefore the focus of this work. The first objective of this work is therefore to develop radioscandium production methods using a compact medical cyclotron. This was accomplished through the production of 43Sc, 44Sc, and 47Sc with a novel solid target holder that slots into the beam-stop of a standard biomedical cyclotron. A procedure was also developed for the dissolution of the irradiated target materials and subsequent radiolabeling with PSMA-617. Utilizing the radiolabeled radioscandium materials, the second objective is to characterize the diagnostic and therapeutic efficacy of radioscandium PSMA-617 in vitro and in vivo. This was accomplished through an analysis of uptake and internalization in vitro, PET and SPECT imaging, and DNA double strand break immunohistrochemistry in vivo. All in vitro and in vivo models utilized a PSMA expressing enzalutamide resistant LNCaP cell line and a non-PSMA expressing DU145 cell lines for the negative control. The final objective is to define the dosimetric properties and radiobiological effect of the radioscandiums using Monte Carlo dosimetry simulations. Utilizing the Monte Carlo program TOPAS, simulations were devised to generate radially-varying energy deposition curves, cellular S-values, and DNA double strand break data for the radioscandiums and their clinical analogues, 177Lu and 68Ga.