ORCID
http://orcid.org/0000-0003-2822-8069
Date of Award
Summer 8-15-2020
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Theranostic radiopharmaceuticals enable diagnostic imaging and radionuclide therapy in patients using a single molecular agent labeled with a diagnostic-therapeutic pair (e.g., 68Ga/177Lu) or a theranostic radionuclide (e.g., 131I). This theranostic approach can help inform patient-specific treatment plans and improve clinical outcomes. Radionuclide pairs used in theranostic agents fall into two categories: pseudo matched-pairs (e.g., 68Ga/177Lu) and matched-pairs (e.g., 124I/131I). Pseudo matched-pair radionuclides have similar chemistries and pharmacokinetics when bound to the same bioconjugate molecule. In contrast, identical chemistries and pharmacokinetics can be obtained by using the matched-pair radionuclides.
The isotopes of Sc include two diagnostic radioisotopes, 43Sc & 44Sc, and one theranostic radioisotope, 47Sc, that have nuclear properties well-suited for use with bioconjugate molecules that target disease. These novel Sc radioisotopes can be produced using Ca or Ti nuclei; however, the optimal route for their production is still being actively investigated. Thus, the aim of this work was to investigate the production of 43Sc, 44Sc, and 47Sc using proton- and photon-induced nuclear reactions at energies up to 24 MeV on Ti nuclei, the digestion of Ti target material, and the purification of Sc radioisotopes from radioactive and non-radioactive impurities. Additional studies were carried out to investigate the in vitro properties of PSMA-617 labeled with these radioisotopes.
Solid target holders fabricated from Al, Nb, and Ta were designed and tested for use on a negative-ion cyclotron and medical electron linear accelerator. These targets mounted metal foil and metal oxide materials for irradiation and were tested at varying conditions (beam energy and current) to determine their durability and the best parameters for maximizing radionuclide yield. These targets were used to experimentally validate the predicted yields from the natTi(p,x)43,44g,44m,47Sc, 48Ti(_,p)47Sc, 46Ti(p,_)43Sc, 47Ti(p,_)44g,44mSc, 48Ti(p,2p)47Sc, and 50Ti(p,_)47Sc nuclear reactions. Methods to digest Ti foil and TiO2 were developed that combined pressure, heat, and the in situ generation of HF in a closed-vessel. The typical digestion times for these methods were 45 min (Ti foil) and 75 min (TiO2) and the average digestion efficiencies were (98 _ 3)% and (95 _ 1)%, respectively. The purification of aqueous Sc was investigated using three cation exchange resins, branched N,N,N�,N�-tetra-2-ethylhexyldiglycolamide (BDGA) and two styrene divinylbenzene copolymer lattices functionalized with either sulphonic acid (AG MP-50) or iminodiacetic acid (CHELEX 100). Average Sc recoveries of (77 _ 7)% and (94 _ 3)% were realized using either a two-step purification (AG MP-50 followed by CHELEX 100) or a single-step purification using BDGA, respectively. After purification, the concentrations of common trace metal contaminants (e.g., Fe, Cu, and Zn) that can interfere with Sc chemistry were approximately 1 mg/L or less. Enriched Ti target materials (i.e., 46Ti, 47Ti, 48Ti, and 50Ti) were irradiated and recovered via alkali precipitation at pH 8 using ammonia solution as a titrant. Recovered precipitant was combusted to regenerate the enriched TiO2 for iterative use. The average percent recoveries of Ti from digested natTi foil and natTiO2 collected after precipitation and combustion were (108 _ 8)% and (104 _ 5)%, respectively. High-purity Sc radioisotopes were used to label two bioconjugates: DOTATOC and PSMA-617, and the in vitro properties of these radiolabeled compounds were investigated using AR42J or LNCaP cells. The radiochemical yield of DOTATOC labeled with 47Sc (1.28 mg/mL) was greater than 99.9%. A blocking study with the somatostatin receptor subtype 2 (SSTR2) agonist Octreotide showed receptor-mediated uptake of [47Sc]Sc-DOTATOC in AR42J (SSTR2+) cells. Similarly, the radiochemical yields of PSMA-617 labeled with 43Sc and 47Sc were greater than 99.9% at molar activities between 32-74 MBq/nmol. The stability of [43Sc/47Sc]Sc-PSMA-617 was greater than 95% at 168 h in PBS, human serum, and mouse serum. The percentages of [43Sc/47Sc]Sc-PSMA-617 associated with LNCaP (PSMA+) and PC3 (PSMA-) cells after 4 h of incubation at 37 _C were (22 _ 1)% and (0.30 _ 0.01)%, respectively.
These results demonstrated a robust method for the cyclotron production of Sc radioisotopes via proton-induced reactions that could be used with natural or enriched TiO2 target material. In turn, DOTATOC and PSMA-617 were labeled with high-purity Sc radioisotopes produced via these methods and their in vitro properties were investigated. The strategies developed in this work and data from initial studies will be used to support future work to compare the in vitro and in vivo efficacy of [43Sc/47Sc]Sc-PSMA-617 to [68Ga/177Lu]Ga/Lu-PSMA-617.
Language
English (en)
Chair and Committee
Lee G. Sobotka Suzanne Lapi
Committee Members
John R. Bleeke, Sophia E. Hayes, Buck E. Rogers,
Recommended Citation
Loveless, Christopher Shaun, "Production of Medical Radioisotopes using Titanium Accelerator Targets" (2020). Arts & Sciences Electronic Theses and Dissertations. 2328.
https://openscholarship.wustl.edu/art_sci_etds/2328
Included in
Inorganic Chemistry Commons, Nuclear Commons, Nuclear Engineering Commons, Other Chemistry Commons, Radiochemistry Commons