Investigation of thorium-based generator concepts – improvements, labeling and speciation

Targeted alpha therapy (TAT) is one of the most promising therapeutic approaches in the fight against advanced-staged cancer. For this purpose, radiopharmaceuticals are commonly employed, which traditionally consist of radionuclide, chelating agent, linker entity and targeting molecule. In TαT, both the optimization of existing and the development of novel options of each pharmaceutical fragment remains continuously in demand. In regards to applied radionuclides, α-emitters, e.g. 225Ac or 223Ra are promising candidates, and can be obtained from radionuclide generators.
Hence, this work deals with the investigation and optimization of two different radionuclide separation systems: 227Th/223Ra surrogated by 232Th and natBa and 229Th/225Ra/225Ac surrogated by 232Th/natBa/natLa.
Subsequently, element yields and corresponding purities were evaluated by ICP-MS (Inductively Coupled Plasma Mass Spectrometry). Binding behaviors and elution processes of the three elements were evaluated by X-ray Absorption Near Edge Structure Spectra (XANES) spectroscopic technique on both loading solutions and loaded columns. Additionally, X-ray fluorescence (XRF) maps of the generator columns were recorded to localize the elements during the column elution processes. ... mehrThe experiments were performed at the Synchrotron Laboratory for Environmental Studies (SUL-X) at the KIT Light Source.

After the radionuclide’s elution, the next important step is represented by its prospective chelation. In this work, we focused on Macropa chelator which is used commonly for 225Ac complexation. For this purpose, native Macropa and its derivative for more straightforward conjugation were successfully synthesized. Additionally, DOTA was labeled with the radionuclide 177Lu and five further non-radioactive metals (natLa, natBa, natLu, natGa and natBi). Yields and purities were investigated in correspondence to different peptide backbones or reaction conditions like time, pH and temperature. In addition, the internalization of 177Lu-labeled DOTA conjugates investigated in corresponding cancer cell lines.
In conclusion the experiments resulted in improved radionuclide elution strategies for radionuclide separation, exemplary chelator synthesis for radionuclides' coordination, pharmaceutical synthesis providing targeted delivery of chelated radionuclides, radiolabeling results and proof-of-concept on functional ability of different radiopharmaceuticals. Through the improvement of the individual components of a radiopharmaceutical a holistic view and multiple avenues for future research were found.