61Cu/67Cu theranostic pair production, chemical separation and radiolabeling
Historical relations between physics and medicine accelerated with the discovery of X-ray radiation and shortly thereafter with the discovery of radioactivity in the 19th century. At present, the term medical physics refers to physicists whose work is mainly concerned with medical applications of radiation. One of the most prominent applications of physics and chemistry in the medical field is nuclear medicine. Nuclear medicine can be defined as the medical specialization that uses radionuclides to investigate organ metabolism and to provide diagnosis and therapeutic interventions. The origin of nuclear medicine and radiopharmaceutical chemistry was started with the fundamental research started by George De Hevesy, and the first cyclotron was built by Ernest Orlando Lawrence in 1930. About 95% of the radiopharmaceuticals are employed in nuclear medicine for diagnosis, while the rest are used for therapy. A radiopharmaceutical consists of two components: a radionuclide and a pharmaceutical compound. First, a pharmaceutical compound is chosen that preferentially targets a given receptor or other cellular targets, then an appropriate radionuclide is attached to it for diagnosis or therapy. According to the available data at the International Atomic Energy Agency (IAEA), 134 countries use nuclear medicine facilities and equipment. Due to the rising prevalence of NCDs (Non-Communicable Diseases), the availability of new tracers, and the high demand for early and accurate diagnoses, NCD are expected to be the fastest-growing segment in nuclear medicine. There is an increasing demand for a personalized medicine approach in this era with scientific and technological developments. Several factors have resulted in the growth of personalized medicine, such as advances in molecular biology, a better understanding of processes, and more excellent knowledge of individual diseases’ mechanisms.
Theranostics, which is a combination of therapy and diagnosis, has introduced a new chapter in the field of nuclear medicine for providing personalized treatment to the patient. Among the different radioisotopes, Cu offers several radioisotopes potentially appropriate for use in nuclear medicine. One of the most promising pairs is 61Cu/67Cu that could be applied in theranostic applications. However, its optimized production and its availability in large quantity have been among the main challenges in nuclear medicine and constitute our inspiration to start this Ph.D. study.
This thesis was performed in the framework of the Sinergia project â€śPHOtonuclear Reactions (PHOR): Breakthrough Research in Radionuclides for Theranosticsâ€ť funded by Swiss National Science Foundation (SNSF). This enterprise is based on a collaboration among the Department of Chemistry, Biochemistry, and Pharmacy (DCBP) and the Laboratory of High Energy Physics (LHEP) of the University of Bern, and the Federal Institute of Metrology (METAS).
This thesis is structured in 5 chapters:
The first chapter introduces and deals with the basics of radiopharmaceutical chemistry and different production methods. In addition, the first chapter presents an introduction of nuclear medicine and its applications in diagnosis and therapy, along with introducing different radionuclide production facilities such as cyclotron, reactor, and electron accelerators. Chapter two focuses on the investigation of 61Cu and 67Cu production through different nuclear reactions and finally production of 61Cu by irradiation of 64Zn using a proton cyclotron at SWAN Isotopen AG at Inselspital Bern and production of 67Cu via irradiations of 68Zn with Bremsstrahlung generated by a 22 MeV Microtron at METAS. Chapter three introduces a novel method based on an evaporation technique for the efficient separation of Cu from the irradiated Zn targets, followed by a liquid chemical separation using extraction chromatography. To achieve this, an automated system (using a Modular-Lab PharmTracer system) was developed and installed in the framework of this thesis. With this automated system, Cu was completely separated and purified from the irradiated Zn targets. Moreover, in chapter three, radiolabeling of Cu with DOTA peptide was investigated. In chapter four, as a part of this study, the production of further potentially suitable radionuclides for medical applications such as 167Tm, 165Er, and 135La were investigated. Chapter five gives a summary of all processes that were considered and employed in this Ph.D. thesis and provides an outlook for further studies in the near future.