Within PRISMAP, we are investigating innovative isotope enrichment techniques that could lead to a new European supply chain. We investigate the technique of laser-enhanced isotopically selective condensation, that has been demonstrated by the team of Hubert van den Bergh from Ecole Polytechnique de Lausanne in the 1980s. It consists in the nucleation and clusterisation of argon atoms to a volatile molecule as the mixture of argon and titanium- or calcium-containing molecules is expanding through the nozzle of a gas cell. During the gas expansion, dramatic cooling of the gas mixture from room temperature (~300K) down to ~15K occurs, enabling this process. However, by applying infrared (IR) excitation at a frequency specific to an isotopomer (molecule containing a specific isotope), that molecule can be heated up hereby preventing the nucleation and thus the cluster formation. The clusters and the free molecules experience then different drag forces in the jet that allows their physical separation.
In our recent investigation at KU Leuven, we have explored many different titanium- or calcium-containing molecules with density functional theory (DFT) calculations. Those have allowed to identify different IR transitions in those molecules, as well as which ones are sensitive to the mass of the titanium or calcium isotopes. Simple calculations were first performed on TiFx [x=1,2,3,4] molecules to benchmark the approach and challenge the DFT calculations against experimental IR spectra. We then proceeded on exploring the binding with argon atoms as TiFxArn at room temperature and 15K, which demonstrated the lack of cluster formation at room temperature while more than 20 atoms can cluster around a cold molecule.
Finally, we performed our calculations on more complex molecules that might be more practical to synthesize and manipulate. From this investigation, it was concluded that the IR region where the sensitive transitions were identified do not vary substantially between molecules and are all located around 12µm to 13µm, corresponding to those transitions arising from a substantial motion of the titanium or calcium atom, while transitions in more accessible IR regions are originating from the motion of other parts of the molecule, which are thus not sensitive to the different isotopes of titanium or calcium.
Research into the efficient production of laser light in that region, as well as the experimental validation of those DFT spectra will now be investigated at CERN.
In May 2022, PRISMAP work package 9 (WP9-transport and logistics) published a report, which describes and outlines the existing rules and means of transport (primarily air and road) and how these rules and their implementation induces important constraints on the optimal distribution of novel radionuclides within the network. Based on input from the project partners and the analysis of the most urgent transportation needs arising from the first round of user projects, the report describes important bottlenecks for the efficient and reliable transport of novel PRISMAP radionuclides.
The medical use of open radioactive sources (radioactive material) for diagnosis and therapy has traditionally relied heavily on transport of the radionuclide and/or the relevant radioactive compound from the point of production (typically reactors or accelerators) to the point of use (typically departments of nuclear medicine in major hospitals). Over decades, a specialized transportation system has been developed by the radionuclide and radiopharmaceutical industry, but it has proven difficult for the specialized producers of the novel PRISMAP radionuclides to utilize such distribution channels effectively.
In the report, the present and future needs (including the mass separation steps) and the perceived shortcomings of existing transport channels are highlighted. The aim of this report is to establish a commonly useful transportation system for air and road transport of radioactivity between partners together with the establishment of a common, easily applicable set of rules and guidelines allowing the easy and swift transport within Europe of non-standard, developmental, preclinical and early clinical radionuclides, thus resulting in a faster and more efficient shipping process across the consortium and to the end-users of the research community.
The report highlighted that all the day-1 radionuclide production facilities already have experience with the transport of radioactive materials (type A and type B), and they can by existing methods reach the PRISMAP medical facilities more or less rapidly. The problems at present mainly lie with the short-lived isotopes with half-lives under 1 day. Here, even conventional air transport has led to significant, perhaps even prohibitive decay losses, because of the combined delays in the connecting road transports and the now necessary check-in/check-out procedures. An additional problem arises from the vulnerability of such transports to delays far beyond the planned time. Reasons can be attributed to: road congestion, airport congestion, delays in dangerous goods clearing, denied or delayed boarding of the radioactive transports to passenger planes (where airlines will often prioritize differently from our PRISMAP needs), cancelled flights, and bad weather. It was deduced that some of the delays could in some part be prevented by better procedures and better contact and understanding between the shipping laboratories and the carriers.
Based on the first PRISMAP user project requests received, we have analysed the challenges and provided solutions to the delivery plan of the required radionuclides in a timely manner. It was established that most radionuclide shipments for the first call of project requests could be delivered from the producer to the end-user faster through road transport than air transport. Subsequent PRISMAP user project requests will also be critically reviewed in a similar manner and advice will be provided accordingly.
Typical Type A package for shipping novel PRISMAP radionuclides
Going forward, it is the intention during PRISMAP to develop a set of simple-to-use packaging and shipping instructions that can help prevent common errors in preparing packages and shipping documents. Additional gains may be made through a dialogue with selected airlines that can commit to priority handling of our PRISMAP shipments. Similarly, it will be attempted to make existing international courier services interested in serving our needs. However, this will require both high-level business decisions in the courier sectors as well as time for implementation. If such schemes are to work, many drivers, handlers and cargo agents will need to be additionally trained in radioactive transports. However, none of the above proposals can solve all the time and reliability issues. Under this background, the possible use of small fixed-wing aircrafts for point-to-point services between local airports/airfields shall be further investigated. This will require a further clarification of rules and procedures for such small aircraft transports. Some of these steps will require the assistance from both the national and international regulators.
Transport and logistics is collecting knowledge about the many small and big obstacles to rapid transfer of radioactivity between the PRISMAP partners. At present the focus is on the transport to ARRONAX in France of Cu-64 samples for the intercomparison tests. Negotiations with airlines, transport companies, handling agents and authorities are under way to clarify the possibilities for short-term exceptions and also more general solutions in the future. When off-line mass separation is to be used regularly there is a double pressure on the rapid transfer, as activity first needs to go from reactor/cyclotron to the mass separator, and then from the separator to the end user.
An interim report describing the present transport situation will be delivered within the next few months.
The use of radionuclides in nuclear medicine for diagnostics and therapy has significantly increased over the last decay. As a result, there is an urgent need to explore the usage of new radionuclides and relative innovative production methods. Depending on both half-life and decay emission, these radionuclides can be used for imaging, via positron emission tomography (PET) or single-photon emission computed tomography (SPECT), and for therapy via α, β−, or conversion and /or Auger electron emission. Within each of these categories, there are several radiolanthanides with a variety of tissue ranges and half-lives offering attractive decay properties.
Production of sufficient amounts of high quality radiolanthanides requires systematic research in targetry, irradiation, radiochemistry and quality control. In some cases, it is difficult to produce carrier-free and/or radionuclidically pure products with conventional reactor-based or accelerator-driven production routes. Thus, the use of mass separators to produce carrier-free radionuclides for nuclear medicine is becoming an attractive method. In the frame of PRISMAP WP12, together with eleven universities and research laboratories, scientists are going to investigate the potential of novel radiolanthanides for nuclear medicine applications.
The main tasks of this WP are the development of specific radiochemical separation methods and preclinical research studies for novel radiolanthanides (149Tb, 152Tb, 155Tb, 161Tb, 175Yb, 153Sm, 167Tm, 165Er, 169Er, and 135La). In particular, an assessment of the quality control and radiolabelling processes of these radiolanthanides will be established. This information will be of great interest for developing clinical methods using different Tb radionuclides for theragnostic applications. The produced data will also implement the use of conversion/Auger-electron-emitting radionuclides towards the treatment of disseminated tumor cells and small metastases. Enhanced knowledge of these novel radiolanthanides and exploration of their therapeutic effects will be greatly appreciated by the scientific community of nuclear medicine and will pave the way towards more efficient cancer treatments.
As PRISMAP looks to make a new generation of radionuclides easily accessible to researchers, it is vital that any pre-clinical and clinical research is underpinned by accurate and reproducible measurements of activity and dosimetry. In the clinical setting these measurements are typically performed using a radionuclide calibrator before administration to a patient, with traceability to a national metrology institute such as the National Physical Laboratory (UK) or the Institute of Radiation Physics (Switzerland). This traceability comes through the primary standardisation of activity and underpins all clinical use of any radiopharmaceutical. To this end, the translational data generation work package (WP11) will seek to provide this traceability for the novel radionuclides being generated by the PRISMAP consortium and disseminate these standards to the wider community. Alongside this development, accurate nuclear decay data will be determined to provide confidence in this fundamental data. A challenge of molecular radiotherapy is the understanding of the dose delivered at a cellular level and the biological effect of the emissions of a radionuclide to tumour cells. To improve our understanding, Riga Technical University (Lativia) will investigate the doses absorbed from the emissions from the radioactive decay of radionuclides using nano-dosimeters. The University of Oslo will look at developing a traceable link of the activity standards of the PRISMAP radionuclides to their relative biological effectiveness through the dose response.
Production of medical radionuclides has always benefited from high level technologies developed in the context of nuclear and accelerator physics research. In particular, some important ISOL technologies adopted for targets, ion sources, and isotope separation demonstrated an enormous potential for medical radionuclides. WP10-JRA2 is organised in three different tasks: target design and characterisation (task 1), ion sources (task 2), and isotope separation techniques (task 3). They are all oriented to improve the scientific instruments and the technologies required for the production of medical radionuclides. This approach will benefit from the collaboration among prestigious international research institutes in the framework of PRISMAP.
Task 1 and task 2 will mainly focus on the optimization of targets and ion sources, respectively, with the aim to increase as much as possible the production rate of specific medical radionuclides. In particular, new high performance materials will be studied and characterized, especially at high temperature ranges. New targets and ion sources will be designed making use of complex multiphysics simulation tools.
The object of task 3 is the strong enrichment of Ca and Ti isotopes from their natural abundance to an abundance useful for radionuclide production in reactors or cyclotrons. Indeed, production of theranostic scandium isotopes (43Sc, 44Sc, 44mSc and 47Sc) relies on the availability of highly enriched Ca or Ti isotopes respectively. With this in mind, task 3 will investigate the enrichment via laser-enhanced isotopically selective condensation, an innovative technique pioneered at EPFL and successfully used in the past for the enrichment of different isotopes.
As a concluding remark, it is clear that WP10-JRA2 will lay the foundations for a structured community of scientists and research engineers deeply focused on the technologies for the production of pure medical radionuclides.