Reference : UMR9012-ALEHEN-027
Workplace : ORSAY
Date of publication : Monday, May 2, 2022
Scientific Responsible name : Charles-Olivier BACRI
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 September 2022
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
-The need for new medical radionuclides continues to grow as the personalisation of the treatment becomes more widespread. The diversity of their decay mode as well as the variety of their half-life make them valuable tools for both medical imaging and therapy. An important criterion for their development is the possibility to produce them in sufficient quantity with high chemical purity (optimisation of chelation chemistry and isotope delivery to target organs) and isotopic purity (minimisation of unnecessary radiation emitted by the radiopharmaceutical). The objective of the thesis is to propose an alternative method, based on the isotopic separation of the stable precursor of the desired radionuclide, Tb-155, for its production.
Several experiments will be carried out to determine the optimal parameters for this production.
The work will be carried out in a collaboration that explores the entire production process, from the stable precursor of the radionuclide, to the design of the Tb-155 radio-labelled molecule.
Detailed presentation of the research project (+ cooperative aspect)
The need for new medical radionuclides continues to grow as the personalisation of the treatment becomes more widespread. The diversity of their decay mode as well as the variety of their half-life make them valuable tools for both medical imaging and therapy. An important criterion for their development is the possibility to produce them in sufficient quantity with high chemical purity (optimisation of chelation chemistry and isotope delivery to target organs) and isotopic purity (minimisation of unnecessary radiation emitted by the radiopharmaceutical).
This subject is part of the PRISM project (Production d'Isotopes et Séparation pour le Médical) coordinated by the IJCLab laboratory in Orsay in collaboration with laboratories in Nantes (SUBATECH and ARRONAX) and Caen (GANIL). It aims to propose a production method for radionuclides that we do not know how to produce today under conditions compatible with their use in a medical environment. In this context, the ANR TTRIP (Tools for Tb RadioIsotope Production for nuclear medicine) which has just been accepted and which will finance this thesis, has made it possible to extend the collaboration to two other laboratories located in Dijon (ICMUB) and Strasbourg (IC-UNISTRA) in order to develop a new bi-functional chelator (a sort of cage allowing the radioisotope to be retained in the vector molecule which will guide it to the target organs) compatible with a biological vector. The collaboration in which the thesis will be carried out is multidisciplinary, consisting of nuclear physicists, a metrologist, organic and coordination chemist's specialists in the production of medical isotopes, of materials science, and of medical imaging. The thesis will be carried out in the IJCLab « Physics for Health» team.
The thesis will focus on the production of Tb-155 which belongs to the théranostic (contraction of therapy and diagnosis) quadruplet of Terbium. This quadruplet is particularly interesting since it has both isotopes of diagnostic interest (Tb-152 for PET imaging and Tb 155 for SPECT imaging) and others of therapeutic interest (Tb-149 for alpha therapy, and Tb-161 for beta therapy). Their identical chemistry gives them identical bio- and pharmaco-cinetic properties, thus allowing better personalisation of the treatments.
The production method proposed by the collaboration consists of using a stable precursor isotope of high isotopic purity, Gd-155, to produce Tb-155 through the Gd-155(p,n)Tb-155 reaction. The minimisation of parasitic reactions on other Gadolinium isotopes (natural Gd is generally used) will thus make it possible to simplify as much as possible the necessary purification phase of the Tb produced.
We will take advantage of the use of the high-performance isotope separator SIDONIE to separate Gd-155 from natural Gd with high purity. Several targets will be produced by implantation with SIDONIE and then characterised: their chemical purity by PIXE, RBS and MEB/EDX techniques, their homogeneity by RBS and confocal microscopy, and their isotopic purity by various techniques, including proton activation. The measurement of the excitation function of the Gd-155(p,n)Tb-155 reaction (cross-section as a function of the proton incident energy) will be then performed on the ARRONAX cyclotron in order to determine the optimal energy of the proton beam. This energy will be a compromise between the quantity of Tb-155 produced (maximum cross-section) and its purity (minimisation of contaminants). A parametric study will complete this study, in order to determine the optimal parameters of the whole production process.
The minimum necessary purity of Gd-155 will be determined by comparing the results obtained with SIDONIE (expected purity of the order of 10E-5) and targets of 90% enriched Gd-155 (with different techniques using commercially available raw material). The aim will also be to find the best compromise between the isotopic purity of Gd-155 (separation time required with SIDONIE), and the contamination rate of the Tb-155 produced (isotopic and chemical purities), as well as a compromise between the thickness of the targets produced (large number of Gd-155 atoms to maximise the production of Tb-155) and the constraints linked to the intensities of the ARRONAX beams (maximum intensity and thermal power deposited on the target). An optimised production method will thus be proposed.
As a first step, targets will be fabricated from commercial Gd-155 by different laboratories in the collaboration (including IJCLab) using different techniques. One part of the thesis will therefore consist of developing a reproducible method for target fabrication, for their characterisation and their analysis after irradiation. This work will be carried out in collaboration with the project's partner laboratories and with the help of IJCLab chemists. Targets will also be fabricated by implantation with the SIDONIE electromagnetic separator.
A characterisation phase of the produced targets (chemical and isotopic purity and homogeneity) will then be carried out, mainly at Orsay. The proton activation technique will be implemented on the tandem of the ALTO installation of IJCLab and/or at GANIL-NFS (Neutrons for Science, where a proton beam is available) to measure the isotopic purity.
In a second phase, the targets fabricated at IJCLab with different techniques (with commercial Gd-155 and with Gd-155 separated with SIDONIE) and those fabricated by the partners of the project will then be irradiated with the ARRONAX cyclotron (Nantes) at different energies in order to produce Tb-155. Data analysis will make it possible to determine excitation function of the Gd-155(p,n)Tb-155 reaction and particular care will be taken to evaluate precise error bars. Finally, proton activation experiments will make it possible to compare the isotopic purity of the Tb-155 produced according to the targets used and thus to optimise its production.
Material and financial scientific conditions of the research project
The student will be required to work in a controlled area (experiments on the Alto tandem in Orsay, on the ARRONAX cyclotron in Nantes and potentially at GANIL-NFS in Caen. As such, he/she will be likely to handle radioactive sources.
The thesis is funded by the ANR TTRIP obtained in July 2021.
Objective of promoting the research work of the doctoral student
Thesis, presentation of results to the collaboration, participation in at least one conference, writing an article in a peer-reviewed scientific journal.
- N. Chauvin, F. Dayras, D. Le Du, R. Meunier; SIDONIE: an electromagnetic isotope separator for preparation of high purity thin targets; Nucl. Instr. Meth. A 2004, 521, 149 155
- C.-O. Bacri, et al.; SCALP, a platform dedicated to material modifications and characterization under ion beam; Nucl. Instr. Meth. B 2017, 406, 48–52
- F. Haddad, ..., A. Guertin, ..., N. Michel, et al.; ARRONAX, a high-energy and high-intensity cyclotron for nuclear medicine; Eur. J. Nucl. Med. Mol. Imaging 2008, 35, 1377–1387
- U. Köster, ..., C.-O. Bacri, et al.; Electromagnetic isotope separation of gadolinium isotopes for the production of 152,155Tb for radiopharmaceutical applications; Nucl. Inst. Meth. B 2020, 463, 111–114
- C. Müller, et al.; Future prospects for SPECT imaging using radiolanthanide terbium-155 – production and preclinical evaluation in tumor-bearing mice; Nucl. Med. Biol. 2014, 41, e58 e65
- C.Duchemin ; Étude de voies alternatives pour la production de radionucléides innovants pour les applications médicales. Soutenue en 2015 à Subatech (Nantes).
The Irène Joliot-Curie Laboratory of Physics of the 2 Infinites is a laboratory under the supervision of the CNRS, the University of Paris-Saclay and the University of Paris-Cité, born in 2020 from the merger of five UMRs located on the Orsay university campus: Centre de sciences nucléaires et de sciences de la matière (CSNSM), Imagerie et modélisation en neurobiologie et cancérologie (IMNC), Institut de physique nucléaire d'Orsay (IPNO), Laboratoire de l'accélérateur linéaire (LAL) and Laboratoire de physique théorique (LPT).
The laboratory's research themes are nuclear physics, high-energy physics, astroparticles and cosmology, theoretical physics, particle accelerators and detectors as well as technical research and development and associated applications for energy, health and the environment.
The structure has a very important technical capacity (about 280 engineers and technicians) in all the major fields required to design, develop and implement the experimental devices necessary for its scientific activity: mechanics, electronics, computing, instrumentation, acceleration techniques and biology. These technical strengths represent a major asset for the design, development and use of the necessary instruments (accelerators and detectors). The presence of research infrastructures and technological platforms on the laboratory site is also a major asset. Finally, around 90 ITAs (Engineers, Administrative Technicians) from the administrative and support services work alongside the scientists and engineers.
The thesis will be attached to the doctoral school Particules, Hadrons, Énergie et Noyau: Instrumentation, Image, Cosmos et Simulation; medical imaging and radioactivity speciality.
Il will be carried out within the Physics and Health Pole, which has about fifteen members. The thesis director is the scientific coordinator of TTRIP (Tools for Tb RadioIsotope Production for nuclear medicine) funded by the ANR (Agence Nationale de la Recherche), and scientific leader of the PRISM (Production d'Isotopes et Séparation pour le Médical) project. The student will benefit from the multidisciplinary expertise of the collaboration, consisting of nuclear physicists, a metrologist, organic and coordination chemists, specialists in isotopes production for medicine, materials science and medical imaging. Several experiments will be carried out, on the ALTO (Accélérateur Linéaire et Tandem à Orsay) from IJCLab, at the ARRONAX (Accélérateur pour la Recherche en Radiochimie et Oncologie à Nantes Atlantique) cyclotron in Nantes and possibly at GANIL-NFS in Caen. As the thesis work is part of the ANR TTRIP, regular collaboration meetings will allow the work to be placed in a broader perspective and to present intermediate results to the collaboration. Follow-up meetings of the thesis will take place regularly.
Constraints and risks
As IJCLab is subjected to ZRR (Zone à Régime Restrictif) military regulation, hiring choices must be approved by the Haut Fonctionnaire Securité Défense (HFSD). Therefore, the date of employment written above should be understood as provisional, and may need to be delayed.
Travels to Nantes (ARRONAX cyclotron) and to Caen (GANIL) will be required (see above)
Dosimetric monitoring will be provided.
Education, scientific skills and experience required
Experimental nuclear physics
Data analysis (computing, if possible, in C or C++)
Material physical chemistry (production/ characterization of targets)
English read-written-spoken, C1 level.
Scientific articles reading
Qualities to be strengthened or developed during the thesis work
Ability to work in a team
Ability to work independently, organisational ability and ability to account for one's own actions
Adaptable to the constraints of the work, ability to communicate and to argue a case, powers of analysis, summary and critical evaluation, ability to learn and develop one's skills, flexibility and adaptability, creativity, able to take the initiative, resilience)
The candidate must have a degree in engineering and/or a master's degree in Physics. The position requires a strong background, mainly in nuclear physics, and the candidate should be interested in medical applications. Good oral and written communication skills in French and English are required to present at conferences and to write papers in scientific journals. We are looking for a young researcher who will be able to get involved in his/her project, who is curious, has a certain autonomy and a strong motivation to integrate and work with a multidisciplinary collaboration including physicists and chemists in interaction with the medical world. Many interactions will also take place with the operating team of the experimental platform that uses our electromagnetic separator.
We talk about it on Twitter!