Sujet de thèse pour la rentrée 2021

Production and exploration of the chemistry of Auger-emitter generators

Origine du financement : GIP ARRONAX / Région PdL
Mots clés : Cancer, Chimie, Emetteurs Auger

Unité/équipe encadrante : ARRONAX, Subatech – Université de Nantes

Directeurs de thèse : Sandrine HUCLIER-MARKAI
Encadrants scientifiques : Cyrille ALLIOT

N° de tél : +33 (0)2-28-21-25-23
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Contexte socioéconomique et scientifique
High linear energy transfer radionuclides emitting particles such as alpha particles or Auger electrons, much more efficient to kill isolated tumor cells, are being tested for RIT in the clinic. The short penetration path of Auger electrons in matter gives them the advantage of inducing minimal toxicity to healthy cells even at high injected activities. Among all the Auger emitters identified, this work will focused on 2 emitters specifically, that could be further employed as generators.

Hypothèses et questions posées
First the radio-lanthanide 140Nd (t1/2 = 3.4 d) together with its short-lived positron emitting daughter 140Pr (t1/2 = 3.4 min), has promise as an in vivo generator for Auger therapy and theranostic approach using the PET emission associated to 140Pr. However, the electron capture decay of 140Nd is chemically disruptive to macrocycle-based radiolabeling, meaning that an in vivo redistribution of 140Pr can occur. The issue is related to the redox properties of the elements that are not very well known (Pourbaix diagram not fully established) and notably the possibility of having tetravalent element. Second, 103mRh has a relatively short half-life (56 min) and is produced via β–-decay of 103Ru or EC decay of 103Pd. Thus it is possible to elaborate a 103Ru/103mRh generator. The chemistry of Rh, and especially with regards to its complexation with chelates for radiopharmaceutical use, needs to be further explored.

Grandes étapes de la thèse
The goals of this PhD work are :
- To examine the production of 140Nd/140Pr and 103Ru/103mRh at Arronax facility,
- To optimize the extraction/purification process in order to reach high molar activities,
- To scrutinize the fundamental chemistries of Nd, Pr, Ru and Rh that could undergo several redox states and thus lead to different complexation properties,
- To study the complexation properties of 140Nd/140Pr and 103Ru/103mRh with polyaminopolycarboxylic ligands together with new types of ligands,
- To evaluate the post-effect on these generators and potentially circumvent it
- To optimize the radiolabeling and assess the in vitro-stability of the resulting complexes

Compétences scientifiques et techniques requises par le candidat
The candidate will have obtained a Master's degree (or equivalent) during which he/she will have completed a research internship in chemistry, and must have knowledge in analytical chemistry. Knowledge of radiochemistry would be appreciated. Please attach your application, your CV, official Master's transcript and a short cover letter. A good level of English is required.

3 publications de l’équipe d’accueil relatives au domaine (5 dernières années) :
1. R. Mikolajczak, S. Huclier-Markai, C. Alliot, F. Haddad, D. Szikra, V. Forgacs, P. Garnuszek .Production of Scandium radionuclides for theranostic applications. Towards standardization of quality requirements. Eur. J. Nucl. Med. Mol. Imag. Radiopharmacy and Chemistry,
2021.DOI : 10.1186/s41181-021-00131-2
2. J. Muñoz-Garcia, M. Mazza, C. Alliot, C. Sinquin, S. Colliec-Jouault, D. Heyman and S. Huclier-Markai. Antiproliferative properties of scandium exopolysaccharide complexes on several cancer cell lines. Mar. Drugs 2021, 19(3),
3. M.Mazza, C. Alliot, C. Sinquin, P.E. Reiller and S. Huclier-Markai. Marine exopolysaccharide complexed with Scandium aimed as theranostic agents. Molecules, 2021,26 (4), 1143. DOI: 10.3390/molecules26041143

Collaborations nationales et internationales :
Nationales : Réseau labex IRON ; GdR AIM ; IPHC Strasbourg ; ILL
Internationales : Triumf (Canada) ; University of Wisconsin –Madison (USA), Brookhaven National Lab (USA) ; Polatom (Pologne) ; NCSR Demokritos (Grèce) ; Basel Hospital (Suisse)