Sujet de thèse pour la rentrée 2021

Preclinical development of the innovative theranostic pair of scandium in breast cancers

Mots-clés : Théranostique, Cancer, Imagerie préclinique

Origine du financement : Isite NExT

Unité/équipe encadrante : ARRONAX, Subatech and CRCINA –Université de Nantes; University of Alabama at Birmingham (AL, USA)
Directeurs de thèse : Sandrine HUCLIER-MARKAI ; Suzanne LAPI (USA)
Encadrants scientifiques : Latifa RBAH-VIDAL
Contact :
N° de tél : +33 (0)2-28-21-25-23
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This PhD will be co-directed between Nantes University (F) and University of Alabama at Birmingham (AL, USA). The PhD student will have to spend 1/3 of the PhD duration over University of Alabama at Birmingham. The allocated grant will provide the financial support for the living expenses in US for this period (apartment and visa) and the travel.

Contexte socioéconomique et scientifique
Scandium radioisotopes were identified at the end of the 1990’s as promising for applications in nuclear medicine. 43Sc and 44Sc are interesting for positron emission tomography (PET) imaging while 47Sc is interesting for therapy. 44Sc/47Sc or 43Sc/47Sc pairs are chemically identical theranostic pairs. For both radionuclides, the half-life is compatible with the pharmacokinetics of a fairly wide range of vectors (such as peptides, antibodies, antibody fragments, and oligonucleotides). The validity, utility and benefits of 44Sc have been demonstrated. Very recently, a radiopharmaceutical labelled with 44Sc has been used in patients. It is of utmost importance to further evaluate scandium-based radiopharmaceuticals drugs in pre-clinical studies for further translation into clinics. As part of the "ICoN" (Isite NExT Funding) project, we are looking to test the diagnostic and therapeutic potential of radiolabelled vectors for breast cancer. Using the imaging performances of 44/44mSc and the “theranostic” properties of 44/47Sc, this pre-clinical project will allow the development of innovative scandium-based radiotracers to identify and image target biomolecules involved at various stages of this disease. The limitation of this drug development has been so far, the biological vectors to be conjugated with and the preclinical evaluation in animal models.

Hypothèses et questions posées
For this work, the injection of these vectors coupled with Scandium-44 in preclinical models of breast cancer will allow us to perform PET imaging and biodistribution experiments, evaluate their pharmacokinetics and estimate the doses of radiation absorbed by the different organs as part of internal radiotherapy. The results obtained from imaging, biodistribution and dosimetry studies will enable the evaluation of the potential of internal radiotherapy using the same vectors radiolabelled with Scandium-47 (therapeutic radionuclide). The results of this project will provide essential information and new perspectives for the future clinical transfer of innovative theranostic tools. In nuclear medicine, the theranostic approach, combining imaging and targeted cancer therapy, will make a significant contribution to personalized
medicine and could play an increasingly important role in the future, thereby reducing the cost of patient care by avoiding unnecessary and costly treatments.

Grandes étapes de la thèse
- Production of cost-effective, high purity scandium for broad distribution. This involves: (i) Optimized targetry and production methods enabling routine supply of research and clinical quantities of Sc radionuclides; (ii) Development of an original automated extraction/purification process. (iii) standardized procedures of production for reaching high molar activities
- Test novel chelates that will label scandium at low temperatures in high yield and/or high specific activities; develop optimized radiolabeling conditions; evaluate in vitro stability of the chelator-scandium complexes; develop conjugation methods to attach chelates to vectors and evaluate their labelling and in vitro stability; synthesize and test small-molecule targeting moieties.
- Develop and pre-clinically evaluate a series of 43/44/44mSc-labelled molecular probes for their use in imaging of breast cancer. The selected 44/44mSc-labelled molecular probes will be thoroughly evaluated in-vitro/in-vivo using suitable cancer cell lines and animal models. The proposed molecular probes comprise large molecular weight proteins (antibodies, peptides and small molecules).

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 cell biology or preclinical experimentation, and must have basic knowledge of immunology. Knowledge of chemistry and/or biochemistry would be appreciated. Additional skills in radiochemistry would certainly be valued. 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)