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H/F thesis proposal at the interface chemistry/radiochemistry/biology

This offer is available in the following languages:
Français - Anglais

Date Limite Candidature : lundi 30 mai 2022

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General information

Reference : UMR7177-NADBOU-003
Workplace : STRASBOURG
Date of publication : Monday, May 9, 2022
Scientific Responsible name : Jean-Claude Chambron
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 3 October 2022
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

Context of the thesis : The pancreatic neuroendocrin tumors (pNET) are highly vascular neoplasms that originate from pluripotent cells of exocrine pancreas. Most of the patients that are affected by pNETs show liver metastases and lymph nodes at the diagnosis, which involve the vital prognosis with a reduced survival period. Angiogenesis playing an important role in the development of pNET, the targeted molecular therapy with anti-angiogenic agents has been used. However, the occurrence of resistances requires that techniques allowing for a global evaluation of the therapeutic response in the course of the treatment are developed. The in vivo study by positron emission tomography (PET), before and after the treatment, of an anti-angiogenic activity that has been increased pathologically would allow a better dosage of the drug or a modification of the therapeutic strategy.

Subject of the thesis : The project consists in the development of a 89Zr-based immunoPET probe specifically targeting, owing to the ramucirumab/VEGFR-2 interaction, the tumoral angiogenesis in order to identify patients bearing a pancreatic neuroendocrin tumor (pNET) who are susceptible to undergo a targeted therapy by anti-angiogenic agents. The probe will be constituted of a chelator showing a very strong affinity for Zr4+ and bioconjugated to ramucirumab, a monoclonal antibody (mAb). The bioconjugate will be finally radiolabeled with the isotope 89 of zirconium, an emittor of positrons of relatively low energy (395 keV) and long lifetime (78 h) that is compatible with the slow kinetics of bioaccumulation of the antibody on the surface of the tumor cells.
The work is multidisciplinary and will cover all the steps of the development of the probe, from the design and the synthesis of bio-inspired chelators and the study of their solution coordination chemistry until the obtention and the interpretation of images of murine tumor pNET xenograft mice models, via the preparation of [89Zr]Zr-oxalate by the nuclear reaction 89Y(p,n)89Zr at the Cyrcé cyclotron of IPHC, the bioconjugation of the chelator to the mAb, the radiolabeling, and the study of the probe stability in various media.

Work Context

The student will work at the Institut de Chimie de Strasbourg (UMR CNRS 7177) and the Institut Pluridisciplinaire Hubert Curien (IPHC, UMR CNRS 7178), laboratories distant of about 30 minutes from each other in Strasbourg

Constraints and risks

Radioprotection for the work done at IPHC in the course of handling Zirconium-89

Additional Information

Profile of the candidates : Must hold a Master diploma in chemistry with a strong emphasis on synthetic organic chemistry ; knowledge in biological and analytical chemistry ; attracted by radiochemistry.

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