PhD in chemistry (M/F) – In silico modeling of labeling with radium-223 radioisotope

Targeted alpha therapy is expected to expand the applications of radium-223 in oncology, based on the principle of binding the radioisotope using a BFC. However, the development of chelators suitable for complexing radium-223 remains a challenge due to the lack of knowledge regarding the behavior of the Ra2+ cation in solution.1 Radium (Z = 88) has no stable isotopes, and spectroscopic characterizations are also limited by radiation protection concerns. Computational chemistry allows us to overcome these limitations and characterize chemical species in detail. Furthermore, we can build on the advances made through the TESMARAC Joint Laboratory regarding the modeling of radium coordination chemistry.2,3 The information obtained will guide the synthesis of radium-223 chelators by colleagues, a crucial step in the development of innovative radiopharmaceuticals.

The research work will be carried out in parallel with experimental studies conducted at the SUBATECH (UMR CNRS 6457) and CRCI2NA (Inserm U1307) laboratories. It will be organized around two axes:

• DFT calculations of the complexation properties of the Ra²⁺ cationic form with various model chelators. The aim is to identify trends for parameters such as the magnitude of thermodynamic complexation constants, in relation to the nature of the heteroatoms interacting with the Ra²⁺ cation and their pre-organization within the structure. Comparison with equilibrium constant measurements—either reported in the literature or measured by radiochemists (SUBATECH)—will provide a better understanding of the complexation and coordination properties of the Ra2+ cation in solution.
• the design of specific chelators, i.e., chelating agents that not only exhibit a high affinity for the Ra²⁺ cation but also high selectivity toward other cations present in biological media (Ca²⁺, Mg²⁺). DFT calculations are particularly effective for predicting changes in complexation constants for a series of metal cations. Where possible, comparisons of affinity and selectivity will be made with data from the literature or determined through experiments (SUBATECH). The in silico approach will enable the low-cost proposal and evaluation of numerous innovative chelator structures. This work will be carried out in collaboration with colleagues (CRCI2NA, CEISAM), who will synthesize the most promising chelators.

Refs.

1  Doing away with radium’s proxies, J.J. Woods, R.J. Abergel, Nat. Chem. 16, 147–148 (2024)

2  223Ra-radiolabeling: predicting stability using molecular modelling, H. Mohaman, G. Montavon, N. Galland, Nucl. Med. Biol. 108-109, S154-S155 (2022)

3  Tailoring an efficient computational methodology for studying ligand interactions with heavy radiometals in solution: the case of radium, H. Mohaman, S. Happel, G. Montavon, N. Galland, New J. Chem., 47, 12914-12925 (2023)

Cancer remains the leading cause of death in France today. To better fight it, a ten-year national strategy was launched in 2021 to support research and develop more effective treatments. Currently, researchers are developing increasingly specific approaches capable of destroying cancer cells while preserving healthy tissue. Among the promising approaches is targeted alpha therapy. Its principle is based on combining a radioactive isotope that emits alpha (α) particles—capable of destroying cancer cells—with a biological vector (e.g. antibodies) that specifically recognizes these cells. This combination is facilitated by a bifunctional chelator (BFC), a molecule that acts as a particularly stable chemical link.

Only one alpha-emitting drug, Xofigo® (223RaCl2), is currently available for the treatment of bone metastases in prostate cancer. To date, no method exists that allows for the use of radium-223 in other types of cancer. The objective of this thesis project is to expand the scope of application for radium-223. This requires the development of BFC capable of effectively binding radium-223 to biological carriers, a process known as radiolabeling.

This thesis project is one of the scientific priorities of the DHOLMEN Laboratory of Excellence (LabEx), supported by the I-SITE Nantes Excellence Trajectory (NExT), which brings together 20 academic teams with complementary expertise centered around the new Nantes University Hospital and the Arronax cyclotron. This multidisciplinary scientific community is a key asset for accelerating discoveries in radium-223 radiolabeling, with a breakthrough approach based on molecular modeling.

The successful candidate will have a Master degree with honors in chemistry, physical chemistry or a similar degree, and should have a solid background in quantum chemistry with good experience of a current molecular modeling program such as Gaussian, Turbomole, Q-Chem or ADF. A background in coordination chemistry is an asset. He/she must speak English fluently and must be motivated to learn French.