DS10 - Défi des autres savoirs

Search And Destroy with Aza-Macrocycles – SADAM

Submission summary

Ligands synthesis and their coordination studies with several cationic metals are responsible of spectacular advances in medical diagnostic and therapy. Among the various studied chelators, polyazacycloalkanes have proved to be more efficient in almost all imaging modalities and therapy methodologies, leaving a glimpse of such derivatives in theranostics technics: procedures involving a same agent for both diagnostic and therapeutic modalities.
The three research groups involved in the SADAM project (UMR CNRS 6521 in Brest, UMR CNRS 5281 at ENS Lyon and INSERM U892 in Nantes) have recently demonstrated the interest of picolinates ligands based on chelating macrocycles as cyclam, cyclen and tacn platforms, for applications in MRI (Magnetic Resonance Imaging), luminescence and nuclear medicine as PET (Positron Emission Tomography). The idea is now to combine an innovative process of 2g-PDT (two photons photodynamic therapy) to these imaging agents. The work will involve organic/macrocyclic chemistry, coordination/physico-chemistry and bio-applications in living cells and in vivo.
The Brest group (P1) has demonstrated the interest of picolinate derivatives based on tacn, cyclen and cyclam platforms for the complexation of Mn2+, Gd3+ for MRI and 64-Cu2+ for PET imaging. Some of these compounds already present positive results in vivo in small animals, as demonstrated in collaboration with the INSERM team in Nantes (P3). After functionalisation of picolinate groups by pegylated chromophore antennas, some of their lanthanide complexes have been studied by the ENS group (P2) for their two-photon absorption properties and their potential for cell penetration to recently reach to first images of living cells.
From these results, the consortium aims to combine the compounds based on Mn2+, Gd3+, 68-Ga3+ and 64-Cu2+ to new modified picolinate arms functionalized this time by pegylated antennas based on dibromobenzene opening the way to new objects combining MRI or PET imaging to 2P-PDT. The latter will allow, using a same object, to carry out the diagnosis and therapy of many pathologies depending on the biologic vector to which it will be conjugated. The project will mainly focus on the study of hypoxia, one of the priority target identified by the ANR for Health applications.
This work has the objective of achieving the first single-object theranostic probe. To increase the chances of success, two types of imaging modalities will be explored, MRI and PET, and in each case two metal centers will be targeted. Mn2+ may for example be an alternative to Gd3+ in the case of weak stability (and therefore toxicity). In the same way, gallium complexes may prove to be a relevant alternative to copper complexes in case of photoinduced energy transfer processes in Cu2+ complexes (reduction to Cu+ leading to luminescence quenching).

The best chelates will be studied to test their behavior and their stability in serum medium, in living cells and in vivo. The most interesting models will then be redesigned under their bifunctional forms to enable their conjugation to biological vectors. The ligands will be modified via a carbon atom of their ring structure to preserve all of their coordination properties. This technique whose efficiency has been proven in a previous ANR program is largely controlled by the consortium for all the targeted compounds. The bifunctional analogues will allow the introduction of a nitroimidazole moiety for the in vivo studies in the case of hypoxia but many other biological targets could be investigated downstream from the program.

Project coordination

Raphael Tripier (Université de Brest, CNRS)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


ENS Lyon Université de Lyon, ENS, CNRS
UMR, CRCNA INSERM U892 Unité mixte de recherche, Centre de recherche en cancérologie Nantes-Angers, INSERM U892
UBO, UMR CNRS 6521 Université de Brest, CNRS

Help of the ANR 497,809 euros
Beginning and duration of the scientific project: September 2016 - 48 Months

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