64Cu radiolabeled nanomaterials for diagnostic and radiotherapy – Copper nano-pincers

Luminescent nanocrystals are functionalized with chelates on their surface in order to complex radioactive 64-copper. In this purpose, new bispidine ligands are developed. The study of their complexation properties (affinity, selectivity, kinetics ..) will allow us to optimize the architecture of ligands so that they bind strongly to Cu (II) while having little interaction with other cations presents in the biological medium .

New bispidine-typed bicyclic ligands have been synthesized. The influence of substituents on their stereochemistry has been studied in detail.
The first ligand tested has very good complexing/selectivity properties and meets the required criteria for its application to the complexation of 64Cu.
A microwave method for the synthesis of luminescent water soluble semiconductor nanocrystals has been developed. Their surface functionalization has been developed using a fluorescent marker.

The ultimate goal of this project is to evaluate the effectiveness of these new multifunctional nanoparticles for in vitro and in vivo diagnostics. These studies may be made directly to the IPHC which possess a platform for the functional imaging of small animals (ImaBio) and a cyclotron (CyrCE).

Bispidone-based ligands : Stereochemical control upon substitution
T. Legdali, A. Roux, A. M. Nonat, C. Platas-Iglesias, L. J. Charbonnière, J. Org. Chem., 2012, 77, 11167-11176

The Copper nano-pincers project aims at developing a new generation of nanoparticles that can act both as imaging and radiotherapeutic agents. These new objects called theranostic agents are particularly helpful for targeted radiotherapy. Indeed, by monitoring the biodistribution of the radiotherapeutic agents, it will allow to evaluate the success of the therapy and help to optimise the injected radioactive dose, thereby reducing the side effects. In this context, we also propose to improve the quality of the diagnostic by developing bimodal contrast agents that will be able to gather informations at both the anatomic and the sub-cellular level.
To achieve this goal, we will synthesise luminescent nanoparticules which surface will be functionalised by radioactive 64Cu complexed by bispidine ligands. Such nano-architectures possess (i) a bimodality in detection since they can be detected by Positron Emission Tomography (PET) and optical imaging and (ii) an in vivo demonstrated potentiality in radiotherapy since 64Cu can be used for both diagnostic and therapeutic purposes.
This multidisciplinary project stands at the interface of organic chemistry, physico-chemistry, photophysics and nanomaterials. Our approach will thus be stepwise, and organized as follows:
- synthesis of the bispidine ligands,
- conjugation on the nanoparticles and characterisation,
- and then, optimisation of their stability and their efficiency as luminescent contrast agents.
The ultimate goal is to dispose of multi-functional nanoparticles suitable for radiolabelling and vectorisation and ready to be tested on small animals at the end of this 3-year project.

This project will be held at the Institut Pluridisciplinaire Hubert-Curien (IPHC UMR 7178 CNRS), in Strasbourg, which is currently developing facilities for small animals imaging and in particular for PET with, in particular, the starting up of a research cyclotron in 2012. The proposed team consists of five permanent staff (Dr. Loïc Charbonnière, researcher CNRS; Dr. Véronique Hubscher, assistant professor at the Université de Strasbourg; Dr. Zouhair Asfari, research engineer, Sylvie Michel, assistant engineer CNRS and Dr. Aline Nonat, researcher CNRS) and one PhD student to be recruited for 36 months. All four permanent staff are members of the « Département des Sciences Analytiques » (DSA) of the IPHC. The proposed team has been selected for the success of this project with members working in complementary chemistry areas such as organic synthesis, coordination chemistry, physico-chemistry and photophysics. In addition, a collaboration with Pr. W. Parak, at the University of Marburg, in Germany will provide us the knowledge and techniques required for the functionalisation of the nanoparticles. As a result, the application will bring novel competences in nanomaterials to the Institut Pluridisciplinaire Hubert-Curien, which would be particularly valuable for the new multifunctional imaging platform developed by the physicists of the intitute.