We study different imaging techniques. Our research starts from the synthesis of tools to go towards their valorization in order to asses answers to biological problems through molecular imaging.
Optical Imaging
Our research activity around fluorophores attempts to cover different aspects of this specialty, from the discovering, design, synthesis and study of the photophysical properties of fluorophores to their use for bio-analytical applications.
One part of this topic focuses on the synthesis and functionalization of original organic fluorophores. The structures of the fluorophores that we study are inspired by both well-known molecules of literature and original natural skeletons. The main objective of this study is to optimize their photophysical properties (quantum yield, absorption wavelengths and emission …) but also their behavior in biological medium (solubility, targeting of cell compartments). It is a fundamental step that allows to obtain ideal molecules for very specific biological applications. Among the applications envisaged in our laboratory, their use as antenna for the sensitization of lanthanide chelates is studied as well as their implication in more complex systems aiming to associate the optical imaging to the MRI in a bi-modal imaging strategy. Another use of these fluorophores aims their functionalization to give them fluorogenic detection properties in order to highlight new enzymatic activities in cellulo, in given cell compartments or within microorganisms.
MRI
Using targeted contrast agents for magnetic resonance imaging (MRI) is a promising strategy to increase the potential of this high-resolution imaging modality for cancer diagnosis and stratification. However, molecular imaging by MRI suffers from low sensitivity with respect to positron emission tomography or optical imaging.Shiga toxin B-subunit (STxB) is a natural ligand of Gb3, a glycosphingolipid highly overexpressed at the surface of certain tumour cells. STxB is a homopentamer protein and has been previously engineered with a C-terminal cysteine (STxB-SH). The coupling of multiple Gadolinium chelates (Gd3+) to STxB-SH through a cyclopeptide scaffold, combined with the high expression of Gb3, should allow Gd3+ accumulation at the tumour site, sufficient for its detection. We design scaffolds functionalized with 6 to 9 paramagnetic DOTA[Gd3+]. These high relaxivity MRI contrast agents target Gb3 expressing cancer cells in cellulo.
Multimodal Imaging
While enzyme activity is routinely determined using in vitro assays, its in vivo visualization remains a challenge. This is a subject of increasing interest in molecular imaging since dysregulation of these biological catalysts is associated with many diseases. In this context, we designed lanthanide-based probes that are responsive to a specific enzyme activity (-galactosidase for instance). These probes can be monitored by one to three different modalities depending on the lanthanide used: T1-MRI, paraCEST-MRI and optical imaging. .
This project is conducted in close collaboration with E. Toth’s and S. Petoud’s teams (CNRS, Orleans). A series of probe were based on the conversion of 2-benzyl carbamoyl pyridines derivative into their corresponding 2-amino analogs. Non-responsive prototypes were first synthesized and their physicochemical properties assessed to validate the concept. Then enzyme-responsive probes were set up by using a self immolative benzyl carbamate. However structural modifications of the amino pyridine moiety proved necessary to weaken carbamoyl coordination to the lanthanide and speed up probe activation. Combining in silico and chemical studies (collaboration with R . Pollet from CEA) we tried to understand the magnetic (paraCEST and T1 effect) and physico chemical relashionships of our probes. We are also interested in the design, the synthesis and the evaluation of new safe self-immolative spacers.
Nanotheranostic: Surface coating optimization for inorganic nanoparticles
In the context of the research in innovative and efficient systems for both treating and detecting diseases, NanoParticles (NPs), because of their nanoscale size, offer the opportunity: i) to improve in vivo pharmacokinetic by extending circulation time and ii) to modify biodistribution by targeting diseased tissues. However, while many inorganic NPs have been identified as promising since the 90’s, less than 10 are nowadays approved for patient healthcare.
Toxicity issues related to colloidal instability in biological media and functionalization control/characterization difficulties are important unsolved drawbacks that remain serious bottlenecks in the development of inorganic NPs for biomedical applications.
To overcome these issues, we develop new multidentate polymers with a perfectly defined structure to coat NPs in a highly stable and stealth manner. These multi-anchoring polymers carrying biocompatible moieties increase the avidity of the ligands for the NPs surface while conferring stealth and colloidal dispersion in biological media. In this project, we explore an innovative approach to design and synthesize multidentate functionalized peptides, before validating their potential to coat very promising inorganic NPs, Gold NanoRods (GNRs). These rod-like NPs are especially attractive, due to their unique optical properties and potential applications in functional nanodevices thanks to photoacoustic, radio-enhancer or photothermal properties. This project will pave the way to the development of GNRs as targeted nanomedicines (e.g. tumor photothermal ablation).
Considering the promising potential of inorganic nanoparticles for biomedical uses, this project will allow targeted inorganic NPs to reach the clinic to contribute to better medical solutions in the foreseeable future.
