ANR 2018 - JCJC - WazaBY - Water-soluble aza-BODIPY platform for multimodal imaging and trackable therapeutics

Among the different disciplines in medical imaging, molecular imaging is an emerging powerful tool, which enables the detection of pathophysiological changes in living subject at the cellular and molecular levels. More particularly, it can be used to perform a fast and accurate diagnosis, or to monitor the success of a treatment. Even if it plays a central role in oncology, the use of molecular imaging opens up an incredible number of possibilities for other medical applications as for cardiovascular diseases, infections, bone disorders, thyroid disorders, brain disorders, gastrointestinal diseases… Among the different molecular imaging methods, optical imaging (OI) is the method of choice for in vitro and ex vivo studies, and is used more and more for small animal imaging studies. It is a non-ionizing technique, which presents the high resolution and the high sensitivity needed for molecular imaging investigations. It is more restricted for clinical applications, due to its tissue limited penetration, but it is of major interest for endoscopy investigations, as well as for fluorescence imaging guided surgery. The increasing interest in OI is also due to two emerging fields: bimodal imaging and trackable therapeutics. Indeed, OI is a modality of choice for bimodal imaging: its high sensitivity is suitable for a coupling to a PET/SPECT probe, which will take over the fluorophore for in vivo imaging. Concerning trackable therapeutics, grafting a fluorescent probe to a therapeutic moiety enables to track in real time the resulting therapeutic in vitro and in vivo, giving crucial information on its biodistribution and its cellular targets.

Aiming at performing in vivo studies, the use of near infrared (NIR) light offers several advantages, such as low absorption coefficient of most of the biomolecules, lower scattering, minimization of autofluorescence signals and risks to disturb the normal metabolism of the biological system to study. It therefore requires the use of called NIR fluorescent probes, which absorb and emit in the “diagnostic window” (between 650 and 900 nm). However, the choice of the fluorescent dye is almost always limited to commonly used cyanines. Despite some advantages, these fluorophores suffer from poor fluorescence efficiency, but above all from a chemical instability, rapid photobleaching, and today, there is no ideal NIR-fluorescent probe suitable enough for biological applications (water-soluble, stable, low toxic…), enabling a large scope of functionalizations, and able to be synthesized in large scale.

We are offering to solve this problematic and to develop a NIR-fluorescent platform displaying the properties above-mentioned, and we are targeting an original and promising family of fluorophores, the aza-BODIPYs, because their synthesis is straightforward, they absorb and emit in the NIR region, they present outstanding chemical and photochemical stability, and can be produced easily in the gram scale. Therefore, the aza-BODIPYs compounds presents all the advantages for biomedical applications, except their high lipophilic character and their very poor solubility. That is why we will develop a simple strategy to solubilize them, and we aim at elaborating a highly funtionalizable water-soluble aza-BODIPY platform, and to design, starting from this platform, new Monomolecular Mutimodal Imaging Probes (MOMIP) and optical metal-based trackable therapeutics. In the scope of the project, we will suggest simple synthetic routes to get access to the water soluble aza-BODIPY platforms, the resulting optical imaging probes, MOMIP and theranostic constructs. The most promising systems will be bioconjugated to different biovectors, and, in the last part, we will demonstrate, through an imaging pilot study, the potential of the new systems.

Principal Investigator: Dr Christine Goze