Metal complexes are widely used nowadays to treat numerous pathologies (cancer, rheumatoid arthritis, osteoporosis, etc.). However, despite their daily clinical use, their mechanisms of action are still poorly understood. An interesting strategy for elucidating them consists in grafting a probe onto the therapeutic agent in order to be able to follow it in vitro and in vivo by medical imaging. However, the problem of most trackable therapeutic agents is the reliability of the information they provide. Indeed, if the link between the probe and the therapeutic part is broken, the signal observed will correspond only to the probe and not to the therapeutic agent, rendering this information useless. It is therefore essential to know whether this link is intact or not. <br />Thus the main objective of this project is to develop so-called smart probes to ensure in real time the integrity of the trackable therapeutic agent, but this will be accompanied by a search for systems compatible with in vivo studies and new and more effective therapeutic agents.
In order to answer the main question of the project, several intermediate steps are necessary. Thus, we must first design a probe that behaves like a switch: fluorescent when the compound is intact and off when it is no longer. Then, the fluorescent probe part must be compatible with its use in vivo. It must be soluble in water, stable in a biological medium and during monitoring, and be able to be excited and to emit in the near-infrared (area of the light spectrum where biological tissues are more transparent). Therapeutic agents must then be developed or optimized and have to keep their biological activity once bound to the fluorescence probe, without quenching it. And finally, design a system bringing together all these parts.
We have therefore worked mainly with azaBODIPYs, which are fluorophores, which have experienced strong development in recent years. We have been able to transform them into a non-toxic water-soluble fluorescent platform and bind them to therapeutic agents based on titanium or gold complexes, without losing their fluorescence and activity in vivo.
This project has made it possible to design a new family of perfectly biocompatible water-soluble fluorescent probes that can be linked to drugs, other probes and biomolecules. This has been the subject of a patent, a distribution contract, numerous publications and has enabled the laboratory to gain international recognition in the field and to establish new collaborations. In addition to the very promising in vivo results of some of our trackable therapeutic agents, that we will be pushing further, we are developing a new line of research around fluorescence-guided surgery.
This project has so far led to around twenty publications relating to the various aspects of the project: new probes for in vivo imaging, new smart probes, therapeutic agents, trackable therapeutic agents (the compounds under study should allow the production of at least 5 other articles). In addition, a EUR and WO patent has been filed on a family of probes and a company is interested in working with us on the subject.
Metal complexes are widely used for the treatment of numerous pathologies (cancer, rheumatoid arthritis, osteoporosis…). Despite their use in clinics, their mechanisms of action are still poorly known. An elegant way to elucidate them is to synthesize labelled therapeutic agents that can be tracked in vitro and in vivo by medical imaging. The problem of most reported labelled drugs is the reliability of the information that they provide. Indeed, if the link between the probe and the therapeutic moiety is broken, the observed signal will only enable to track the label moiety. So knowing if this link is broken or not is crucial.
The main aim of this project is to design “smart probes” that can enable the tracking of metal based drugs and at the same time give information on the state/integrity of the compound. Two types of probes will be investigated: “ON/OFF” probes which emit fluorescence (“on” mode) when they are attached to the metal centre and not when the metal decoordinates (“off” mode) and “multicolour” probes which display different fluorescent emission depending on the state of the complex.
Monsieur Ewen Bodio (Institut de Chimie Moléculaire de l'Université de Bourgogne)
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.
ICMUB Institut de Chimie Moléculaire de l'Université de Bourgogne
Help of the ANR 229,478 euros
Beginning and duration of the scientific project: December 2016 - 36 Months