Design, synthesis and optimization of Fe(III) based porphyrins for use as next-generation MRI probes

Description du projet

Améliorer la sécurité de l’IRM avec des agents de contraste à base de fer

L’imagerie par résonance magnétique (IRM) est essentielle au diagnostic précoce d’une affection et au suivi du traitement. Les agents de contraste à base de gadolinium (Gd-CA) utilisés pour l’IRM soulèvent toutefois d’importantes préoccupations de sécurité et environnementales. Le défi consiste à trouver une alternative viable à la fois efficace et non toxique. Les porphyrines de fer (Fe(III)) sont certes prometteuses, mais souffrent de problèmes tels que la formation de μ-oxo-dimères, qui réduit leur efficacité. Avec le soutien du programme Actions Marie Skłodowska-Curie, le projet PorphIRON entend surmonter ces limitations en développant de nouveaux agents de contraste à base de fer. En optimisant la structure des porphyrines Fe(III), PorphIRON améliorera leur stabilité et leur efficacité tout en assurant leur biocompatibilité. Ce projet associe la chimie avancée des porphyrines à des analyses informatiques et à l’expertise de l’IRM pour créer des agents de contraste sûrs et performants en vue d’une future utilisation clinique.

Objectif

Magnetic resonance imaging (MRI) plays a pivotal role in early diagnosis and therapy follow-up of many diseases. The substitution of current Gd-based MRI contrast agents (CA), which raise both safety and environmental concerns, is one of todays most important challenges in imaging-related chemistry. High complex stabilities and inertness attainable with Fe(III) make it a high potential alternative to Gd. Porphyrins have met great clinical success, exhibit biocompatibility, stable metal complexes and easy structural modulation., but formation of -oxo-dimers in Fe(III) porphyrins (FePo) reduces their relaxation efficacy. PorphIRON will tackle these limitations and develop new families of biocompatible FePo fine-tuned for MRI use. PorphIRON will focus on structural optimization to i) maintain the oxidation and the high spin state of Fe(III), yielding relaxation effect comparable to clinical CA, and ii) adjust physicochemical properties to preserve biocompatibility. To achieve this, PorphIRON will rely on a synergic combination of the ERs experience in porphyrin chemistry and computational studies with that of the supervisor in MRI CA development, and an iterative approach with: i) initial synthesis of newly designed FePo, followed by their physicochemical and biological evaluation; ii) computational rationalization of the experimental results and prediction of new optimized structures; iii) second-round optimized FePo synthesis and characterization. PorphIRON will deliver fully characterized, stable, biocompatible and high efficacy FePos with preliminary preclinical in vivo MRI validation, thereby actively contributing to the implementation of next-generation non-toxic CA in clinic. PorphIRON will strengthen ERs experience in organic synthesis, computational chemistry, while significantly expanding his knowledge to CA development and preclinical MRI. It will expand his career perspectives and open new opportunities in the emerging field of theragnostics.