Description du projet
Le criblage de médicaments dans les sphéroïdes tumoraux
Le développement de médicaments contre le cancer doit tenir compte de la nature tridimensionnelle et hypoxique des tumeurs. Financé par le programme Actions Marie Skłodowska-Curie, le projet ImageTumor utilisera des sphéroïdes de cellules tumorales pour reproduire les conditions de la tumeur parentale et tester l’efficacité et la perméabilité des médicaments candidats. Les travaux cibleront les composés métalliques anticancéreux et examineront leur localisation cellulaire en recourant à la spectrométrie de fluorescence des rayons X et à l’interaction avec différentes protéines. Les résultats jetteront les bases pour un processus de criblage des médicaments plus représentatif qui permettra de commercialiser la prochaine génération de traitements anticancéreux.
Objectif
According to estimates from the World Health Organization (WHO) in 2019, cancer is the second leading cause of death after heart failure before the age of 70. The field of metal-based anticancer drugs has been on the rise ever since the discovery of the anticancer properties of cisplatin in 1965, which is in daily clinical use against various types of cancer. Many compounds failed to enter clinical studies since their anti cancer activity is mainly studied in two dimensional (2D) monolayer cells which does not mimic the complex tumor micro environment in humans. In the human body the cancer tumors grow in 3-dimensional structure, hence it is vital to study the anticancer activity of a drug molecules in the 3D tumors rather in 2D mono layer cells. Next, tumor hypoxia (1% Oxygen), a situation where tumor cells are deprived of oxygen, is a major challenge for oncology. In this project we propose the synthesis of N-Heterocyclic Carbene/1,8-naphthalicanhydride conjugated series of metal complexes (Gold, Rhodium, Iridium) to study the anticancer activity and penetration depths in 3D tumor spheroids under hypoxia. We also investigate the activation by reduction mechanism in presence of cellular thiols and cytotoxicity in vitro (3D cell spheroids) and compare the results among the three metal centers. The metal protein interactions play key role in many biological processes; hence we also investigate the metal-protein interaction studies using capillary electrophoresis inductively-coupled mass spectrometry (at secondment). We will investigate the structure activity relationship between metals and of related coordinating ligands in 3D spheroid under hypoxic conditions. We mainly utilize X-Ray Fluorescence (XRF) imaging and synchrotron radiation to test the cellular localizations and penetration depth for the proposed metal complexes. This project is expected to yield unique insights towards optimization of next-generation anti-tumor drugs.
Champ scientifique
- natural scienceschemical sciencesinorganic chemistrytransition metals
- medical and health sciencesclinical medicineoncology
- natural scienceschemical scienceselectrochemistryelectrophoresis
- medical and health sciencesclinical medicinecardiology
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Mots‑clés
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régime de financement
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinateur
44801 Bochum
Allemagne