Descripción del proyecto
Cribado de fármacos en esferoides tumorales
El desarrollo de fármacos contra el cáncer debe tener en cuenta la naturaleza tridimensional e hipóxica de los tumores. El equipo del proyecto ImageTumor, financiado por las Acciones Marie Skłodowska-Curie, utilizará esferoides de células tumorales para reproducir las condiciones del tumor parental y probar la eficacia y permeabilidad de los fármacos candidatos. La labor del equipo se centrará en compuestos antineoplásicos basados en metales y examinará su localización celular mediante técnicas de fluorescencia de rayos X, así como su interacción con diversas proteínas. Los resultados sentarán las bases de un proceso de cribado de fármacos más representativo que permitirá comercializar la próxima generación de tratamientos contra el cáncer.
Objetivo
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.
Ámbito científico
- natural scienceschemical sciencesinorganic chemistrytransition metals
- medical and health sciencesclinical medicineoncology
- natural scienceschemical scienceselectrochemistryelectrophoresis
- medical and health sciencesclinical medicinecardiology
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Palabras clave
Programa(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Régimen de financiación
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinador
44801 Bochum
Alemania