Project description
Drug screening in tumour spheroids
Drug development for cancer must take into consideration the three-dimensional and hypoxic nature of tumours. Funded by the Marie Skłodowska-Curie Actions programme, the ImageTumor project will use tumour cell spheroids to recapitulate the conditions of the parental tumour and test the efficacy and permeability of candidate drugs. The work will focus on metal-based anticancer compounds and examine their cellular localisation using X-ray fluorescence imaging as well as interaction with various proteins. Results will lay the groundwork for a more representative drug screening process that will help bring to the market the next generation of anticancer treatments.
Objective
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.
Fields of science
- natural scienceschemical sciencesinorganic chemistrytransition metals
- medical and health sciencesclinical medicineoncology
- natural scienceschemical scienceselectrochemistryelectrophoresis
- medical and health sciencesclinical medicinecardiology
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
44801 Bochum
Germany