DESIGN AND DEVELOPMENT OF BIOACTIVE METAL SYSTEMS FOR THERAPEUTIC APPLICATIONS

THIS PROJECT ENTITLED "DESIGN AND DEVELOPMENT OF BIOACTIVE METAL SYSTEMS FOR THERAPEUTIC APPLICATIONS" (DEBIOMET) HAS TWO MAIN, CLOSELY RELATED OBJECTIVES: THE DEVELOPMENT OF NEW METAL-CONTAINING ANTICANCER COMPOUNDS AND THE DEVELOPMENT OF AN ANALYTICAL METHODOLOGY FOR MEASURING THE CONCENTRATION OF METALLOTHIONEINS (MT) IN HUMAN FLUIDS TO EVALUATE THEIR POSSIBLE USE AS BIOMARKERS IN DIFFERENT DISEASES THAT ALTER THE HOMEOSTASIS OF ESSENTIAL METALS. GIVEN THE EXTENSIVE EXPERIENCE OF OUR GROUP IN THE FIELD, THE FIRST PART OF THE PROPOSAL IS BASED ON THE DEVELOPMENT OF NEW ANTICANCER COMPOUNDS CONSIDERING 2 MAIN STRATEGIES: 1) THE USE OF UPCONVERTING NANOPARTICLES TO ALLOW THE ACTIVATION OF METALLIC COMPOUNDS BY NIR IRRADIATION; AND 2) THE SYNTHESIS OF PHYSIOLOGICAL METAL COMPLEXES IN ORDER TO REDUCE THEIR CYTOTOXICITY AND INVESTIGATE ALTERNATIVE MECHANISMS OF ACTION OTHER THAN THE INTERACTION WITH DNA. MOST OF THE LIGANDS AND THE CORRESPONDING METALLIC COMPLEXES WILL BE INSPIRED BY ACTIVE CENTERS OF METALLOPROTEINS AND OTHER METAL-CONTAINING BIOLOGICAL SYSTEMS. WE ALSO PLAN TO USE PEPTIDE-FUNCTIONALIZED LIGANDS TO IMPROVE THE PHYSIOLOGICAL PROPERTIES OF THEIR METALLIC COMPOUNDS. IT IS IMPORTANT TO HIGHLIGHT THAT THESE STRATEGIES WILL BE COMBINED WITH EACH OTHER WHEN NECESSARY TO OBTAIN THE BEST CANDIDATES TO ACT AS ANTICANCER AGENTS. THE PROPOSED WORK INVOLVES NOT ONLY THE SYNTHESIS AND CHARACTERIZATION OF METAL COMPOUNDS, BUT ALSO THE STUDY OF THEIR IN VITRO REACTIVITY WITH BIOMOLECULES (MAINLY PROTEINS), AS WELL AS THEIR BEHAVIOR IN CELL CULTURES. THIS PART OF THE PROJECT IS FOCUSED ON SOLVING SPECIFIC PROBLEMS IN CURRENT ANTICANCER THERAPIES, MAINLY CONSIDERING THE SELECTIVITY OF THE TREATMENTS. TAKING ADVANTAGE OF THE KNOWLEDGE ACQUIRED IN THE FIELD OF METALLOTHIONEINS (MT) IN THE LAST 30 YEARS, THE SECOND PART OF THE PROJECT CONSISTS IN DEVELOPING AN ANALYTICAL METHODOLOGY, BASED ON THE USE OF HIGH PURITY RECOMBINANT MT, WHICH ALLOWS TO MEASURE QUANTITATIVELY AND RELIABLY THE CONCENTRATION OF MT IN BIOLOGICAL FLUIDS. IF SO, THEY CAN BE USED AS BIOMARKERS IN MENKES DISEASE AND, IN ITS EXTENSION, IN OTHER DISEASES RELATED WITH THE PRESENCE OF METAL IONS. THE FACT OF HAVING ACCESS TO REAL SAMPLES OF MENKES PATIENTS TREATED WITH THERAPEUTIC COPPER COMPOUNDS WILL FACILITATE THE EVALUATION OF THE METHODOLOGY. ALL THE RESULTS OBTAINED IN THIS PROJECT WILL PROVIDE KNOWLEDGE TO FACE THE DESIGN OF NEW METALLIC COMPOUNDS SUITABLE FOR THERAPEUTIC USE AND HAVE A METHODOLOGY TO HELP DIAGNOSE A DIVERSE SET OF DISEASES.