Objetivo This proposal aims to develop custom designed anticancer therapeutic frameworks that are effective, stable, safe, and tumor targeted, based on the biocompatible TiIV metal. The Tshuva group has established that water stable phenolato TiIV complexes are especially effective as anticancer agents both in vitro and in vivo, with markedly reduced side effects. Optimal derivatives will be developed to combine activity, stability, and biological accessibility, by maintaining small steric bulk while incorporating strong binding donors and hydrophilicity. The mechanism of action will be investigated by chemical and biological methods, including analyzing bio-distribution, cellular pathways and targets, and interaction with bio-molecules. Specifically, the active metal centers will be linked to bioactive moieties through redox-sensitive S–S bonds to enable tumor targeting. Cell penetrating peptides will facilitate cellular penetration for redox-dependent release of the active species selectively in cancer cells; steroid moieties will direct selectivity to hormone-dependent cancer cell types. Since the combination of TiIV- with Pt-based drugs has shown synergistic effects, multi-active entities will include two or more metal centers, possibly also linked to a transport unit. In addition to linear conjugates, polymeric and dendritic assemblies, exploiting the enhanced permeability of cancer cells, will be constructed with theoretically unlimited options for targeted delivery of multiple active sites. Most importantly, flexible well-defined redox-sensitive cages, as well as rigid pH sensitive complex cages, constructed with customized 3D geometries, will enable specific targeting of any active compound or conjugate and selective dissociation only where desired. This study should yield superior anticancer drugs, while unraveling the mystery of their complex biochemistry, and will contribute to the development of novel chemical and medicinal research directions and applications. Ámbito científico natural scienceschemical sciencesinorganic chemistrytransition metalsnatural sciencesbiological sciencesbiochemistrybiomoleculesmedical and health sciencesclinical medicineoncologynatural sciencesmathematicspure mathematicsgeometrymedical and health sciencesbasic medicineimmunologyimmunotherapy Palabras clave TiDrugArchitectures Programa(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Tema(s) ERC-CoG-2015 - ERC Consolidator Grant Convocatoria de propuestas ERC-2015-CoG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-COG - Consolidator Grant Institución de acogida THE HEBREW UNIVERSITY OF JERUSALEM Aportación neta de la UEn € 2 000 000,00 Dirección EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Israel Ver en el mapa Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 2 000 000,00 Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación neta de la UE Ampliar todo Contraer todo THE HEBREW UNIVERSITY OF JERUSALEM Israel Aportación neta de la UEn € 2 000 000,00 Dirección EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Ver en el mapa Tipo de actividad Higher or Secondary Education Establishments Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Participación en los programas de I+D de la UE Opens in new window Red de colaboración de HORIZON Opens in new window Coste total € 2 000 000,00