Cel 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. Dziedzina nauki natural scienceschemical sciencesinorganic chemistrytransition metalsnatural sciencesbiological sciencesbiochemistrybiomoleculesmedical and health sciencesclinical medicineoncologynatural sciencesmathematicspure mathematicsgeometrymedical and health sciencesbasic medicineimmunologyimmunotherapy Słowa kluczowe TiDrugArchitectures Program(-y) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Temat(-y) ERC-CoG-2015 - ERC Consolidator Grant Zaproszenie do składania wniosków ERC-2015-CoG Zobacz inne projekty w ramach tego zaproszenia System finansowania ERC-COG - Consolidator Grant Instytucja przyjmująca THE HEBREW UNIVERSITY OF JERUSALEM Wkład UE netto € 2 000 000,00 Adres EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Izrael Zobacz na mapie Rodzaj działalności Higher or Secondary Education Establishments Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 000 000,00 Beneficjenci (1) Sortuj alfabetycznie Sortuj według wkładu UE netto Rozwiń wszystko Zwiń wszystko THE HEBREW UNIVERSITY OF JERUSALEM Izrael Wkład UE netto € 2 000 000,00 Adres EDMOND J SAFRA CAMPUS GIVAT RAM 91904 Jerusalem Zobacz na mapie Rodzaj działalności Higher or Secondary Education Establishments Linki Kontakt z organizacją Opens in new window Strona internetowa Opens in new window Uczestnictwo w unijnych programach w zakresie badań i innowacji Opens in new window sieć współpracy HORIZON Opens in new window Koszt całkowity € 2 000 000,00