doi:10.1021/acs.jmedchem.0c00781engPérez-López, A.M.Rubio-Ruiz, B.Valero, T.Contreras-Montoya, R.Álvarez de Cienfuegos, L.Sebastián, VíctorSantamaría, JesúsUnciti-Broceta, A.Bioorthogonal Uncaging of Cytotoxic Paclitaxel through Pd Nanosheet-Hydrogel FrameworksART-2020-120397The promising potential of bioorthogonal catalysis in biomedicine is inspiring incremental efforts to design strategies that regulate drug activity in living systems. To achieve this, it is not only essential to develop customized inactive prodrugs and biocompatible metal catalysts but also the right physical environment for them to interact and enable drug production under spatial and/or temporal control. Toward this goal, here, we report the first inactive precursor of the potent broad-spectrum anticancer drug paclitaxel (a.k.a. Taxol) that is stable in cell culture and labile to Pd catalysts. This new prodrug is effectively uncaged in cancer cell culture by Pd nanosheets captured within agarose and alginate hydrogels, providing a biodegradable catalytic framework to achieve controlled release of one of the most important chemotherapy drugs in medical practice. The compatibility of bioorthogonal catalysis and physical hydrogels opens up new opportunities to administer and modulate the mobility of transition metal catalysts in living environs.2020http://zaguan.unizar.es/record/9618410.1021/acs.jmedchem.0c00781http://zaguan.unizar.es/record/96184oai:zaguan.unizar.es:96184info:eu-repo/grantAgreement/EC/H2020/658833/EU/Development of Palladium-Labile Prodrugs for Bioorthogonally-Activated Chemotherapy/ChemoBOOMThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 658833-ChemoBOOMinfo:eu-repo/grantAgreement/EC/H2020/749299/EU/Integrated drug discovery approach to generate brain-penetrant inhibitors of glioblastoma cell proliferation/BRAINHIBThis project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No H2020 749299-BRAINHIBinfo:eu-repo/grantAgreement/ES/MICINN/RTI2018-099019-A-I00Journal of medicinal chemistry 63, 17 (2020), 9650-9659byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess