Adam, CatherineBray, Thomas LPérez-López, Ana MTan, Ee HongRubio-Ruiz, BelénBaillache, Daniel JHouston, Douglas RSalji, Mark JLeung, Hing YUnciti-Broceta, Asier2023-05-032023-05-032022-01-03http://hdl.handle.net/10668/225895-Fluorouracil (5-FU) is an antineoplastic antimetabolite that is widely administered to cancer patients by bolus injection, especially to those suffering from colorectal and pancreatic cancer. Because of its suboptimal route of administration and dose-limiting toxicities, diverse 5-FU prodrugs have been developed to confer oral bioavailability and increase the safety profile of 5-FU chemotherapy regimens. Our contribution to this goal is presented herein with the development of a novel palladium-activated prodrug designed to evade the metabolic machinery responsible for 5-FU anabolic activation and catabolic processing. The new prodrug is completely innocuous to cells and highly resistant to metabolization by primary hepatocytes and liver S9 fractions (the main metabolic route for 5-FU degradation), whereas it is rapidly converted into 5-FU in the presence of a palladium (Pd) source. In vivo pharmokinetic analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits a longer half-life than 5-FU. In vivo efficacy studies in a xenograft colon cancer model served to prove, for the first time, that orally administered prodrugs can be locally converted to active drugs by intratumorally inserted Pd implants.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AnimalsAntimetabolites, AntineoplasticBiotransformationFluorouracilHCT116 CellsHalf-LifeHepatocytesHumansLiverMetabolic Networks and PathwaysMicePalladiumProdrugsProtein BindingRatsXenograft Model Antitumor Assaysresearch article34979089open access10.1021/acs.jmedchem.1c017331520-4804https://doi.org/10.1021/acs.jmedchem.1c01733