A 5-FU precursor designed to evade anabolic and catabolic drug pathways and activated by Pd chemistry in vitro and in vivo

5-FU (5-fluorouracil) is an antineoplastic antimetabolite 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, a diversity of 5-FU prodrugs has 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-activatable 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 (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 PK analysis shows the prodrug is rapidly and completely absorbed after oral administration and exhibits 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 into active drugs by intratumorally-inserted Pd-implants.