Discussion
Chemotherapy is widely used to treat various forms of cancer. However, some chemotherapeutic drugs, due to their antineoplastic properties, also act upon healthy cells which normally replicate rapidly causing a plethora of undesirable side effects. One rising and promising therapeutic strategy is the development of prodrugs. Prodrugs contain various masking groups on selective functional groups within the drug, which play a critical role in the drugs mechanism of action. Once the prodrug undergoes an enzymatic or chemical transformation in vivo, it becomes activated, exerting the desired pharmacological effect1. As a novel prodrug approach, the Unciti-Broceta group is pioneering the use of a bioorthogonal organometallic (BOOM) activation strategy to develop spatially-controlled anticancer treatments. Bioorthogonal reactions are selective chemical processes between two abiotic reagents in a biological system that do not interfere with the system’s biotic components2-4. We are investigating the synthesis of prodrugs masked with bioorthogonal protecting groups sensitive to activation by a catalysts-based “activating device”. Specifically, we and our collaborators have designed Pd0-functionalized resins (the activating device) capable of activating clinically used 5-fluorouracil (5FU) masked with a Pd0-sensitive chemical group, to make a “BOOM-activated prodrug” (Pro-5FU). Herein we demonstrate that although both the Pd0 implant and Pro-5FU are independently non-cytotoxic, once combined together they exhibit comparable antiproliferative properties to the unmodified 5FU in vitro. The Pd0 resins also display biocompatibility and local catalytic activity inside zebrafish embryos5. This approach is intended to generate a more targeted therapeutic approach while minimizing harm to normal healthy tissues.
References.
[1] Rautio et al. Nature Rev Drug Discov 2008, 7, 255-270; [2] Prescher & Bertozzi. Nature Chem Biol 2005, 1, 13–21; [3] Unciti-Broceta et al. Nature Protocols 2012, 7, 1207–18; [4] Yusop, Unciti-Broceta et al. Nature Chem 2011, 3, 241–245; [5] Weiss, J. T. et al. Nat. Commun. 5:3277.
