Activation of anticancer prodrug by palladium particles to prevent toxicity outside tumors

The major drawback of traditional chemotherapeutic drugs is that they don’t selectively kill or prevent proliferation of tumor cells; instead, they act on all dividing cells, causing the well-known, debilitating side effects of chemotherapy such as nausea and fatigue. Thus, a major goal in cancer drug development is to eliminate these off-target effects while preserving the drugs’ ability to block tumor growth. This challenge is one of the major motivations for the development of the field of nanomedicine, but targeting drug-carrying nanoparticles is only one solution. Another approach is to modify the drug so it’s activated specifically within the tumor; that is, to create a prodrug. However, no tumor-specific means of activation is active enough to ensure generation of sufficient drug; current prodrugs generally involve less specific mechanisms like acid-catalyzed hydrolysis.

A research group at the University of Edinburgh has recently introduced a potential solution to this challenge: creating a prodrug activated by a non-biological catalyst, and implanting that catalyst in the tumor. Ideally, the catalyst would not affect other biological processes; as an entire field has recently developed around this type of chemistry (termed “bioorthogonal”), the group, led by Asier Unciti-Broceta, had plenty of knowledge on which to build their work. Of the materials known to catalyze bioorthogonal reactions, the most biocompatible is palladium-zero (chemical symbol Pd0). First author Jason Weiss and the rest of the team chose to create a prodrug from 5-fluorouracil, a chemotherapeutic for which dosages are severely limited by its toxicity to bone marrow and the intestinal epithelium (causing low white blood cell counts and diarrhea), because the reaction by which it’s incorporated into nucleotides points to a modification that would block its activity. They made several modifications to 5-fluorouracil that would be stable against biological enzymes but susceptible to Pd0-mediated activation, then examined whether any could be activated by Pd0 at 37 °C in physiological buffer (Pd0 is generally used at much higher temperatures). Luckily, one of these modifications proved compatible with biological conditions.

Implanted catalyst to activate prodrug
Activation of 5-fluorouracil prodrug by Pd0. Upon activation, the drug diffuses into cells and is incorporated into a uracil nucleotide, which then inhibits production of an essential nucleoatide for DNA replication, or is incorporated into DNA or RNA, which prevents further synthesis. Both actions prevent tumor cell growth and proliferation.

The study’s key results are that the Pd0-activated prodrug kills cancer cells and that implantation of Pd0 does not affect development of zebrafish embryos, suggesting that it would be safe. However, Unciti-Broceta’s group did not assess tumor growth inhibition in vivo. Though the reason for this limitation is not discussed, it may relate to the number of variables involved in setting up such a study, since the distance the activated drug can diffuse and the amount of Pd0 required to convert sufficient prodrug to significantly affect tumor growth, among other parameters, remain unknown.

Given the requirement for implantation of the Pd0 catalyst, this strategy has better potential as a follow-up than a first-course treatment. The Pd0 particles could be implanted following resection to ensure eradication of any potentially remaining tumor cells.

Source: Weiss JT, Dawson JC, Macleod KG, Rybski W, Fraser C, Torres-Sánchez C, Patton EE, Bradley M, Carragher NO, Unciti-Broceta A. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat Commun 2014; 5.