Local tumor conversion of a prodrug to an active agent using clinically relevant radiotherapy may herald a new era in targeted and directed cancer chemotherapy.

This may lead to the development of more tolerable cancer treatment regimens, without the potentially treatment-limiting systemic toxicities often associated with conventionally delivered chemotherapies, scientists at the University of Edinburgh and Shenzhen Institute of Advanced Technology suggest in the June 10, 2021, edition of Nature Chemistry.

Local conversion of a prodrug to active therapy via radiotherapy has been attempted by other groups, but unlike the present study, "these have failed to show a therapeutic effect," said senior author Mark Bradley, a professor in the School of Chemistry at Edinburgh University.

In addition, these groups "have not developed a generic approach that allows any anticancer agent with a free amine or alcohol group to be 'prodrugged'," Bradley told BioWorld Science.

Among numerous efforts made to improve the therapeutic index of anticancer drugs, the prodrug approach is attractive, as it has a proven clinical track record of improving drug administration routes and enhancing selectivity.

"While we have not assessed enhanced selectivity with prodrugs in our studies, prodrugs are generally used to allow their activation by enzymes localized to tumors et cetera, but these are never 100% specific," said Bradley.

However, the prodrug approach is known to reduce systemic toxicity, which is particularly important as the adverse effects associated with conventional chemotherapy adversely impact patients' treatment outcomes.

"This problem is huge, with our clinicians telling us that [systemic toxicity] is often a reason why patients stop their treatments," noted Bradley.

Consequently "drug levels have to be reduced to reduce toxic effects, but this further negatively impacts on treatment efficacy," he said.

In the new Nature Chemistry study, researchers co-led by Bradley and Jin Geng, a postdoctoral researcher in Bradley's laboratory at the study onset and now a professor in the Shenzhen Institute of Advanced Technology, sought to develop a reliable strategy to activate cancer prodrugs using clinically relevant doses of ionizing irradiation.

The study established the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates activation of a cancer prodrug, enabling simultaneous chemo-radiotherapy with radiotherapy locally activating the prodrug.

"Currently, radiotherapy is given in a defined three-dimensional (3D) volume using systems such as CyberKnife (Accurway), so therapy is activated in the 3D tumor volume and not elsewhere, which was proven by giving the prodrug and isolating the drug itself," said Bradley.

In an initial demonstration, the researchers had shown the activation of a fluorescent probe using this approach.

This provides "an optical illustration of the technology in action, since when giving the drug and the activatable fluorescent probe together, [detection of a] fluorescent tumor would show that the prodrug activation has been successful," explained Bradley.

Using a clinical radiotherapy system and subsequent analysis of the related drug, the research team then demonstrated how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib (Votrient; Novartis) and doxorubicin (Adriamycin) could be released using clinically relevant doses of ionizing radiation.

These reactions were clearly mediated via free-radical chemistry and through reductive loss of nitrogen, although the exact reductive mechanisms remain unclear and will be investigated in future studies.

This strategy differs from conventional chemo-radiotherapy radiation, whereby tumor chemo-sensitization occurs, so subsequent radiotherapy was more effective and allowed more effective site-directed rather than systemic chemotherapy.

"In animal models, this prodrug strategy was shown to be associated with less toxicity than that seen with doxorubicin alone," Bradley said.

Moreover, this strategy was shown to allow 'real time' drug release at the tumor site both in vitro and in vivo, thereby representing a new era in targeted and directed chemotherapy.

Given these promising initial results, said Bradley, in future "we will be moving toward human studies and investigating the use of antibody-drug conjugates (ADCs) and nanoparticles" in this regard.