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X-rays activate cancer drug

Radiation removes molecular mask to free anti-cancer agent, offering simultaneous chemotherapy and radiotherapy with fewer side effects in mice.

by Mark Peplow, special to C&EN
June 24, 2021


Structure of masked doxorubicin prodrug.
X-rays trigger a rearrangement that removes the mask (red) from a doxorubicin prodrug.

X-rays can activate an anti-cancer drug at a tumor site, researchers have found. Experiments in mice showed that this simultaneous chemotherapy and radiotherapy was effective at treating tumors, with minimal side effects (Nat. Chem. 2021, DOI: 10.1038/s41557-021-00711-4).

The method relies on a prodrug, a medicinal compound carrying a chemical ‘masking’ group that renders it inactive and nontoxic. Once the prodrug reaches a treatment site in the body, removing the mask frees the active drug to go only where it is needed, avoiding systemic side effects.

Researchers have previously developed a panoply of different ways for unmasking prodrugs, including enzymes, chemical catalysts, and light. The advantage of using radiation for this purpose is that it can be targeted very precisely, says Mark Bradley of the University of Edinburgh, who led the new study. “You can localize to a volume of a few milliliters,” he says.

The X-ray doses that unmask the drug are comparable to those used in cancer radiotherapy, so the treatment acts as combined chemotherapy and radiotherapy, which tends to be more effective than either alone. Although researchers have previously investigated radiation-activated cancer prodrugs, these efforts were ineffective in vivo (Molecules 2008, DOI: 10.3390/molecules13102370).

Bradley’s team attached a (p-azido)-2,3,5,6-tetrafluorobenzyl oxycarbonyl group to the powerful cancer drug doxorubicin and delivered it to tumor tissues. When X-rays hit tissue near the prodrug, they generate hydroxyl radicals that reduce the azide to an amine, triggering a rearrangement that frees doxorubicin. Although naked doxorubicin has toxic side effects, its masked form is nontoxic at clinically relevant concentrations.

When the researchers injected mice bearing tumors with masked or unmasked doxorubicin and supplied a dose of X-rays, the combination therapy effectively halted tumor growth. The mice survived for the full 50 days of the experiment in both cases, yet those receiving masked doxorobucin did not experience the weight loss and heart toxicity that the other group did. “By using radiotherapy to turn on prodrugs, this work opens a new avenue in chemotherapy,” says Peng Chen of Peking University, in an email interview.

Bradley hopes that the same mask could be applied to a wide variety of other cancer drugs. “In principle, we can attach this group to any cancer drug that contains a free amine or hydroxyl group,” he says. His team is already planning to develop the masked doxorubicin prodrug so that it is ready for clinical testing. “We’re gearing up to take this technology into first-in-human studies,” Bradley says.



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