In 2013 then-Secretary of State John Kerry called out Syrian president Bashar al-Assad for a chemical attack on Syrian civilians that left more than 1,400 dead. The gas used was sarin, one of a class of compounds known as organophosphates (OPs).
Although antidotes to OPs like sarin are available, the fast action of these nerve agents means such measures often come too late. Researchers have eagerly pursued prophylactics for decades, ever since German chemists first developed this group of chemicals prior to World War II. Initially, they had created OPs on a quest for pesticides, producing sarin in 1938 for that purpose. Although the Nazi regime soon turned its attention to its lethal effects on humans, OP pesticides such as chlorpyrifos continue in widespread use globally today.
About 300,000 people die each year from exposure to OP pesticides, which are applied to crops and used in household roach and ant poisons. Most deaths occur in developing countries among people who work in unsafe conditions. Some U.S. researchers have called for phasing out these chemicals because of studies suggesting harm to child development. In August 2018 a U.S. federal appeals court ordered the Environmental Protection Agency to ban use of chlorpyrifos within 60 days, but the U.S. Department of Justice requested reconsideration of the ruling, so no ban is in place.
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OPs can interfere with enzymes that regulate nerve signaling used by both insects and humans. If an OP inhibits these cholinesterases, the muscles, including those that control breathing, can eventually stop working. Several molecules have been identified that can either mop up or break down OPs before they interfere with this signaling. But efforts to bring these chemical scavengers into real-world use have suffered from two main obstacles: the molecules work only for very short times and they tend to attract an unwanted immune response.
Stealth “nanoscavengers”—coated nanoparticles that target OPs—might be a solution to both problems. Findings published January 2 in Science Translational Medicine describe a nanoscavenger that disables both pesticide and nerve gas OP compounds, and persists much longer than other candidates while evading by “stealth” the recipient’s immune system. Because of the nanoscavengers’ persistence and immune evasion, the findings are a significant advance over previous work, says Alexander Kabanov, director of the Center for Nanotechnology in Drug Delivery at the University of North Carolina at Chapel Hill who was not involved in the study.
The investigators tested their scavenger against two OPs: paraoxon—an active breakdown product of the OP pesticide parathion—and sarin. To produce a stealth nanoscavenger, they wrapped a water-swollen gel coating around an OP-scavenging enzyme. The gel works as an invisibility cloak for the enzyme, hiding it from the immune system—yet it is just porous enough for the enzyme to interact with and disable OPs.
Rats exposed to paraoxon showed no symptoms if they received an injection of the coated nanoscavenger beforehand. The enzyme—organophosphorus hydrolase, or OPH, which breaks down OPs into harmless components—also worked without the cloak, but only for a few brief hours. When it was tucked into its gel coating, though, it worked for as long as week in the rats and triggered negligible immune reaction. Given these results, says study author Shaoyi Jiang, professor of chemical engineering at the University of Washington, the nanoscavengers are expected to carry little risk. “However, further safety evaluations in humans are needed,” he says.
To try their nanoscavenger against the far more lethal OP compound sarin, the team turned to guinea pigs, which have long been used in this type of testing, Jiang says. The “cloaked” nanoscavenger also protected sarin-exposed animals for more than a week, disabling the deadly OP agent and rendering it harmless, even with repeated sarin exposures. “The possibility of protection against OP exposure for nearly a week makes this approach practical when the exposure is inevitable or likely,” says Kabanov, whose team previously reported successful prophylaxis with a gel applied to the skin. A topical gel might serve as a barrier to skin exposure, he says, but “given the imminent and mortal threat in case the OP gets inside of the body, systemic bio-scavengers like the one described in this publication are necessary.”
Civilians living in war-torn areas where combatants are willing to use nerve gas, members of the military and workers who deal with pesticides are just a few populations who might benefit from a long-lasting OP prophylactic. “Increasing use of OP warfare by rogue actors and terrorists makes this problem even more severe,” Kabanov says.
The stealth nanoscavenger that Jiang and colleagues developed targets one class of OP compounds whereas the gel Kabanov and co-workers developed targets another. The ultimate goal, Jiang and co-authors say, is a “nanoscavenger cocktail” that will disable a broad spectrum of OPs, perhaps someday providing a shield against attacks like the one Assad unleashed on his own people.