Not all antivenom is created equal. Different types of snakes produce different types of toxins. That means snake bite victims not only need to get a dose of antivenom as soon as possible, but they have to get the right one. Now, researchers report that they have devised nanoparticles that sop up a variety of common venom toxins in test tube studies, a key stride in coming up with the first ever broad-spectrum snake antivenom. The strategy could eventually be used to combat toxins from scorpions, spiders, bees, and other venomous creatures.
“This approach to treating snake bite sounds quite promising,” says Stephen Mackessy, a snake biologist at the University of Northern Colorado in Greeley, who was not involved with the work. “If they can develop a family of specific particles to target the major toxin families specifically, then this approach would have real value as a therapeutic.”
The lack of such a therapeutic is part of the reason that more than 100,000 people a year die from snake bites, mostly in Africa and Southeast Asia. That’s not the only danger. Venomous snakes bite an estimated 4.5 million people every year, nearly 3 million of whom suffer serious injuries, such as the loss of a limb. That’s because almost all snake bites occur in rural areas where people lack ready access to a clinic stocked with antivenom. And in many cases, victims receive the incorrect antivenom.
Producing conventional antivenom isn’t easy. The process starts by injecting an animal, often a horse, with a small amount of diluted venom from a particular snake. The animal’s immune system produces a mixture of antibodies capable of binding to and inactivating the toxins. Blood is then extracted from the animal, and the antibodies are purified and formulated for injecting into bite victims.
But conventional antivenoms have several problems. For starters, producing antibody-based antivenoms is time consuming and expensive, making it difficult for drug companies to make money on their sale, says Ken Shea, a chemist at the University of California, Irvine, who led the new work. That has contributed to a recent worldwide shortage. The antibody formulations must also be refrigerated, making them less accessible in the poorest parts of the developing world where they are often needed most.
So Shea and his colleagues are looking to nanotechnology for help. They previously designed nanoparticles capable of binding a powerful toxin in bee venom, known as melittin, and removing it from blood. But for their current work they wanted to create particles capable of binding not just one toxin, but many.
Their target was a family of toxins known as PLA2 proteins. Snakes produce hundreds of varieties of different PLA2s, which range from mildly toxic to powerful neurotoxins. PLA2 proteins normally wedge themselves into cell membranes. Shea and his colleagues started with the notion that nanoparticles made from similar lipidlike molecules that exist in cell walls had a good chance of binding to a wide range of PLA2 molecules.
But they didn’t make just one type of nanoparticle. Rather, they assembled a variety of different polymer building blocks that carried different chemical functions, such as having an acidic appendage, an alkaline sidearm, or being able to create a network of weakly interacting hydrogen bonds. They then assembled these components in different combinations and concentrations and carried out a chemical reaction that coaxed them all to form small, porous polymer nanoparticles. They incubated their nanoparticles with a cocktail of PLA2 molecules and isolated the nanoparticles that bound the PLA2s the best. Those nanoparticles served as the starting material for additional rounds of chemical optimization.
After several such rounds, Shea and his colleagues had nanoparticles that bound tightly to a wide range of PLA2. They do bind some other proteins as well. But after incubating their nanoparticles with blood serum and then adding a mix of PLA2 molecules, the researchers found that the toxins pushed the other proteins out of the way, binding more tightly to the nanoparticles than anything else, they report this month in the Journal of the American Chemical Society.
Shea notes that although he and his colleagues have yet to finalize their measurements on how well their nanoparticles bind to various PLA2 molecules, their test-tube results suggest that they could have a similar high affinity for PLA2s as their previous nanoparticles had for melittin, the bee venom protein that stopped the toxin in animal studies. He says that animal studies to test their broad-spectrum particle antivenom are expected to begin next month.
If those prove successful, Shea says the next step will be to devise nanoparticles that bind to other common protein families found in snake venoms. “Eventually we’d like to have a cocktail of two or three or four nanoparticles optimized against the principle protein toxins,” Shea says. And because such a cocktail would consist of synthetic polymers, it would likely be cheap to make and wouldn’t need to be refrigerated. That could prove a boon for helping doctors quickly provide effective antivenom to snake bite victims, possibly even saving thousands of lives every year.