The few sensors that detect and measure molecules in the body depend on the specific chemistry of the target analyte. For example, glucose sensors quantify levels of the sugar thanks to glucose oxidase, which oxidizes glucose and nothing else.
But what about the vast range of metabolites, drugs, and other molecules that a doctor or patient might want to measure? “What we really want is a generic platform that works in vivo, something that can detect any molecule irrespective of its chemistry,” says Kevin W. Plaxco, a chemist at the University of California, Santa Barbara.
Now, Plaxco and his coworkers have made such a general platform that works not only in living animals but even in ones that are awake and moving around (Proc. Natl. Acad. Sci. USA 2017, DOI: 10.1073/pnas.1613458114).
To do that, they use aptamers, ligand-binding nucleic acids, to bind to and detect a target molecule. To generate a signal, they modify those aptamers with an electrochemically active reporter molecule and tether the complex to electrodes. When the aptamers bind their targets, they fold up and change the electrochemical signal produced by the reporter. The team built the aptamer-decorated electrodes into a device that can be inserted into a vein in an animal so researchers can measure levels of a molecule in real time via changes in the electrical signals.
Plaxco’s group has been working on aptamer-based sensors for more than a decade. “When we first invented these sensors, they immediately worked in blood serum. Nobody else had a generic platform that would work continuously in blood serum for hours, making us optimistic that they’d work in vivo,” Plaxco says. “That turned out to be a big jump, though. We slowly chipped away at all the challenges. Now it works great.” For example, they needed to add a membrane to protect the sensor from fouling by blood cells. They also came up with a way to correct for drift in the electrical signal over time.
The researchers made two types of sensors, one with an aptamer that binds the cancer drug doxorubicin and another with an aptamer that binds aminoglycoside-containing antibiotics. They used the sensors to measure clinically relevant drug concentrations in rats that were awake and freely moving.
“This is the first time aptamer sensors have been demonstrated in living animals,” says Yi Lu, a chemist at the University of Illinois, Urbana-Champaign, who also develops aptamer-based sensors. The method is “limited only by the aptamers that have been selected. The results are very promising for potential clinical applications.”
Plaxco wants to expand the platform to other targets. “We’re very excited about expanding it to drugs where the window between the minimum effective dose and the toxic dose is narrow,” he says. Such measurements would allow feedback-controlled drug delivery to keep concentrations at safe levels. He also wants to develop sensors for biomolecules such as creatinine, which could be used as a real-time indicator of kidney function.
“We’ve only put three sensors in the body so far, but in vitro we’ve had great success at converting aptamers into sensors,” Plaxco says. “We believe our platform is as general as aptamers are.”