Nanoparticle sensors detect drug damage in the liver


A new way to screen animal livers for drug-related damage in real time, using tiny sensors embedded in nanoparticles, has been developed by researchers in the US. Liver toxicity is the leading cause of drug failure, so the advance could help streamline the drug development process, resulting in fewer toxic drugs and a greater success rate for clinical trials.

Measuring common metabolites that are indicators of oxidative stress – reactive oxygen species (ROS) and reactive nitrogen species (RNS) – can be predictive of drug toxicity, but detecting ROS and RNS directly in the liver is tricky. Now, Jianghong Rao and colleagues at Stanford University have created nanoparticle-based sensors that can image these metabolites in animal livers, which they say could help eliminate toxic drug candidates before they are given to humans.

To make the sensors, called chemiluminescence-fluorescence semiconducting polymer nanoparticles (CF-SPNs), Rao’s team used two small organic molecules that change their ability to give off light when reacting with ROS or RNS. One detects ROS by emitting light when in contact with hydrogen peroxide, while the other detects RNS by changing the way it fluoresces in the presence of peroxynitrite. ‘Both metabolites are mechanistically linked to drug-induced liver cell death for the majority of drug molecules,’ says Rao.

The nanoparticles allow ROS and RNS in the liver to be monitored in real time © Adam Shuhendler

The researchers inserted these sensors into nanoparticles composed of a fluorescent semiconducting polymer. Once in the liver, the nanoparticles emit light in the presence or absence of peroxynitrite or hydrogen peroxide, which can be detected outside the animals. In this way CF-SPNs can be used to ‘see’ these toxic metabolic by-products in real time. The team successfully tested the sensors on mice taking two commonly used drugs – paracetamol (acetaminophen), and isoniazid, a common tuberculosis medication.

‘This is the first study that demonstrates how to measure reactive oxygen and nitrogen species simultaneously,’ says Niren Murthy at University of California Berkeley, US, who was not involved in the research. He adds that while the technology could be useful for toxicity screening in animals, it is not possible to use it on humans. The detection is based on photon emission, and while it is possible to detect light through the 1cm of tissue in a mouse’s liver, the human liver is much larger and would require penetration depths of tens of centimetres.

But there are ways to overcome this, says Rao. Both magnetic resonance imaging and positron emission tomography can provide images through the entire depth of human liver tissue. The next challenge is to design sensors that change the way they interact with magnetic fields, for example, in the presence of ROS or RNS.

References

A J Shuhendler et al, Nat. Biotechnol., 2014, DOI: 10.1038/nbt.2838


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