The layers of mucus that protect sensitive tissue throughout the body have an undesirable side effect: they can also keep helpful medications away.
To overcome this hurdle, investigators at Johns Hopkins University have found a way to coat nanoparticles with a biocompatible, water-soluble polymer that helps them slip through this sticky barrier. Even better, experiments with these coated nanoparticles revealed that mucus layers have much larger pores than previously thought, providing a doorway that should allow larger and longer-acting doses of medicine to reach the protected tissue.
These discoveries are important because mucus layers, which trap and help remove pathogens and other foreign materials, can block the localized delivery of drugs to many parts of the body, including the lungs, eyes, digestive tract, and female reproductive system. Because of these barriers, doctors often must prescribe pills or injections that send drugs through the entire body, an approach that can lead to unwanted side effects or doses that are too weak to provide effective treatment. The researchers, led by Justin Hanes, Ph.D., published their findings in the Proceedings of the National Academy of Sciences USA.
"Mucus barriers evolved to serve a helpful purpose: to keep things out," says Hanes. "But if you want to deliver medicine in a microscopic particle, they can also keep the drugs from getting through. We've found a way to keep helpful nanoparticles from sticking to mucus, and we learned that the openings in the mucus 'mesh' are much larger than most people expected. These findings set the stage for a new generation of nanomedicines that can be delivered directly to the affected areas."
To get its particles past the mucus, Hanes' team studied an unlikely model: viruses. Earlier research had established that some viruses are able to make their way through the human mucus barrier. Hanes and his colleagues decided to look for a chemical coating that might mimic the characteristics of a virus. The investigators found that viruses capable of penetrating the mucus layer were attracted to water and had a net neutral electrical charge. As a result of this discovery, the researchers believed that a nanoparticle coated with a chemical that had these characteristics might not get stuck in the mucus barrier.
To make their nanoparticles behave like viruses, the researchers coated them with poly(ethylene glycol), or PEG, a non-toxic material commonly used in pharmaceuticals. PEG dissolves in water and is excreted harmlessly by the kidneys.
The researchers also considered the size of their nanoparticles. Previous studies indicated that even if nanoparticles did not stick to the mucus, they might have to be smaller than 55 nanometers wide to pass through the tiny openings in the human mucus mesh. Using high-resolution video microscopy and computer software, the researchers discovered that their PEG-coated, 200-nanometer particles could slip through a barrier of human mucus.