Researchers develop smart nanoparticles to successfully treat liver disease

Chronic inflammation of the liver is a slow, silent disease that can ultimately lead to scarring, cirrhosis, and even liver failure. For millions of people around the world, the liver's natural healing powers aren't able to keep up with chronic damage.

But one new study led by Dr. Jyothi Menon at Texas A&M University is offering a new cause for hope — and it all comes down to a few billion small particles.

Specific immune cells called Kupffer cells battle infection and break down waste in a healthy liver. They also dampen inflammation after injury. But when the liver gets hurt again and again — as with alcohol-induced liver disease (ARLD) — these very cells begin to break down. Instead of dampening the immune response, they start to exacerbate it by releasing inflammatory molecules that kill off healthy tissue and induce scarring, a process referred to as fibrosis.

Menon's team has been developing a particular way of breaking this vicious cycle. Her researchers developed biodegradable nanoparticles that could find and attach to Kupffer cells selectively without damaging the other liver cells. The particles are roughly a thousand times thinner than a human hair, but size doesn't matter when there's a lot of science behind them.

They are each covered in drug molecules that are receptor-specific for Kupffer cells and bind exclusively to those. They implant after binding, dispersing anti-inflammatory medication directly onto the cells, reprogramming them to function like their healthy, healing counterparts.

"Instead of going after the cells that are producing the scar tissue, we're stepping back and going after the Kupffer cells themselves so that we can prevent them from triggering other cells within the liver and forming this fibrosis growth," said Menon.

Traditional therapies for liver inflammation normally rely on drugs that diffuse across the body, diluting their effect and opening them up to side effects. Menon's nanoparticle design reverses that process by only targeting the rogue cells and releasing their medicine in a controlled fashion. The team's particles were designed to release their drug payload only under acidic conditions — the same conditions that are found in inflamed tissue.

This is a clever aspect that maintains the treatment dormant in normal liver tissue but turns on only in the presence of inflammation. During experiments in laboratory cell cultures mimicking liver cells, DEX-carrying nanoparticles released a lot more medicine in acidic environments than in conditions with normal pH levels. This implies that the drug targets precisely where it is needed most while limiting unnecessary exposure to the rest of the body.

When Kupffer-cell-like cultures were treated with such drug-loaded nanoparticles, the cells secreted far fewer inflammatory molecules. In essence, not only did the treatment attack where it was intended, but it also changed the behavior of those immune cells — lowering their destructive reactions and helping the liver's environment get back in line.

Menon's work is an initial but promising move towards a new era of treatment for the liver. For the moment, however, the work remains in the lab stage, with experiments conducted in cultures of cells rather than in live animals or people. But the potential stretches much further than disease caused by alcohol.

Since the nanoparticles are programmable and biodegradable, it is possible that in the future, they will be tailored to help with other inflammatory diseases — not only in the liver, but anywhere in the body. "Our formulations are versatile," Menon explained. "They can be adapted or modified for treating other types of inflammation and fibrosis in other organs.

Her research is exceptional in an arena where comparatively few treatments ever reach the cause of liver inflammation. Current therapies attempt to focus on symptoms, including swelling or fat buildup, but not on the individual cells that drive disease processes forward. By striking at the issue at its root — the Kupffer cells — Menon's group hopes to keep liver injury from spinning out of control.

"The individual components alone did not have a very therapeutic effect," she said. "But when we gave our last preparation with all of it combined, it suppressed inflammation and lipid droplet formation seen secondary to fat accumulation within the liver. It was the combination of all these things that really made a difference."

More than 1.5 billion individuals worldwide live with chronic liver disease, according to the U.S. Centers for Disease Control and Prevention. The disease kills more than 52,000 Americans annually and is the nation's ninth leading cause of death. Alcohol-associated liver disease, in particular, is one of medicine's most under-researched conditions, with its large burden.

It's one reason that Menon's study is making waves. Her research doesn't just propose a new way to reduce inflammation — it redefines the map for treating liver disease in the future. If these treatments pan out in future trials, nanoparticle-based treatments could allow for smaller doses of medications with higher accuracy, lowering side effects and improving outcomes.

The possibilities for such technology are even more impressive. As these nanoparticles are reliant on the chemical environment of inflammation for release of the drug, they may be used for "smart" treatment in other chronic inflammatory diseases, ranging from lung fibrosis to kidney disease.

As Menon's research partner at the University of Rhode Island described, this type of targeted treatment is a radical departure from traditional medical ideas about delivering medications. It's not what drug you deliver, but where and when it will be effective in the body.

Of course, plenty has to be sorted out before this technique reaches patients. The findings of the study are based on controlled lab tests, and scientists still have to work out how the nanoparticles act inside animals. Problems of safety, dose, and duration of exposure need to be addressed through extensive animal and human trials.

However, Menon's team remains optimistic. "Because one of the initial groups to even attempt something like this with drug delivery systems based on nanoparticles, there wasn't really any sort of precedent literature to provide us an estimate of what challenges might be out there," she said. "The first time that we were able to demonstrate that these particles have the ability to target Kupffer cells, we were very excited about it."

If this nanoparticle system works, it could be an important leap forward in targeted medicine for liver disease. Targeted drug delivery would mean patients improving with reduced side effects, reduced hospitalizations, and reduced long-term complications.

The pH-sensitive release mechanism — activating drugs only where inflammation is present — can be applied to the creation of other "smart" systems for a number of diseases.

Ultimately, this research will allow doctors to move from treating symptoms to stopping the biological causes of organ failure, improving survival and quality of life for millions.

Research findings are available online in the journal ScienceDirect Biomaterials.

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