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Discovery Could Help Deliver Protein Drugs

This article is more than 7 years old.

What’s the best way to embed drug compounds in nanoparticles so they are released into the body at a controlled rate? The answer might be: Don’t.

That’s the surprising conclusion researchers at the University of Toronto came to when they were trying to perfect delivery of proteins that could heal spine and brain tissue, say from a stroke or an accident. Their discovery could help scientists and doctors unlock proteins' promise as medicines, they report in Science Advances.

The group, led by biomedical engineer Molly Shoichet, was trying to find the best way to deliver proteins that might help heal damage in the brain or along the spinal cord. They were using a standard approach. First, they encapsulated the proteins inside biodegradable plastic nanoparticles, then mixed those into a gel patch that can be applied directly to the injured site.

Proteins perform a host of vital tasks in our bodies. Some are already in use as drugs, like insulin, while others show promise that researchers are still trying to harness.

Encapsulation ensures a slow release of the proteins, which emerge from the gel over the course of weeks as the nanoparticles break down. Because it takes some time for the nanoparticles to degrade enough, there's a delay of a few days before any proteins emerge.

But Shoichet wanted to get the proteins to the injured tissue immediately. As an experiment, her group tried mixing some unencapsulated proteins directly into the gel. They thought these would make their way out of the gel right away.

Only, they didn’t. The researchers found it still took a few days for any proteins to leave the gel.

“Once we saw that really interesting phenomenon we tried to understand why, like how was that possibly happening,” says Shoichet.

When they looked into it, they discovered something they say no one else had noticed before. The proteins they were using have a slight positive charge. The nanoparticles, on the other hand, have a slight negative charge. The attraction between the two was slowing down the proteins' release.

“You can imagine a protein diffusing through a gel in which there’s all these sticky points,” says Shoichet. She says that the attraction between the protein and the nanoparticles is pretty weak, likening it to the stickiness of a Post-It note. A computer simulation confirmed that those electrostatic interactions were holding the proteins back.

Not only did it take a few days for the proteins to start emerging from the gel, the researchers found that when they did begin to release, they came out at almost the same rate as proteins that had been encapsulated in nanoparticles. Encapsulation, they say, might not be necessary at all.

Being able to skip the encapsulation step is a big deal, says Michael Sefton. He’s also a biomedical engineer at the University of Toronto, but he wasn’t involved in Shoichet’s research.

Sefton explains that it’s not easy to get proteins inside nanoparticles. Usually, he says, scientists end up wasting a lot of protein trying to get enough embedded in nanoparticles. The process can also damage the proteins, exposing them to chemicals and physical stresses that lessen their therapeutic effectiveness.

Shoichet agrees. “It saves an enormous amount of time and I think an enormous amount of protein,” she says. “Now we don’t have to spend a week or longer encapsulating our protein.” That means more time to find out how the proteins can help us.

During their experiments, Schoichet’s group also found that they could change how quickly the unencapsulated proteins got out, giving them more control. Adding more or bigger nanoparticles to the gel slowed down the proteins' release. Shoichet says that’s because there was more nanoparticle surface area for them to stick to.

They can also speed up protein release, by making the gel more acidic. As the gel's pH gets lower, there are more positively charged hydrogen ions floating around. Those can bind to the negatively charged nanoparticles and make them neutral. Without a charge, the proteins no longer stick to the nanoparticles.

That also explains why in their initial experiments the group still had to wait a few days for the proteins to emerge from the gel, Shoichet says. She explains that the plastic the nanoparticles are made of breaks down into acids. As that happens, the gel becomes more acidic, reducing the nanoparticles’ stickiness until the proteins eventually start to move out of the gel.

All of the proteins the group is exploring for therapeutic use are positively charged, so the delayed release worked with their nanoparticles. When the researchers tried a negatively charged protein it came out of the gel immediately, as they predicted.

There may be positively charged nanoparticles that could work the same way with negatively charged proteins. Or, says Shoichet, proteins with different charges could be used together, if it was advantageous to have one reach the injured tissue immediately and the other more slowly.