A silhouette of the body’s digestive system with pills near the mouth and enzymes in the intestine.

Silk films may enable a shelf-stable, oral form of phenylalanine ammonia-lyase.

CREDIT: ASHLEIGH CAMPSALL

A silk cocoon gives a protective shell to oral drugs in the gut

Researchers are harnessing the power of silk to develop a shelf- and digestive tract-stable enzyme treatment for phenylketonuria.
Sarah Anderson, PhD
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The phrase “everything in moderation” applies even to essential amino acids. High phenylalanine levels due to impaired metabolism are the hallmark of the genetic disorder phenylketonuria (PKU). Scientists have hypothesized that an excess of phenylalanine disrupts signaling in the brain, resulting in developmental and cognitive disabilities. 

Those with PKU adhere to a specialized diet to avoid ingesting sources of phenylalanine. They may also undergo treatment with phenylalanine ammonia-lyase (PAL), an enzyme that breaks down phenylalanine. PAL is currently administered as a daily injection, but the painful prick and injection site inflammation may cause patients to skip doses. The shot also needs to be refrigerated, restricting transportation and distribution.  

While a shelf-stable, oral form of PAL would circumvent these limitations, the protein struggles to maintain its active structure at room temperature and under the extreme conditions of the gastrointestinal tract. In a new study in the journal Molecular Pharmaceutics, researchers at Tufts University developed a silky-smooth system to stabilize PAL for oral administration (1).

The team created films of silk fibroin from Bombyx mori silkworm cocoons and embedded PAL inside. “This enables silk to interact with the protein and create protective microenvironments that help to maintain the folding structure of the protein even in various conditions,” said Luciana d’Amone, a graduate student in the biomedical engineering department at Tufts University and coauthor of the study. The silk is also biodegradable and does not elicit an immune response, making it compatible with drug delivery.

A clear circle is held by tweezers in front of two white, fuzzy silk balls.
Researchers at Tufts University use silk fibroin from Bombyx mori silkworm cocoons to make silk films that stabilize protein drugs.
credit: Luciana d’Amone

To assess silk’s ability to stabilize PAL, the researchers measured its activity in various enzymatic samples. They first tested the shelf stability of different silk film formulations and identified a sweet spot in the relative amounts of enzyme and silk that gave maximum activity. In a long-term experiment at elevated temperature, they found that all formulations showed activity equivalent to or higher than the refrigerated enzyme after 42 days. 

“If you can develop strategies to stabilize protein therapeutics without the need for a refrigerator, it is a significant advantage from a cost, convenience, access, and global health standpoint,” said Matthew Webber, a chemical and biomedical engineer at the University of Notre Dame who was not involved in the study. “This technology has some promise there.”

To evaluate the oral stability of the silk-wrapped PAL, the team exposed the leading silk film to simulated digestive fluids. The enzyme lost activity within hours in salivary and gastric fluid, but activity was preserved for 20 hours in intestinal fluid. 

The poor stability in saliva and stomach acid indicates the need for additional stabilizing agents to enable oral PAL administration, according to Webber. “They would need to do something to protect it on the first half of the oral journey,” he said. The researchers should also investigate if the enzyme can be absorbed from the intestine into the bloodstream and function systemically, he added.

The team is working on further stabilizing PAL against protein-chewing enzymes and fluctuations in ionic strength and pH in digestive fluids. “The gut is a pretty harsh environment,” said Nikhil Nair, a chemical and biological engineer at Tufts University and coauthor of the study. “How do you keep things there for longer? That’s a big challenge that we've been trying to think about more.” One strategy is to encapsulate the silk film in coated gelatin that shields the film as it travels through the upper gastrointestinal tract and dissolves in the small intestine, Nair said. 

The researchers next plan to test their platform in animal models to see if it helps clear phenylalanine that accumulates in the small intestine, and to find out if doing so provides a therapeutic benefit for PKU. 

As scientists develop sturdier protein drugs for a range of conditions, they may use silk films to stabilize other enzymes against degradation. 

Reference 

  1. d’Amone, L., Trivedi, V. D., Nair, N. U. & Omenetto, F. G. A silk-based platform to stabilize phenylalanine ammonia-lyase for orally administered enzyme replacement therapy. Mol. Pharmaceutics (2022). In press. 

About the Author

  • Sarah Anderson, PhD
    Sarah Anderson joined Drug Discovery News as an assistant editor in 2022. She earned her PhD in chemistry and master’s degree in science journalism from Northwestern University and served as managing editor of “Science Unsealed.”

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Published In

October 2022
Volume 18 - Issue 10 | October 2022

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