In a new study in Science Advances, researchers developed a unique molecular structure that shuttles insulin through the gastrointestinal tract and into the bloodstream (1). The system delivered insulin to the intestine in a sustained manner and successfully protected it from degradation, establishing a potential method for oral insulin delivery.
Type 1 and advanced type 2 diabetes are typically managed with routine subcutaneous insulin injections. Regular injections often result in poor patient compliance, so a pain-free convenient oral delivery method should go a long way in helping those who need treatment.
“If a patient has diabetes and they have a choice between an injectable drug that works better and an oral drug that doesn't work quite as well, they'll take that oral drug until they have to move to the injectable drug,” said Alex Abramson, a chemical and biomolecular engineer at the Georgia Institute of Technology who was not involved in the study.
Researchers have attempted to formulate a system to deliver insulin orally, but multiple challenges stand in their way. Protein-degrading acids and proteases in the stomach, mucus, and tightly packed intestinal epithelial layers all hinder oral administration of insulin.
To overcome these challenges, researchers at the University of North Texas and Wuhan University designed a metal-organic framework (MOF) to shield insulin from the harsh conditions of the gastrointestinal tract. MOFs consist of metal nodes bound by organic linkers, forming a cage-like structure. The team built the MOF using zirconium-based nodes and an organic ligand that resists degradation from acids and enzymes. They designed the empty spaces in the cage to fit insulin but to exclude proteases like pepsin. The scientists also decorated the outside of the MOF with the protein transferrin, which helps insulin cross the stomach’s epithelial layer (2).
The researchers first tested their transferrin-coated MOF in a solution that mimicked the gastrointestinal environment and found that it gradually released insulin. They observed that the MOF effectively protected the encapsulated insulin from enzymatic degradation, enabling delivery of active protein.
The team then evaluated their MOF-based platform in mice. While free insulin rapidly degraded in the gastrointestinal tract, the transferrin-coated MOF delivered active insulin to the intestines and liver. The researchers observed superior insulin transport into the epithelial cells when delivered by a transferrin-coated MOF compared to a transferrin-free MOF, indicating that transferrin improved the permeability of insulin in the intestine. “That targeting protein can help a lot of nanoparticles to transport across the epithelial layer,” said Jian Tian, a pharmaceutical scientist at Wuhan University and author of the study.
The team then investigated their system’s ability to reduce blood glucose levels in diabetic rats by orally administering the MOF with and without transferrin and testing it alongside a subcutaneous insulin injection. The MOF coated with transferrin and the injected insulin reduced blood sugar to below a standard level, while the transferrin-free MOF did not.
“The next step in showing whether or not this will be viable in humans is to actually test in large animal models,” Abramson said.
“If it's successful, we want to push it into clinical trials because it has a huge impact,” Tian said. “For oral insulin delivery, it will be very huge.”
- Zou, J.-J. et al. Efficient oral insulin delivery enabled by transferrin-coated acid-resistant metal-organic framework nanoparticles. Sci Adv 8, eabm4677 (2022).
- Zhu, X. et al. Polymeric Nanoparticles Amenable to Simultaneous Installation of Exterior Targeting and Interior Therapeutic Proteins. Angewandte Chemie Int Ed 55, 3309–3312 (2016).