A step towards oral insulin

Oral delivery of insulin and other protein-based drugs can be challenging, as the acidic conditions of the gastrointestinal tract can break them down, rendering them ineffective. Also, the intestinal membrane is poorly permeable to insulin. Some people’s fear of needles and self-injection makes it difficult to start insulin therapy, and though insulin pens can overcome these problems, they are costly and can lead to incorrect dosage delivery. A safe and effective oral delivery method would be of great benefit in diabetes care.

To address these issues, researchers developed an imine-linked covalent organic framework (nCOF); a crystal lattice of two organic molecules, TTA and DFP. The researchers were drawn to the idea of using this for insulin delivery, as TTA-DFP-nCOF is stable even under acidic conditions. But they had doubts that the material could absorb insulin, as the layers, which are stacked a few nanometres apart, are positioned such that one layer partially obscures the pores in the next, meaning insulin might not be able to sit in the pores.

“It turns out the insulin makes its way through the sheets and interpolates between them,” says senior author Ali Trabolsi of New York University Abu Dhabi. “That was quite surprising. Even more surprising was the material’s high insulin loading capacity.”

The researchers demonstrated the stability of TTA-DFP-nCOF/insulin in simulated gastric and intestinal fluid. They then exposed it to a library of molecules found in blood and discovered that only glucose triggered insulin release from the framework. Due to its size and properties, glucose was able to diffuse through the pores of the nCOF substrate, pushing the insulin out from between the stacked sheets.

Cell culture tests showed that TTA-DFP-nCOF/insulin was non-toxic, so the researchers administered it orally to rats with induced type 1 diabetes. The treatment led to slow reductions in fasting blood sugar levels that were sustained for more than 10 hours. By comparison, insulin injections led to a more rapid and transient drop in blood sugar. 

These results are promising, but many more steps remain before human trials can begin. In the meantime, Trabolsi has started a collaboration to use computational methods to investigate the properties of similar materials and figure out which would be useful to test in the lab. His hope is to develop a framework that could be used more broadly. The ultimate goal, he says, is to make a universal material for the oral delivery of protein-based drugs.

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