Dr. Nicholas A. Peppas at The University of Texas at Austin has received a five-year, $2.1 million grant from the National Institutes of Health to analyze a polymer-based approach for providing insulin to the body that may eventually end the need to treat diabetes with daily injections.
Some people with diabetes develop fatty deposits, bruises or other tissue damage from taking multiple shots of the insulin protein each day to manage the disease.
“Some of them complain of scar tissue from the continued piercing of their bodies,” said Peppas, holder of the Fletcher Stuckey Platt Chair in Engineering. “That hurts, but they don’t currently have any other choice besides insulin injections.”
Peppas, a professor of chemical engineering, biomedical engineering and pharmaceutics, first published findings in 1999 on his development of a form of insulin that could be swallowed instead of injected. With the new grant, he will determine what factors make the current form of his oral-insulin-delivery device work well, and seek ways to further improve it.
People with type I diabetes have traditionally taken insulin injections to deliver the protein directly into their bloodstream. This route serves as a way to deliver insulin to the pancreas to perform the function of insulin that would normally be produced there.
Developing a tablet or capsule form required finding a way to keep the protein intact on its way to the small intestine, the site of the drug’s absorption into the bloodstream. That meant researchers had to find a way to protect insulin from acidic (low pH) conditions in the esophagus and stomach, and protein-destroying enzymes in the stomach.
Peppas developed the device to include the molecules methylacrylic acid and polyethylene glycol (PEG) linked together to form a porous polymer network that holds insulin inside. The polymer serves as a barrier, protecting the protein during its journey through the upper digestive tract.
The polymer, called a hydrogel because of its water-carrying capacity, swells once it reaches the basic (high pH) conditions inside the upper-small intestine. Its insulin cargo is released, and can be absorbed by cells lining the small intestine before entering the bloodstream.
Studies by Peppas’ collaborators at Hoshi University in Japan, Thomas Jefferson Medical Center in Philadelphia and elsewhere have revealed that at least 12.8 percent of the insulin in his polymer complexes reaches test animals’ circulation. Efforts to increase insulin's availability in the bloodstream will include extending how long its carrier stays in the upper small intestine.
“We would like to increase the hydrogel’s ability to attach to cells of the upper intestinal tract to last for 10 hours,” Peppas said. “In that time, most insulin that is released hopefully would pass into the intestinal wall and go into the blood.”
But first, his laboratory will perform visual analyses of fluorescently labeled versions of the insulin and polymer, using intestinal cells grown in flasks as an attachment target. This will help answer questions such as how the PEG portion of the polymer helps it stick to small intestine cells, how the polymer dampens the effect of protein-destroying enzymes and how insulin gets inside intestinal cells.
Much of this work will focus on a form of insulin that is physically linked to the protein transferrin. This protein normally serves to ferry iron to cells for uptake, and shows promise of improving insulin’s ability to gain access into intestinal cells.
Peppas’ laboratory will analyze the structure of transferrin-bound insulin to understand how it interacts with the polymer, and will perform fluorescent labeling experiments to study the hydrogel/protein complex’s interactions with upper-small-intestine cells.
The researchers also will investigate other ways to improve the oral-insulin-delivery device, such as adding proteins called lectins to the hydrogel that attach to carbohydrates found on the surface of cells. Their general findings will be used to inform other efforts under way in Peppas’ lab to develop oral treatments for cancer, multiple sclerosis (MS) and other diseases.
Peppas noted that it can be hard to convince someone with MS, for instance, to continue taking injections. Unlike diabetes, where a missed insulin injection quickly harms the body, the tissue-damaging effects of skipping injectable medications for MS can take months to detect.
“This is what these technologies for oral delivery are trying to do — to find better methods to improve the quality of life of patients,” Peppas said, “which is very satisfying work for a scientist.”
A photo of Dr. Peppas is at: www.engr.utexas.edu/news/action_shots/pages/PeppasNIH.cfm
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