There are few treatment options available for people with disorders of the esophagus. Delivering drugs directly to this part of the body is difficult, so patients are usually treated with systemic drugs, which can have unwanted side effects.
To overcome that challenge, MIT engineers developed a gel-like oral drug formulation that can coat the mucosal lining of the esophagus after being swallowed, allowing drugs to pass through the tissue.
The formulation, which includes a hydrogel and other key ingredients that promote rapid drug absorption, could be used to deliver antibodies including infliximab, used to treat a number of autoimmune diseases, or other types of antibodies or small-molecule drugs.
"There are many people with esophageal disease, and if you look at drugs for these conditions, they're very limited in their ability to target this part of the body and it's very difficult to develop them. We hope this platform will make it easier to develop systems that can help patients suffering from these conditions," says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women's Hospital, and an associate member of the Broad Institute of MIT and Harvard.
Traverso is the senior author of the new study, which appears today in Nature Biomedical Engineering . Former MIT postdoc Christina Karavasili, now an assistant professor at Aristotle University of Thessaloniki in Greece, is the paper's lead author.
Direct delivery
One of the most common disorders of the esophagus is eosinophilic esophagitis, a type of inflammation that is caused by food allergies and leads the esophagus to close up, making it impossible to swallow food. Crohn's disease can also cause inflammation of the esophagus.
These disorders are usually treated with systemic drugs, including infliximab, an antibody that neutralizes an inflammatory protein called tumor necrosis factor alpha (TNF-alpha). However, this drug is an immunosuppressant that can lead to a higher risk for infections and other health problems.
Delivering the drug directly to the esophageal tissue could reduce those side effects, but this is inherently challenging because drugs taken orally pass through the esophagus so quickly. Adding to the difficulty, the esophagus is lined by a layer of tissue called stratified squamous epithelium, which is very impermeable to drugs.
Injecting drugs into the esophageal tissue is another option, but that is uncomfortable for patients and inconvenient because it has to be done at a doctor's office. There is also at least one anti-inflammatory steroid drug that is formulated as a thick mixture, allowing it to remain in the esophagus longer after being swallowed, but the drug still has some difficulty passing through the impermeable squamous layer.
In this study, the researchers set out to develop new drug formulations that would include molecules that could increase the permeability of those esophageal cells, allowing more of the drug to pass through.
To identify molecules that would enhance permeability, the researchers designed a screening system that mimics the structure of the esophagus. This system contains esophageal tissue pressed between two vertical plates. Drug formulations can be poured into the top of the system, simulating oral ingestion. The researchers can then measure how much of the drug passes through the tissue and is collected by wells in one of the plates.
Using this system, the researchers were able to measure how different excipients - inactive ingredients that help enhance drug effects - affect the permeability of the esophageal tissue. First, they tested about 100 different compounds and identified several top candidates. Then, they tested pairs of these excipients and found that the most effective combination was a pair of bile salts called sodium chenodeoxycholate and sodium cholate.
These salts appear to work together to loosen up the cell-cell junctions that normally act as a barrier to drug molecule entry. The researchers added those bile salts to a polysaccharide-derived hydrogel, which has a viscous consistency that allows it to lightly coat the lining of the esophagus.
"The hydrogel helps the formulation remain on the esophageal surface for longer, while the bile salts help increase transport across the tissue," Karavasili says. "Our data suggest that the bile salts temporarily loosen these cell-cell junctions, mainly by interacting with calcium ions that help maintain junction integrity. This creates a more permissive pathway between the cells, allowing larger molecules to move into the mucosal tissue more efficiently."
Minimizing side effects
In tests in animals, the researchers showed that this formulation could be used to effectively deliver infliximab to the esophagus. They also found that the loosening of the cell-cell junctions was temporary, and the cells returned to normal within three days.
This kind of delivery could help to avoid the side effects that patients sometimes experience when infliximab is given systemically, the researchers say.
"We were interested in delivering anti-TNFs as a model drug, but also to help people who suffer from conditions like Crohn's disease to have options that could be delivered to the site," Traverso says. "If we have the possibility of site-directed delivery, we may be able to mitigate systemic side effects from these immunosuppressing agents."
The researchers are now working on further optimizing the formulation for potential testing in humans. One key goal is to ensure that the gel adheres for long enough to deliver the drugs, but not so long as to cause discomfort for patients. The researchers are also exploring the possibility of using this approach to deliver other types of drugs.
"This is a platform to enable the development of drug-delivery systems for the esophagus, which hasn't been possible before because the tools haven't existed," Traverso says.
The research was funded by the Karl van Tassel Career Development Professorship, the Department of Mechanical Engineering at MIT, the Division of Gastroenterology at Brigham and Women's Hospital, and the U.S. Advanced Research Projects Agency for Health (ARPA-H), which notes that the views and conclusions contained in this article are those of the authors and should not be interpreted as representing the official policies of the United States government.
