Targeted drug delivery is generally beneficial to reduce amounts of drugs used in treatment while minimizing side effects. For diseases like those of the esophageal tissues, targeting this organ presents a larger challenge by virtue of its location and function.
“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,” said Giovanni Traverso, MD, PhD, associate professor of mechanical engineering at MIT, gastroenterologist at Brigham and Women’s Hospital, and associate member of the Broad Institute of MIT and Harvard.
Traverso and his team developed an oral drug formulation which includes hydrogel to coat the mucosal lining of the esophagus. The formulation includes ingredients that support drug absorption, allowing for the delivery of small molecules or antibodies.
“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 said. “If we have the possibility of site-directed delivery, we may be able to mitigate systemic side effects from these immunosuppressing agents.”
To test a wide variety of formulations, researchers developed a screening system to quickly identify which mixtures enhanced the delivery of drugs to esophageal tissues. “We developed an esophageal tissue screening system consisting of specialized custom plates,” they wrote, “to incorporate gravity effects, and excised esophageal mucosa tissues.”
Data from the intensive screening of over 100 compounds were used to create a library of the most effective and non-toxic permeation components, along with the formulation that adhered to the esophageal mucosa for an extended time period. These components work in synchrony to both maintain contact of the drug delivery gel while allowing for the target tissues to accept the drugs.
“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,” said lead author, Christina Karavasili, PhD, former postdoctoral researcher in the Traverso lab who is now an assistant professor at Aristotle University of Thessaloniki in Greece.
Their selected formulation was validated in both pig and human tissues before being tested in vivo. Pigs treated with the anti-TNF model drug or infliximab (an immunosuppressant antibody dosed systemically, often leading to negative side effects) had effective delivery of the drugs, and while the cell-cell junctions were temporarily loosened, the cells returned to their normal condition within three days.
“The hydrogel helps the formulation remain on the esophageal surface for longer, while the bile salts help increase transport across the tissue,” confirmed Karavasili.
Further testing is currently underway to optimize the formulation for humans. The researchers’ goal is to enable effective and site-specific drug delivery to patients to reduce side effects, while also making the treatment itself as comfortable as possible.
“We hope this platform will make it easier to develop systems that can help patients suffering from these conditions,” Traverso shared. “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.”
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