The small intestine is the site of absorption, both of nutrients and orally delivered drugs. A new paper reports the development of a versatile polydopamine-based solution that can coat and polymerize in situ in the small intestine. This temporary synthetic coating applied to the lining of the small intestine could be adapted to deliver drugs, aid in digestion, or prevent nutrients such as glucose from being absorbed.
The team demonstrated the gastrointestinal synthetic epithelial lining (GSEL) system’s ability to adhere to segments of the gastrointestinal tract from pigs and humans, and, in porcine models, has reported potential applications for the system in treating a variety of conditions, ranging from lactose intolerance to diabetes and obesity to tropical diseases such as schistosomiasis.
The work is published in the paper, “Gastrointestinal synthetic epithelial linings,” in Science Translational Medicine.
The lining consists of a polymer made from dopamine molecules, which can be consumed as a liquid. Once the solution reaches the small intestine, the molecules are assembled into a polymer, in a reaction catalyzed by an enzyme found in the small intestine.
The GSEL system combines two nature-inspired innovations. The first takes advantage of a chemical reaction triggered by catalase, an enzyme that helps break down hydrogen peroxide into oxygen in the small intestine. The second is a mussel-inspired tissue adhesive, similar to what mollusks use to attach themselves to rocks. Using these two concepts, the team designed a synthetic gut lining that can target the small intestine. Their goal is to develop a capsule, pill, or gel that could be ingested, but for now, the team has tested administering the GSEL system endoscopically—that is, directly inserting it into the small intestine.
The synthetic coating adhered to pig and human tissue ex vivo, remaining stable for up to 24 hours. When administered to pigs endoscopically, polydopamine solution with suspended β-galactosidase increased digestive enzyme activity, whereas solution with embedded polydopamine nano–cross-linkers created a coating with transient barrier function that prevented glucose absorption. Encapsulating the anthelmintic drug praziquantel in polydopamine solution enhanced intestinal retention and adsorption in pigs, demonstrating the potential utility of this biomaterial for drug delivery.
To test the lining’s therapeutic potential, the team looked at pig models for testing lactose intolerance, glucose absorption, and the delivery of praziquantel, a drug for treating schistosomiasis. The team found evidence that the lining could deliver the drug in a sustained way, potentially reducing treatment to a once-a-day dose instead of three times a day. It also improved lactose digestion and regulated glucose absorption, indicating its potential for treating type 2 diabetes and preventing obesity.
“These three applications are fairly distinct, but they offer a sense of the breadth of things that can be done with this approach,” said Giovanni Traverso, an MIT assistant professor of mechanical engineering, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study.
“We recognized [the small intestine’s] potential: If we could specifically target this location, it would open up new avenues for drug delivery and nutritional modulation,” said Traverso. “The system we’ve developed has the potential to treat and manage a variety of diseases.”
The MIT team began working on this project with the goal of trying to develop liquid drug formulations that could offer an easier-to-swallow alternative to capsules, especially for children. Their idea was to create a polymer coating for the intestinal lining, which would form after being swallowed as a solution of monomers (the building blocks of polymers).
“Children often aren’t able to take solid dosage forms like capsules and tablets,” Traverso said. “We started to think about whether we could develop liquid formulations that could form a synthetic epithelial lining that could then be used for drug delivery, making it easier for the patient to receive the medication.”
They took their inspiration from nature and began to experiment with a polymer called polydopamine (PDA), which is a component of the sticky substance that mussels secrete to help them cling to rocks. PDA is made from monomers of dopamine—the same chemical that acts as a neurotransmitter in the brain.
The researchers discovered that an enzyme called catalase could help assemble molecules of dopamine into the PDA polymer. Catalase is found throughout the digestive tract, with especially high levels in the upper region of the small intestine.
In a study conducted in pigs, the researchers showed that if they deliver dopamine in a liquid solution, along with a tiny amount of hydrogen peroxide (at levels recognized to be safe), catalase in the small intestine breaks the hydrogen peroxide down into water and oxygen. That oxygen helps the dopamine molecules to join together into the PDA polymer. Within a few minutes, a thin film of PDA forms, coating the lining of the small intestine.
“We found that enzymes in the digestive tract can help synthesize polymers in the small intestine,” said first author Junwei Li, PhD, who will become a research fellow at Brigham this fall. “We anticipate broad adoption of this in situ biomaterial generation idea for various applications.”
“These polymers have muco-adhesion properties, which means that after polymerization, the polymer can attach to the intestinal wall very strongly,” Li said. “In this way, we can generate synthetic, epithelial-like coatings on the original intestinal surface.”
Once the researchers developed the coating, they began experimenting with ways to modify it for a variety of applications. They showed that they could attach an enzyme called beta-galactosidase (lactase) to the film, and that this film could then help with lactose digestion. In pigs, this coating improved the efficiency of lactose digestion around 20-fold.
For another application, the researchers incorporated a drug called praziquantel, which is used to treat schistosomiasis, a tropical disease caused by parasitic worms. Usually this drug has to be given three times a day, but using this formulation, it could be given just once a day and gradually released throughout the day. This approach could also be useful for antibiotics that have to be given more than once a day, the researchers said.
Lastly, the researchers showed that they could embed the polymer with tiny crosslinkers that make the coating impenetrable to glucose (and potentially other molecules). This could help in the management of diabetes, obesity, or other metabolic disorders, the researchers say.
In this study, the researchers showed that the coating lasts for about 24 hours, after which it is shed along with the cells that make up the intestinal lining, which is continually replaced. For their studies in pigs, the researchers delivered the solution by endoscopy, but they envision developing a drinkable formulation for human use. The researchers are also developing other alternative formulations, including capsules and pills.
The researchers performed some preliminary safety studies in rats and found that the dopamine solution had no harmful effects. Their studies also suggested that most or all of the dopamine molecules become part of the synthetic coating and do not make it into the tissue or the bloodstream, but the team plans to do additional safety studies to explore any possible effects the dopamine may have.
Moreover, the researchers investigated the nutrient absorption capacity of the intestine after 24 hours and showed no difference between animals that had received the GSEL and those that hadn’t received the GSEL.
Additionally, the team found that the coating was able to stick well to human GI tissue. In order to move from pig models into human trials, several hurdles remain, including further developing the GSEL system into an ingestible form. For now, Traverso, Li, and colleagues are focused on continuing to evaluate safety in preclinical studies. “For our studies, safety is a key focus of our work,” said Traverso. “There are indications that this system can help patients suffering from many diseases, but before we can translate this technology for humans, we need to fully validate its safety and the effects of chronic use.”
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