Category: Research

Date: Thursday, August 13, 2015

Inflammatory bowel disease (IBD) is an emerging global disease that involves chronic inflammation of some or all parts of the digestive tract from mouth to anus, causing severe diarrhoea, fatigue, pain, and weight loss. Ulcerative colitis (UC) is a type of IBD that inflames colon, the largest section of the large intestine. Current IBD therapies include surgical removal of the entire large intestine, and delivering anti-inflammatory drugs orally or rectally, both of which can lead to unwanted side effects in other organs as well. Therefore, the development of specifically targeted therapies with little side-effects is the need of the hour for treatment of IBD.

A recent paper published in Science Translational Medicine offers a promising approach for targeted therapies for IBD patients. The work is the result of collaboration between Brigham and Women’s Hospital (BWH), Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT), USA and the Institute for Stem Cell Biology and Regenerative Medicine (inStem) in Bangalore. The researchers developed a targeted drug delivery system for the inflamed colon by loading an anti-inflammatory drug in a hydrogel (a network of self-assembled or polymer chains that contains over 90% of water, and is often used for rectal drug delivery); and showed that this inflammation-targeting hydrogel specifically bound inflamed regions in the mouse colon and reduced inflammation significantly. “Targeted local drug delivery at diseased tissue has been a challenging task. Developing custom-designed biomaterials by harnessing the specific characteristics of diseased tissue can provide the solution”, says Dr. Praveen Kumar Vemula, a co-author on the study and head of the Laboratory of Self-Assembled Biomaterials at inStem.

The study showed that these hydrogels, made using a reagent considered to be therapeutically safe, could encapsulate and release drugs efficiently. Besides, owing to their negative surface charge, they often specifically bound to inflamed surfaces in the mouse intestine that are usually positively charged due to the tissue damage caused by inflammation. “This preferential attachment to the inflamed surfaces was also seen in human biopsy samples, thus consistent with our mouse data”, says Dr. Vemula. The attached hydrogel allows a prolonged availability of the drug locally in the intestine, and therefore can significantly reduce the frequency at which it needs to be delivered. “This reduction in dosing frequency addresses a major challenge in current therapies that require frequent rectal delivery. Such frequent delivery is difficult during diarrhea and abdominal pain, the two key symptoms of most IBDs.”, adds Dr. Vemula.

“We realized that if we could develop a disease-targeted hydrogel system that rapidly attaches to ulcers and slowly release drugs at the site of inflammation, then we could create a better way to deliver medicine only where the drug is needed,” said Dr. Jeffrey Karp from the BWH Department of Medicine, co-corresponding author of the study and a principal investigator at Harvard Stem Cell Institute. “Maximizing the treatment of topical therapies for IBD and simultaneously minimizing the potential for side effects from these drugs is an extremely appealing option to both patients and health care providers given the significant risks associated with these drugs that often weaken the immune system,” said Dr. Giovanni Traverso from the Division of Gastroenterology at the MGH and co-corresponding author of the study.

The study also demonstrated that this hydrogel does not release drugs spontaneously, but rather requires the action of enzymes such as Matrix Metallo Proteinases (MMPs) that are usually present at the sites of inflammation/ulcers. Such targeted and localized drug delivery largely reduces the non-specific absorption of the drug by non-inflamed organs, thereby restricting the potential side-effects of the therapy. The team also found 5-10 times lower drug concentrations in the bloodstream, indicating less drug exposure throughout the body. Further -more, these hydrogels are stable over several days, thus enabling a sustained release of the anti-inflammatory drug.

Collectively, the hydrogels made of such Generally Regarded as Safe (GRAS) reagents can have multiple advantages – prolonged and localized drug availability, less systemic exposure to drug and consequent side-effects, and reduced dose frequency. “Our main motivation to develop these hydrogels using a Generally Regarded as Safe (GRAS) reagent was not only that they are therapeutically safe, but also that they are inexpensive and easily available in large amounts, thereby indicating the potential quick application of this platform in the clinic.”, says Dr. Vemula. “Of course, many more animal/preclinical studies are required before we begin evaluating the clinical benefits of these hydrogels in humans.”

These advances into developing strategies that can rapidly translate to the clinic addresses a key unmet need to connect the bench to the bedside. Developing this pipeline can help in controlled drug release at a distant desired location in other diseases too, such as immunosuppressive drugs in auto-immune diseases; or oncogenic drugs in tumors.

The paper was published in Science Translational Medicine.

About Dr Praveen Vemula’s lab at inStem -

 Mohit Kumar Jolly is a writer with the Research Media Services Division of Gubbi Labs.