Researchers at the University of Arizona have developed a novel drug and delivery system to treat inflammation and ulcerations in the colon.
This novel drug and delivery system, a carrier drug the research team has termed a “molecular truck,” shows promise in treating ulcerative colitis, one of the two forms of Inflammatory Bowel Disease (IBD).
The development and testing of the “molecular truck” was completed by Eugene A. Mash Jr., PhD, professor, Department of Chemistry and Biochemistry, College of Science; pediatric gastroenterologist Fayez K. Ghishan, MD, professor and head, Department of Pediatrics and director of the UA Steele Children’s Research Center, College of Medicine – Tucson; and Pawel Kiela, PhD, associate professor, Department of Pediatrics and Steele Center researcher in the area of gastroenterology.
“This drug has the potential to be a major advancement in the treatment of infants and children with ulcerative colitis, who have difficulty taking available medications,” said Dr. Ghishan.
The study, “Design, Synthesis, and Testing of a Molecular Truck for Colonic Delivery of 5-Aminosalicylc Acid,” was published in the August 2012 issue of ACS Medicinal Chemistry Letters. Now, the invention is patent-pending, and the researchers are working closely with Tech Launch Arizona on the intellectual property and commercialization aspects of the technology.
“We need to find investors and funding to establish a company to complete the developmental and pre-clinical work necessary to bring this new drug to the market,” said Dr. Ghishan.
IBD is chronic inflammation in the intestinal tract. The two most common forms of IBD are ulcerative colitis and Crohn’s disease. In ulcerative colitis, the inflammation affects the inner lining of the colon (the mucosa), where painful ulcers may develop. With Crohn’s disease, inflammation may affect the entire digestive tract.
Approximately 1.4 million Americans have IBD, and as many as 70,000 new cases are diagnosed in the United States each year. IBD can occur at any age, but is most often diagnosed between the ages of 15 and 30. An estimated 50,000 children in the U.S. have IBD, a number that has been increasing in recent years. Symptoms include severe abdominal pain, diarrhea, vomiting, cramping, fatigue and weight loss. There is no cure, and long-term management of IBD can be very challenging.
Overcoming Limitations of IBD Treatment
Aminosalicylates are one of five types of medications used to treat IBD. These compounds contain 5-aminosalicylic acid (5-ASA, mesalamine, mesalazine). Examples are sulfasalazine, balsalazide and olsalazine. These drugs are given either orally or rectally to decrease inflammation.
Because 5-ASA is absorbed rapidly in the stomach and small intestines, its ability to reach and treat inflamed areas in the colon is limited. Consequently, modifications to 5-ASA have involved binding it to a “carrier” molecule, enabling the drug to travel through the stomach and intestines to the colon, where bacterial enzymes release the 5-ASA from its carrier. Sulfasalazine, balsalazide and olsalazine are all “carrier-drug” combinations, while mesalamine is used in delayed-release formulations. All of these can reach the colon to treat ulcerative colitis.
Unfortunately, sulfasalazine can cause nausea, heartburn, headache, skin rashes and bone marrow suppression. Although mesalamine, balsalazide and olsalazine have fewer reported side effects, many patients cannot benefit from these drugs due to allergic reactions that cause cramps, abdominal pain and worsened diarrhea.
What’s more, all of the aminosalicylates are available only in large tablet or capsule forms that can be difficult for children to swallow.
“Currently, there is no oral drug in the form of a suspension available for children who can’t swallow large tablets or capsules to treat their IBD,” said Dr. Ghishan.
From MRI Imaging, to Olestra, to the Molecular Truck
“As is often true in science and medicine, concepts and ideas from one area inspire discoveries in another area,” said Dr. Mash.
In previous research, Dr. Mash developed a new contrast agent for MRI (Magnetic Resonance Imaging) that selectively imaged tissue in the GI tract. The inspiration for the new MRI contrast agent came from the failed “fake fat” Olestra—a non-digestible fat substitute derived from sucrose and mixtures of fatty acids. Olestra passes unmodified through the GI tract.
“Once we established selective imaging of the GI tract, selective drug delivery to the colon via oral administration of the drug was a logical next step,” he explained.
Dr. Mash consulted with Drs. Ghishan and Kiela on a new carrier drug design. Together they established four objectives:
- The drug should be administered orally in the form of a suspension;
- The drug should deliver a highly concentrated payload directly to the needed areas of the GI tract;
- The carrier would pass through the GI tract with little or no absorption or breakdown; and,
- The drug would have few, if any, side effects.
Using the model of his Olestra-based MRI contrast agent, Dr. Mash designed and prepared a “molecular truck” to transport 5-ASA through the small intestine to the colon by attaching a 5-ASA to each of the eight arms of an Olestra-like molecule.
Dr. Kiela managed the preclinical studies for the efficacy of the “molecular truck” in a mouse model of ulcerative colitis. It was compared with an analogous dose of sulfasalazine, and showed improved efficacy in reducing colonic inflammation in mice.
One of the main benefits of the new drug is that it can be given in a suspension. This means it can be added to syrup, yogurt, ice cream, juice – anything liquid or frozen.
“Since our new drug can be delivered in more palatable forms, it has the potential to increase patient compliance and advance IBD treatment for infants and children,” said Dr. Ghishan.
“While our molecular truck appears equally, or more effective than sulfasalazine in a mouse model of ulcerative colitis, that is not enough to replace the currently established therapy,” said Dr. Kiela. “To become the therapy of choice, our invention must specifically target sites of inflammation. The anti-inflammatory effects of 5-ASA are directly related to its local concentration in the colonic mucosa. The design of our new drug allows for modifications which would increase retention and release 5-ASA specifically at sites of colonic ulceration.”
“So our next area of research is to focus delivery of the drug to specific regions of the colon damaged by inflammation,” said Dr. Ghishan. “This should lower the drug dosage necessary to achieve the desired outcome.”
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Funding for this research was provided by grants from the National Institutes of Health (NIH), the National Cancer Institute (NCI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NDDK). Grants: R33 CA 95944, RO1 CA 97360, RO1 CA 123547 (NIH); P30 CA 23074 (NCI); RO1 DK 067286 (NDDK)