New Technique To Make Therapeutic Gases Available To Tissues Could Have Broad Applications
BOSTON – Carbon monoxide is best known as a potentially deadly gas. When inhaled at high concentrations, it binds to hemoglobin in the blood and prevents the body from obtaining enough oxygen, which can lead to serious health effects and even death. However, at lower doses, the gas has been shown to reduce inflammation and can help stimulate tissue regeneration.
A team led by researchers at Beth Israel Deaconess Medical Center (BIDMC), MIT and Brigham and Women's Hospital, has now devised a novel way to deliver carbon monoxide to the body while bypassing its potentially hazardous effects. Inspired by techniques used in culinary science known as molecular gastronomy, researchers incorporated carbon monoxide into stable foams that can be delivered to the digestive tract.
In a study of mice, the researchers showed that these foams reduced inflammation of the colon and helped to reverse acute liver failure caused by acetaminophen overdose. The new technique, described today in a Science Translational Medicine paper, could also be used to deliver other therapeutic gases, the researchers say.
"We've known for years that carbon monoxide can impart beneficial effects in all sorts of disease pathologies, when given as an inhaled gas," said co-senior author Leo Otterbein, PhD, a professor of surgery at BIDMC, whose lab focuses primarily on carbon monoxide and its potent therapeutic effects when used at low concentrations in models of shock, transplantation, and vascular surgery. "However, it's been a challenge to use it in the clinic, for a number of reasons related to safe and reproducible administration, and health care workers' concerns, which has led to people wanting to find other ways to administer it."
To tackle that challenge, Otterbein teamed up with co-senior author Giovanni Traverso, MD, PhD, MBBCH, assistant professor of mechanical engineering at MIT and a gastroenterologist at Brigham and Women's Hospital, whose lab specializes in developing novel methods for delivering drugs to the gastrointestinal tract. They came up with the idea of incorporating the gas into a foam.
"The ability to deliver a gas opens up whole new opportunities of how we think of therapeutics. We generally don't think of a gas as a therapeutic that you would take orally (or that could be administered rectally), so this offers an exciting new way to think about how we can help patients," said Traverso.
After showing that they could control the timing of the gas release in the body, the researchers decided to test the foams for a few different applications. First, they studied two types of topical applications, analogous to applying a cream to soothe itchy or inflamed areas. They found that delivering the foam rectally reduced inflammation caused by colitis or radiation-induced proctitis (inflammation of the rectum that can be caused by radiation treatment for cervical or prostate cancer).
Current treatments for colitis and other inflammatory conditions such as Crohn's disease usually involve drugs that suppress the immune system, which can make patients more susceptible to infections. Treating those conditions with a foam that can be applied directly to inflamed tissue offers a potential alternative, or complementary approach, to those immunosuppressive treatments, the researchers say. While the foams were given rectally in this study, it could also be possible to deliver them orally, the researchers say.
The researchers also investigated possible systemic applications, in which carbon monoxide could be delivered to remote organs, such as the liver, because of its ability to diffuse from the GI tract to elsewhere in the body. For this study, they used a mouse model of acetaminophen overdose, which causes severe liver damage. They found that gas delivered to the lower GI tract was able to reach the liver and greatly reduce the amount of inflammation and tissue damage seen there.
In these experiments, the researchers did not find any adverse effects after the carbon monoxide administration. Previous studies in humans have shown that small amounts of carbon monoxide can be safely inhaled. A healthy individual has a carbon monoxide concentration of about 1 percent in the bloodstream, and studies of human volunteers have shown that levels as high as 14 percent can be tolerated without adverse effects.
"With the foam used in this study, we're not even coming close to the carbon monoxide levels that we would typically be concerned about," said Otterbein, "Inhaled gas trials have paved a path to show it is safe, as long as you know and can control how much you're giving, much like any medication. That's another nice aspect of the foam approach — we can control the exact dose."
Co-authors included: David Gallo, Eva Csizmadia, Maria S. Longhi, Sidharth Shankar and Ghee R. Lee of BIDMC; James D. Byrne, Hannah Boyce, Sarah L. Becker, Vivian R. Feig, Aaron Lopes, Jung Seung Lee, Hyunjoon Kim, Adam J. Wentworth, Keiko Ishida, Jacob Wainer, Kaitlyn Wong and Christoph Steiger of Brigham and Women's Hospital; Johannes L. P. Kuosmanen, Josh Jenkins, Aya Aragon, Alison Hayward and Robert Langer of Massachusetts Institute of Technology; Jianling Bi, Emily Witt, Mitchell C. Coleman, Douglas R. Spitz and Dustin E. Bosch of University of Iowa; Kristi M. Kezar, Alicia T. Cotoia and Michael Tift of University of North Carolina; and William R. Jeck of Duke University.
This work was funded in part by grants from the Prostate Cancer Foundation Young Investigator Award, Department of Defense Prostate Cancer Program Early Investigator Award, Hope Funds for Cancer Research fellowship, and Holden Comprehensive Cancer Center, University of Iowa; National Science Foundation 1927616; the Players Association of the National Football League and Department of Defense W81XWH-16-0464; the Department of Mechanical Engineering, MIT; and National Institutes of Health grants R00AR070914 and P01CA217797, P30CA086862.
Otterbein is a scientific advisor to Hillhurst Biopharmaceuticals. Leo E. Otterbein, James D. Byrne, and Giovanni Traverso are co-inventors on a patent application describing gas entrapping materials (GEMs). For a full list of disclosures, please refer to the study.
Adapted from a press release issued by MIT News.
