Most people are familiar with carbon monoxide as a lethal gas. However, it also has advantageous properties in tiny doses: It has been demonstrated to decrease inflammation and accelerate tissue regeneration.
Researchers from MIT, Brigham and Women’s Hospital, the University of Iowa, and Beth Israel Deaconess Medical Center have developed a unique method of administering carbon monoxide to the body while avoiding its potentially harmful side effects. Using techniques from molecular gastronomy as inspiration, they were able to put carbon monoxide into stable foams that can be sent to the digestive system.
In a study with mice, researchers found that these foams helped reverse acute liver failure caused by an overdose of acetaminophen and reduced inflammation in the colon. The researchers claim that the novel method, which they describe in a study published today in Science Translational Medicine, might potentially be used to administer other medicinal gases.
“The ability to deliver a gas opens up whole new opportunities of how we think of therapeutics,” says Giovanni Traverso, “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.”
The paper’s senior authors are Traverso and Leo Otterbein, a professor of surgery at Beth Israel Deaconess Medical Center and Harvard Medical School. James Byrne, a radiation oncologist and physician-scientist at the University of Iowa who was formerly a resident in the Mass General Brigham/Dana Farber Radiation Oncology Program, David Gallo, a researcher at Beth Israel Deaconess, and Hannah Boyce, a research engineer at Brigham and Women’s, are the lead authors.
Foam-based delivery system
Otterbein has been researching the healing properties of modest doses of carbon monoxide since the late 1990s. The gas has been demonstrated to have positive benefits in preventing the rejection of transplanted organs, decreasing tumor growth, and moderating acute tissue injury and inflammation.
High levels of inhaled carbon monoxide bind to hemoglobin in the blood, preventing the body from getting enough oxygen, which can have detrimental consequences on health and even result in death. Otterbein claims that at lower levels, it has advantageous benefits like lowering inflammation and stimulating tissue regeneration.
“We’ve known for years that carbon monoxide can impart beneficial effects in all sorts of disease pathologies, when given as an inhaled gas,” he adds. “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.”
Christoph Steiger, a former MIT postdoc and paper author, introduced Traverso and Otterbein. Traverso’s lab is known for coming up with new ways to get drugs into the digestive system. One solution they came up with to the problem of delivering the gas was to dissolve it in a foam, similar to the way that chefs employ carbon dioxide to infuse foams with fruit, vegetable, or other flavors.
Most culinary foams are made by adding a thickening or gelling agent to a pureed liquid or solid and then whipping the mixture to add air or using a special siphon to add gases like carbon dioxide or compressed air.
To add carbon monoxide to their foam, the MIT team developed a modified siphon that could be connected to any kind of gas cannister. They employed food additives including alginate, methyl cellulose, and maltodextrin to make the foams. The foams also had xantham gum added to stabilize them. Researchers were able to regulate the rate of gas release from the foams by adjusting the concentration of xantham gum used in their formulations.
After demonstrating their ability to regulate the time of gas release in the body, the researchers decided to test the foams for a variety of applications. First, they investigated two types of topical treatments, comparable to applying a lotion to calm itchy or inflamed skin. In a mouse trial, researchers discovered that rectally administering the foam 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).
Drugs that weaken the immune system are usually used to treat colitis and other inflammatory conditions like Crohn’s disease. This can make patients more likely to get infections. The researchers claim that using foam that may be applied directly to inflamed tissue to treat those disorders offers a possible complement to immunosuppressive therapies. The researchers note that although the foams were administered rectally in this study, they might potentially be administered orally.
According to Byrne, “the foams are so easy to use, which will help with the translation to patient care.”
The researchers subsequently investigated potential systemic applications in which carbon monoxide may be administered to distant organs, such as the liver, due to its capacity to diffuse from the gastrointestinal tract to other parts of the body. Overdosing on acetaminophen, which can lead to liver failure, was simulated in mice for this study. They discovered that gas administered to the lower GI tract might enter the liver and significantly lessen the inflammation and tissue damage there.
In these tests, when carbon monoxide was given, the researchers didn’t find any bad side effects. Human studies have demonstrated that it is safe to breath modest amounts of carbon monoxide. The carbon monoxide content in the bloodstream of a healthy individual is approximately 1 percent, and tests of human volunteers have shown that levels as high as 14 percent can be tolerated without horrific consequences.
According to Otterbein, “We think that with the foam used in this study, we’re not even coming close to the levels that we would be concerned about. What we have learned from the inhaled gas trials has paved a path to say it’s safe, as long as you know and can control how much you’re giving, much like any medication. That’s another nice aspect of this approach — we can control the exact dose.”
In this study, the scientists also made carbon monoxide gels and solids filled with gas. They did this in a way that was similar to how Pop Rocks, which are hard candies with carbon dioxide bubbles under pressure, are made. They plan to test these in future studies and also make foams that could be used in tests on people.
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