Scientists headed by a team at the University of British Columbia (UBC) have developed a new approach to drug design that can deliver therapeutics directly to a specific part of the gastrointestinal (GI) tract. The drug delivery system, GlycoCaging, is based on bespoke glycoconjugates of a complex plant oligosaccharide. A proof-of-concept study in mice showed that the system could release drugs exclusively to the lower gut at doses up to 10 times lower than those of current inflammatory bowel disease treatments.
“With this technique, we have the ability to deliver not just steroids, but a range of drugs including anti-microbial compounds directly to the gut, potentially helping people with inflammatory bowel disease, gut infections and more,” said Harry Brumer, PhD, a professor in the UBC department of chemistry and Michael Smith Laboratories (MSL).
Brumer, and Laura Sly, PhD, professor in the UBC department of pediatrics, are co-senior authors of the team’s published paper in Science, titled “Bespoke plant glycoconjugates for gut microbiota-mediated drug targeting,” in which they stated, “GlycoCaging may offer a route to rescue promising drug candidates that currently show unacceptable systemic toxicity.”
An estimated 322,600 Canadians have inflammatory bowel disease (IBD) as of 2023, and Canada has one of the highest incidence rates in the world, according to Crohn’s and Colitis Canada. “It’s a growing problem, and there’s no known cure. It can be completely debilitating, and it hits people in the prime of their life, between 19 and 29 years of age,” said Sly.
One of the treatments for IBD is anti-inflammatory steroids, which are often taken orally or intravenously. They are used to treat flares for children, adults, and the roughly 30% of adults for whom treatment with other medications doesn’t work. But such drugs can have serious side effects, including osteoporosis, high blood pressure, diabetes, and negative mental health outcomes.
Much of the drug is absorbed in the stomach and upper intestine before reaching the inflamed gut area, so doctors administer these treatments in high doses to ensure an effective amount reaches the affected areas. As the authors noted, “Targeted delivery of orally administered pharmaceuticals to the distal GI tract remains a long-standing, unresolved challenge in human health.”
GlycoCaging is a chemical process inspired by the UBC researchers’ realization that certain molecules found in fruit and vegetable fiber can only be digested by bacteria that reside in our gut. “Using molecular insights into dietary fiber metabolism by the human gut microbiota, we designed a targeted drug delivery system based on bespoke glycoconjugates of a complex plant oligosaccharide called GlycoCaging,” they explained. The team bonded the molecule to a steroid, creating a “treasure chest” for which the “key” is a specific gut bacteria.
They reasoned that the hydrophilic, branched oligosaccharide should prevent premature absorption in the upper GI tract, but support targeted release of the drug, resulting from the activity of specific xyloglucanases produced by colonic microbiota. “Building upon our knowledge of microbiota enzyme specificity, we hypothesized that covalent conjugation of small-molecule drugs to a singular xyloglucan heptasaccharide via a glycosidic linkage could make a molecular platform for GI targeting …” the investigators further stated.
They then tested their approach using a steroid not usually used for IBD treatment, to demonstrate GlycoCaging’s potential to repurpose potent drugs. “Among the corticosteroids, dexamethasone is potently anti-inflammatory, yet side effects hinder its use in GI treatment,” they wrote. “Hence, we selected XXXG-Dex as a prototype to demonstrate the ability of GlycoCaging to improve targeting, as well as highlight its potential to enable drug repurposing.”
The team carried out initial tests to demonstrate the enzymatic release of GlycoCaged drugs in vitro. “… the observed hydrolysis of XXXG-Dex in this in vitro system, which mimics the presence of xyloglucan in plant-cell-wall digesta in the GI tract, anticipated successful release in vivo,” they reported. They then tested the drug delivery approach in two mouse models of IBD, for up to nine weeks. The results showed that GlycoCaged doses far lower than non-caged doses had the same anti-inflammatory effects. In one mouse model, they reported, the data showed that “… XXXG-Dex was as effective, or more effective, at reducing pathosis and inflammation in the T cell transfer model of colitis at 3- to 10-fold lower equivalent dose of the drug than free dexamethasone.”
Using GlycoCaged delivery, the drug was also found at lower levels in the rest of the body than the non-caged version. “We observed greatly reduced systemic circulation and targeted delivery of dexamethasone in mice on oral administration of XXXG-Dex versus compared with dexamethasone,” the researchers further reported. And while serum and tissue concentrations of dexamethasone spiked in mice given the free steroid orally—indicating rapid uptake and systemic distribution—there was no spike in circulating dexamethasone levels after oral administration of XXXG-Dex, “… indicating that absorption in the upper GI tract had been prevented.”
Findings from tests in their second mouse model showed that “… GlycoCaging greatly reduced systemic circulation to the point that off-target (non-GI) effects were eliminated,” the team noted. “These results further support the potential of GlycoCaging to mitigate drug side-effects in people with IBD. In one group of animals, inflammation in other areas of the body was not reduced, indicating that the drug only affected the gut.
Co-author Changqing Wang, PhD, research associate in UBC’s department of chemistry and MSL, further stated, “We showed that this technique can be used on other steroids, including those commonly used in IBD treatment, as well as other anti-inflammatory drugs used in high doses with negative side effects.”
To test the potential for treatment in humans, the research team checked to see if the bacteria upon which GlycoCaging relies existed in the gut of those with IBD. They looked for bacterial activity in fecal samples from 33 people, with and without IBD, and in a global database for genetic markers. “We found that all people in the fecal sample study had the ability to activate the drugs, including people with IBD whether they are in remission or have active inflammation,” said co-author Maggie (Wei Jen) Ma, a doctoral student in UBC’s experimental medicine program and BC Children’s Hospital Research Institute. “And, the majority of people had genetic markers indicating the ability to use the GlycoCage system.”
In their conclusion the investigators reported, “The use of a glycoconjugate comprising a complex plant oligosaccharide, as a natural component of dietary fiber cleavable only by gut microbiota, offers the prospect of treatment strategies to improve the therapeutic indices of GI drugs.” They suggested that their data, “… show that GlycoCaging reduces both drug dose and its systemic uptake with the potential to improve established and emerging GI drugs.”
The research team has patented the technology and aims to source funding for more advanced animal trials and human clinical trials.
The post Targeting GI Drug Delivery with GlycoCaging Could Improve IBD Treatments appeared first on GEN - Genetic Engineering and Biotechnology News.
“With this technique, we have the ability to deliver not just steroids, but a range of drugs including anti-microbial compounds directly to the gut, potentially helping people with inflammatory bowel disease, gut infections and more,” said Harry Brumer, PhD, a professor in the UBC department of chemistry and Michael Smith Laboratories (MSL).
Brumer, and Laura Sly, PhD, professor in the UBC department of pediatrics, are co-senior authors of the team’s published paper in Science, titled “Bespoke plant glycoconjugates for gut microbiota-mediated drug targeting,” in which they stated, “GlycoCaging may offer a route to rescue promising drug candidates that currently show unacceptable systemic toxicity.”
An estimated 322,600 Canadians have inflammatory bowel disease (IBD) as of 2023, and Canada has one of the highest incidence rates in the world, according to Crohn’s and Colitis Canada. “It’s a growing problem, and there’s no known cure. It can be completely debilitating, and it hits people in the prime of their life, between 19 and 29 years of age,” said Sly.
One of the treatments for IBD is anti-inflammatory steroids, which are often taken orally or intravenously. They are used to treat flares for children, adults, and the roughly 30% of adults for whom treatment with other medications doesn’t work. But such drugs can have serious side effects, including osteoporosis, high blood pressure, diabetes, and negative mental health outcomes.
Much of the drug is absorbed in the stomach and upper intestine before reaching the inflamed gut area, so doctors administer these treatments in high doses to ensure an effective amount reaches the affected areas. As the authors noted, “Targeted delivery of orally administered pharmaceuticals to the distal GI tract remains a long-standing, unresolved challenge in human health.”
GlycoCaging is a chemical process inspired by the UBC researchers’ realization that certain molecules found in fruit and vegetable fiber can only be digested by bacteria that reside in our gut. “Using molecular insights into dietary fiber metabolism by the human gut microbiota, we designed a targeted drug delivery system based on bespoke glycoconjugates of a complex plant oligosaccharide called GlycoCaging,” they explained. The team bonded the molecule to a steroid, creating a “treasure chest” for which the “key” is a specific gut bacteria.
They reasoned that the hydrophilic, branched oligosaccharide should prevent premature absorption in the upper GI tract, but support targeted release of the drug, resulting from the activity of specific xyloglucanases produced by colonic microbiota. “Building upon our knowledge of microbiota enzyme specificity, we hypothesized that covalent conjugation of small-molecule drugs to a singular xyloglucan heptasaccharide via a glycosidic linkage could make a molecular platform for GI targeting …” the investigators further stated.
They then tested their approach using a steroid not usually used for IBD treatment, to demonstrate GlycoCaging’s potential to repurpose potent drugs. “Among the corticosteroids, dexamethasone is potently anti-inflammatory, yet side effects hinder its use in GI treatment,” they wrote. “Hence, we selected XXXG-Dex as a prototype to demonstrate the ability of GlycoCaging to improve targeting, as well as highlight its potential to enable drug repurposing.”
The team carried out initial tests to demonstrate the enzymatic release of GlycoCaged drugs in vitro. “… the observed hydrolysis of XXXG-Dex in this in vitro system, which mimics the presence of xyloglucan in plant-cell-wall digesta in the GI tract, anticipated successful release in vivo,” they reported. They then tested the drug delivery approach in two mouse models of IBD, for up to nine weeks. The results showed that GlycoCaged doses far lower than non-caged doses had the same anti-inflammatory effects. In one mouse model, they reported, the data showed that “… XXXG-Dex was as effective, or more effective, at reducing pathosis and inflammation in the T cell transfer model of colitis at 3- to 10-fold lower equivalent dose of the drug than free dexamethasone.”
Using GlycoCaged delivery, the drug was also found at lower levels in the rest of the body than the non-caged version. “We observed greatly reduced systemic circulation and targeted delivery of dexamethasone in mice on oral administration of XXXG-Dex versus compared with dexamethasone,” the researchers further reported. And while serum and tissue concentrations of dexamethasone spiked in mice given the free steroid orally—indicating rapid uptake and systemic distribution—there was no spike in circulating dexamethasone levels after oral administration of XXXG-Dex, “… indicating that absorption in the upper GI tract had been prevented.”
Findings from tests in their second mouse model showed that “… GlycoCaging greatly reduced systemic circulation to the point that off-target (non-GI) effects were eliminated,” the team noted. “These results further support the potential of GlycoCaging to mitigate drug side-effects in people with IBD. In one group of animals, inflammation in other areas of the body was not reduced, indicating that the drug only affected the gut.
Co-author Changqing Wang, PhD, research associate in UBC’s department of chemistry and MSL, further stated, “We showed that this technique can be used on other steroids, including those commonly used in IBD treatment, as well as other anti-inflammatory drugs used in high doses with negative side effects.”
To test the potential for treatment in humans, the research team checked to see if the bacteria upon which GlycoCaging relies existed in the gut of those with IBD. They looked for bacterial activity in fecal samples from 33 people, with and without IBD, and in a global database for genetic markers. “We found that all people in the fecal sample study had the ability to activate the drugs, including people with IBD whether they are in remission or have active inflammation,” said co-author Maggie (Wei Jen) Ma, a doctoral student in UBC’s experimental medicine program and BC Children’s Hospital Research Institute. “And, the majority of people had genetic markers indicating the ability to use the GlycoCage system.”
In their conclusion the investigators reported, “The use of a glycoconjugate comprising a complex plant oligosaccharide, as a natural component of dietary fiber cleavable only by gut microbiota, offers the prospect of treatment strategies to improve the therapeutic indices of GI drugs.” They suggested that their data, “… show that GlycoCaging reduces both drug dose and its systemic uptake with the potential to improve established and emerging GI drugs.”
The research team has patented the technology and aims to source funding for more advanced animal trials and human clinical trials.
The post Targeting GI Drug Delivery with GlycoCaging Could Improve IBD Treatments appeared first on GEN - Genetic Engineering and Biotechnology News.