A192 'GLYCOCAGED' DRUGS: PHARMACOKINETICS AND TRANSLATIONAL POTENTIAL FOR PEOPLE WITH IBD

TL;DR

A new drug delivery system called GlycoCage reduces inflammation in IBD without causing side effects by targeting the gut and avoiding systemic absorption.

Contribution

The novel glycoconjugate drug delivery system, GlycoCage, enables targeted drug release in the gut, improving therapeutic efficacy and reducing side effects in IBD.

Findings

Caged dexamethasone reduced inflammation at 10-fold lower doses than free dexamethasone in a mouse model of IBD.

Caged dexamethasone did not enter systemic circulation or affect inflammation outside the gut in SHIP-/- mice.

All individuals, including those with IBD, have the enzymatic activity needed to cleave the prodrug.

Abstract

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the gastrointestinal tract. Despite the alarming global increase in IBD burden with 1 in 121 Canadians affected, no cure exists. Systemic administration of anti-inflammatory drugs like corticosteroids is a front-line therapy for inducing remission. However, these drugs are limited in their application by deleterious off-target side effects. To target the drug to sites of inflammation and reduce systemic uptake, we developed a microbiome-cleavable, glycoconjugate drug delivery system, termed GlycoCage. We have demonstrated that GlycoCaged dexamethasone (Dex, a potent steroid), is effective at reducing inflammation at 10-fold lower doses than its uncaged counterpart in the SHIP-deficient (SHIP-/-) mouse model of CD-like intestinal inflammation.

We hypothesize that GlycoCaged technology can expand the therapeutic window of IBD drugs by lowering effective doses and eliminating side effects.

Aims:

1) Quantify Dex in systemic circulation.

2) Assess status of inflammation outside of the gut in SHIP-/- mice treated with caged Dex.

3) Measure decaging activity in people with IBD.

To compare systemic distribution of Dex to caged Dex, we orally gavaged SHIP+/+ and SHIP-/- mice with 3 mg/kg of Dex or the molar equivalent of caged Dex and collected serum for LC-MS/MS analysis at multiple timepoints post oral gavage. In addition to CD-like ileitis, SHIP-/- mice spontaneously develop enlarged mesenteric lymph nodes (MLNs) and inflamed lungs. After daily treatment of Dex or caged Dex for 2 weeks, MLNs and lungs were collected and analyzed for size and histopathology. We also obtained stool samples from healthy control participants and people with IBD to investigate the prevalence of prodrug-cleaving activity by direct enzymatic activity assay using fluorogenic resorufin as a prodrug proxy. Data from people with IBD were stratified to fecal calprotectin.

Unlike free dexamethasone, caged dexamethasone did not enter systemic circulation or impact inflammation outside of the gut in SHIP-/- mice. All people have decaging activity that is not affected by IBD or the individual’s disease activity.

Our results highlight a novel glycoconjugated prodrug strategy to improve and broaden treatment options for people with IBD. In the future, we will evaluate GlycoCaged Dex in a mouse model of colitis and test the efficacy of other GlycoCaged drugs.

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