A192 'GLYCOCAGED' DRUGS: PHARMACOKINETICS AND TRANSLATIONAL POTENTIAL FOR PEOPLE WITH IBD
Bibliographic record
Abstract
Abstract Background 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. Methods 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. Results 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. Conclusions 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. Funding Agencies CCCGlycoNet
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".