SUMMARY
Oral colonic drug delivery systems (CDDSs) are oftentimes associated with a short duration of action and poor tissue specificity. To address these challenges, we engineered an oral prodrug that leverages the engraftment and semi-permanence of gut commensals to create a long-acting colonic drug depot. We show that two synthetic stem peptide probes can be stereoselectively incorporated onto the surface of gut bacteria in C57BL/6 mice following oral administration. We then show that a prodrug consisting of budesonide, a corticosteroid with otherwise limiting side effects used to treat ulcerative colitis (UC), conjugated to one of these probes via a hydrolyzable ester is significantly less bioactive and is cleaved over a period of days to weeks in simulated physiological fluids. This prodrug can be integrated into the bacterial peptidoglycan in vitro and be cleaved into free budesonide over time, thereby improving drug localization and potentially rendering it safer for longer-term use.
SIGNIFICANCE Corticosteroids are highly effective anti-inflammatory drugs used in the treatment of a variety of conditions. Unfortunately, long-term corticosteroid ingestion can lead to a host of dangerous and undesirable side effects including osteoporosis, glaucoma, and a higher risk of infection, among others. Topical corticosteroids delivered via inhalation (chiefly, budesonide and fluticasone) are the primary long-term treatment modality for chronic asthma symptoms. In contrast to oral corticosteroids, they are considered safer for long-term use when given in moderation because they are directly applied to the airways and exhibit low systemic bioavailability. We sought to apply this successful paradigm to another autoimmune-related disease, ulcerative colitis (UC). We developed a drug delivery system that combines the weakly targeting method of ingestion with a highly specific parameter, microbe prevalence along the gastrointestinal tract, to help improve the specificity and colonic retention of the corticosteroid budesonide, which is currently limited to being used as a short-term treatment for moderate-to-severe UC. Our approach utilizes a largely inert prodrug that can be incorporated into the peptidoglycan of commensal bacteria found at high densities in the colon. After tethering to the bacterial surface via a synthetic stem peptide, the prodrug passively hydrolyzes (cleaves) to release the active, unadulterated form of the drug into the local area, whereas prodrug that traffics elsewhere has a higher chance of being cleared from the body before cleavage. In this manner, we can achieve targeted immunosuppression and sustained release, rendering corticosteroids, and potentially other small molecules, safer for longer term use in treating patients with UC.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
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