Oral Delivery of Encapsulated All-Trans Retinoic Acid Ameliorates Disease in Rodent Models of Colitis

Abstract

Background All-trans retinoic acid (ATRA) is a biologically active isomer of retinoic acid (RA). Topical ATRA (retin-a, retin-a micro, atralin, renova, and avita) is the active pharmaceutical ingredient for FDA-approved treatments for acne and skin wrinkles. Oral formulations (Vesanoid) treat acute promyelocytic leukemia, but oral dosing can induce severe side effects. Despite benefits in various rodent models of inflammatory bowel disease (IBD), toxicity and controversial clinical observations have diminished enthusiasm for ATRA IBD clinical trials. To circumvent these issues and to use ATRA’s key role in maintaining gut tolerance, we developed a poly(lactic-co-glycolic acid) (PLGA) microsphere (MS) encapsulated ATRA formulation aimed at directing ATRA delivery to immune structures of the gut, limiting systemic exposure. Initially, ATRA MS was developed as a component of a combinatorial product (TreXTAM) that also contained encapsulated transforming growth factor (TGF)-β and ATRA in a 1:2 w/w ratio. Although the combination was optimal, benefit was also observed when ATRA MS was given alone in the CD4+ CD25-T-cell adoptive transfer (ACT) colitis model. Methods We used the ACT and DSS-induced murine models of colitis to expand on the dose-dependent effects of oral ATRA MS when given alone. The DSS model was also used to compare the efficacy of ATRA MS and soluble ATRA, while healthy animals were used to compare the pharmacokinetics of the two drugs. Results In both the ACT and DSS-induced murine models of colitis, ATRA MS was observed to be effective in ameliorating disease. ATRA MS was also observed to be more effective than soluble ATRA in these models and displayed more favorable pharmacokinetics. Conclusions We suggest ATRA MS, as a standalone product, may attenuate IBD and perhaps limit fibrosis, while limiting systemic side effects.

Lactobacillus Intestinalis Primes Epithelial Cells to Suppress Colitis‐Related Th17 Response by Host‐Microbe Retinoic Acid Biosynthesis

“…[ 19 ] RA is a key derivative of vitamin A, which has been considered to relieve colitis. [ 16 ] We found that L. intestinalis treatment elevated fecal RA levels in colitis mice, as well as in culture media inoculated with L. intestinalis ( Figure A; Figure S6A, Supporting Information). In addition, RA supplementation exerted an anti‐colitis effect (Figure 4B–D; Figure S6B–E, Supporting Information).…”

“…RA, an important derivative of vitamin A metabolism, has a therapeutic effect on UC according to several clinical and preclinical studies. [ 16,17 ] Here, we showed that L. intestinalis not only metabolized vitamin A via its intrinsically high ALDH activity, but also enhanced RA metabolism in the host intestine. Hence, co‐metabolism of L. intestinalis and the host contributes to increased RA biosynthesis in vivo, and L. intestinalis is a safe and effective probiotic in boosting the beneficial effect of vitamin A in UC treatment.…”

“…Gut microbes with unique genes could expand the metabolic repertoire of their host by producing numerous metabolites. [ 15 ] Retinoids, including retinol, retinal and retinoic acid (RA), are key regulators of various physiological processes, which attenuate inflammation and promote mucosal healing in murine colitis models, [ 16 ] and UC patients. [ 17 ] RA is a primary mediator of the biological function of vitamin A by directly activating retinoic acid receptors (RARs).…”

Unlocking the potential of cosmetic dermal delivery with ethosomes: A comprehensive review

“…It works by increasing cell turnover and reducing the formation of comedones (clogged pores) that reduce the formation of blackheads and whiteheads. Tretinoin is usually used in topical form under the brand name Retin‐A 61 . However, tretinoin can be irritating to the skin, which limits its effectiveness.…”

“…Tretinoin is usually used in topical form under the brand name Retin-A. 61 However, tretinoin can be irritating to the skin, which limits its effectiveness. By incorporating tretinoin into ethosomes, the drug can be delivered directly to the sebaceous glands, where it can target the underlying causes of acne, leading to improved efficacy and reduced side effects.…”