Prevention of trinitrobenzene sulfonic acid-induced experimental colitis by oral administration of a poly(lactic-coglycolic acid) microsphere containing prostaglandin E₂ receptor subtype 4 agonist.
Prostaglandin E₂ receptor subtype 4 (EP4) agonists are known to reduce intestinal inflammation and enhance epithelium regeneration. We explored the possibility of colonic delivery of an EP4 agonist, 2-[(4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoyl)oxy]ethyl nonanoate (ONO-AE2-724), using poly(lactic-coglycolic acid) (PLGA) microspheres. Colitis was induced in mice by the intrarectal administration of trinitrobenzene sulfonic acid (TNBS). ONO-AE2-724-PLGA microspheres (EP4-MS) were prepared by the standard technique. Drug distributions after oral administration of EP4-MS were determined by liquid chromatography-tandem mass spectrometry analysis. To evaluate the protective effect of EP4-MS, animals were orally treated by gavage with single doses of EP4-MS 24 h before TNBS instillation. The changes in body weight, histopathology, immunohistochemistry, and expression of inflammatory cytokines were evaluated. Oral administration of EP4-MS enhanced colonic tissue drug concentration without any increase in the serum concentration during the 48 h after intake. EP4-MS pretreatment, but not unloaded ONO-AE2-724, significantly attenuated TNBS-induced colitis and diminished colonic mRNA expression levels of proinflammatory cytokines. In addition, a significant increase in the expression of CD25 and FoxP3 was found in isolated lamina propria CD4+ T cells of EP4-MS-treated mice. Immunohistochemical analysis of Ki-67 and single-stranded DNA revealed that EP4-MS pretreatment significantly suppressed apoptosis of colonic cells and promoted epithelial cell proliferation. These results suggest that EP4-MS protect mice from TNBS-induced colitis by intestinal local ONO-AE2-724 delivery. The EP4-MS may offer a promising new therapeutic strategy to treat inflammatory bowel diseases.
Department of Surgery-Hepato-pancreatico-biliary and Transplantation, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tatsuya
T
Okamoto
Shinji
S
Uemoto
Yasuhiko
Y
Tabata
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008863:Microspheres; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists* / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D016207:Cytokines; D004277:DNA, Single-Stranded; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C545651:Ptger4 protein, mouse; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D014302:Trinitrobenzenesulfonic Acid