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
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
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DOI：
10.1124/jpet.111.190447
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发表时间：
2012-05-01
影响因子：
3.5
通讯作者：
Tabata, Yasuhiko
中科院分区：
文献类型：
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作者：
Okamoto, Tatsuya;Uemoto, Shinji;Tabata, Yasuhiko
已知前列腺素E-2受体亚型4（EP 4）激动剂可减少肠道炎症并增强上皮再生。我们探索了使用聚（乳酸-共乙醇酸）（PLGA）微球结肠递送EP 4激动剂2-[（4-{[2-（（1 R，2 R，3R）-3-羟基-2-{（1 E，3S）-3-羟基-4-[3-（甲氧基甲基）苯基]丁-1-烯基}-5-氧代环戊基）乙基]硫基}丁酰基）氧基]乙基壬酸酯（ONO-AE 2 -724）的可能性。通过直肠内施用三硝基苯磺酸（TNBS）在小鼠中诱导结肠炎。通过标准技术制备ONO-AE 2 -724-PLGA微球（EP 4-MS）。采用液相色谱-串联质谱法测定口服EP 4-MS后的药物分布。为了评估EP 4-MS的保护作用，在TNBS滴注前24小时通过管饲法用单剂量的EP 4-MS口服处理动物。评价体重变化、组织病理学、免疫组织化学和炎性细胞因子表达。口服给予EP 4-MS增强结肠组织药物浓度，而在摄入后48小时内血清浓度没有任何增加。EP 4-MS预处理，而非未负载的ONO-AE 2 -724，显著减弱TNBS诱导的结肠炎并降低促炎细胞因子的结肠mRNA表达水平。此外，在EP 4-MS处理的小鼠的分离的固有层CD 4（+）T细胞中发现CD 25和FoxP 3的表达显著增加。Ki-67和单链DNA的免疫组化分析表明，EP 4-MS预处理显着抑制结肠细胞凋亡，促进上皮细胞增殖。这些结果表明，EP 4-MS通过肠局部ONO-AE 2 -724递送保护小鼠免受TNBS诱导的结肠炎。EP 4-MS可能为治疗炎症性肠病提供一种有前途的新治疗策略。
Prostaglandin E-2 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.