Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the intestine, with increasing incidence worldwide. At present, the management of IBD is an unmet medical need due to the ineffectiveness of currently available drugs in treating all patients, and there is strong demand for novel therapeutics. In this regard, vasoactive intestinal peptide, a potent anti-inflammatory endogenous hormone, has shown promise in managing multiple immune disorders in animal models. However, when administered in the free form, VIP undergoes rapid degradation in vivo, and with continuous infusion, it causes severe dose limiting side effects. To overcome these barriers, we have developed a superior mode to deliver VIP in its native form, using sterically stabilized micelles (VIP-SSM). Our previous studies demonstrated that, VIP, when administered in SSM, prevented joint damage and inflammation in a mouse model of rheumatoid arthritis at a significantly lower dose than the free peptide, completely abrogating the serious side effect of hypotension associated with VIP. In the current study, we demonstrate the therapeutic benefit of VIP-SSM over free peptide in reversing severe colitis associated with IBD. First, we conducted preliminary studies with dextran sulfate sodium (DSS) induced colitis in mice, to determine the effectiveness of VIP administered on alternate days in reducing disease severity. Thereafter, a single intra peritoneal injection of VIP-SSM or the free peptide was used to determine its therapeutic effect on the reversal of colitis and associated diarrhea. The results demonstrated that when administered on alternate days, both VIP-SSM and VIP were capable of alleviating DSS colitis in mice. However, when administered as a single dose, in a therapeutic setting, VIP-SSM showed superior benefits compared to the free peptide in ameliorating colitis phenotype. Namely, the loss of solid fecal pellets and increased fluid accumulation in colon resulting from DSS insult was abrogated in VIP-SSM treated mice and not with free VIP. Furthermore, reduced protein and mRNA levels of the major chloride bicarbonate exchanger, down regulated in adenoma (DRA), seen with DSS was reversed with VIP-SSM, but not with the free peptide. Similarly, VIP-SSM treatment significantly reduced the elevated mRNA levels of pro-inflammatory cytokines and showed significant histologic recovery when compared to mice treated with free VIP. Therefore, these results demonstrated that as a single dose, the anti-inflammatory and antidiarrheal effects of VIP can be achieved effectively when administered as a nanomedicine. Therefore, we propose VIP-SSM to be developed as a potential therapeutic tool for treating ulcerative colitis, a type of IBD.

中文翻译：

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血管活性肠肽纳米药物治疗炎性肠病

炎症性肠病（IBD）是一种肠道慢性复发性疾病，在全球范围内发病率不断上升。目前，由于目前可用的药物在治疗所有患者方面均无效，因此IBD的管理尚未满足医疗需求，并且对新型疗法的需求也很大。在这方面，血管活性肠肽是一种有效的抗炎性内源激素，在治疗动物模型中的多种免疫疾病中显示出了希望。但是，当以游离形式给药时，VIP在体内会迅速降解，并且连续输注会导致严重的剂量限制副作用。为了克服这些障碍，我们开发了一种高级模式，可以使用空间稳定的胶束（VIP-SSM）以其原始形式提供VIP。我们以前的研究表明，在SSM中管理VIP时，在风湿性关节炎小鼠模型中，其剂量明显低于游离肽，可预防关节损伤和炎症，从而完全消除了与VIP相关的低血压的严重副作用。在当前的研究中，我们证明了VIP-SSM优于游离肽在扭转与IBD相关的严重结肠炎中的治疗作用。首先，我们对硫酸葡聚糖硫酸钠（DSS）诱发的小鼠结肠炎进行了初步研究，以确定隔日服用VIP可以降低疾病严重程度。此后，腹膜内注射VIP-SSM或游离肽用于确定其对逆转结肠炎和相关腹泻的治疗效果。结果表明，隔天服用时，VIP-SSM和VIP均可缓解小鼠DSS结肠炎。然而，当以单剂量给药时，在治疗环境中，与游离肽相比，VIP-SSM在改善结肠炎表型方面显示出优越的优势。即，在用VIP-SSM治疗的小鼠中，而不是在没有免费的VIP的情况下，废除了由于DSS侵害导致的固体粪便颗粒的损失和结肠中积液增加。此外，使用VIP-SSM可以逆转在DSS中在腺瘤（DRA）中下调的主要氯化物碳酸氢盐交换子的蛋白质和mRNA水平降低，而VIP-SSM却可以逆转，但游离肽则不能。类似地，与用游离VIP治疗的小鼠相比，VIP-SSM治疗显着降低了促炎细胞因子的升高的mRNA水平，并显示出明显的组织学恢复。因此，这些结果表明，单次服用，当作为纳米药物给药时，可以有效地实现VIP的抗炎和止泻作用。因此，我们建议将VIP-SSM开发为治疗溃疡性结肠炎（一种IBD类型）的潜在治疗工具。