Strategy for Safe Colon-targeted Local Therapy of Inflammatory Bowel Disease

炎症性肠病(IBD)是一种使人衰弱的疾病，在美国每年约有70,000人受到影响 美国。此外，IBD还会增加患结肠癌的风险。由于疾病的长期性和 目前抗炎症性肠病药物的治疗结果不一致(例如，约30%的抗肿瘤坏死因子α药物无效)， 以及相关的致命副作用(如脓毒症)，大多数IBD患者(以数百万计)转向补充 和替代药物(CAMS)。因此，除了追求“安全精确”之外，当务之急是 药物“，有一个未得到满足的需求，以发展具有强大的抗炎性能的安全凸轮。在这 在这方面，安全的饮食成分姜黄素的抗炎作用被广泛认识，因为它 炎症通路中的多个靶点，这可能有助于控制炎症爆发 由IBD的多种机制引起，其中可能包括对精确药物无反应者。 最近，由于姜黄素在其他几个临床试验中的失败，人们对姜黄素的热情已经降低 疾病，主要是由于其生物利用度较低。持续提高姜黄素的临床生物利用度 由于其非常高的代谢率，进步一直是具有挑战性的。与现有的 策略，我们的工作假设是通过将可溶的生物活性姜黄素局部输送到炎症 在没有全身暴露的情况下，长期使用姜黄素可以绕过路障。 IBD及相关癌症的补充治疗。为此，一种独特的基于聚合物的工程设计 ORA-姜黄素-S(OC-S)技术是由姜黄素与一系列 名为Eudradits®的聚合物。已公布的初步数据显示，OC-S的市盈率为2000倍。 比姜黄素更易溶，并将高比例的可溶姜黄素输送到结肠腔而不被检测到 健康小鼠和结肠炎小鼠的吸收。此外，它还抑制免疫细胞上的TLR4活性，从而干扰 与IBD的免疫失调和上皮向癌症的转变有关的多个途径。重要的是 OC-S有效抑制小鼠结肠炎相关免疫紊乱和粘膜损伤 结肠炎的剂量比报道的姜黄素研究低3-60倍。OC-S复合体为首次报道 结肠靶向姜黄素给药系统，在水中高度溶解和稳定。因此，OC-S，对于 第一次，将使我们能够测试姜黄素用于IBD的局部治疗。这项提案的总体目标是 进行彻底的临床前评估，并检查炎症靶向OC的细胞机制 S复方对溃疡性结肠炎的抑制作用。该提案的具体目标包括：1)建立 OC-S结肠炎模型的安全性和靶向性给药：2)鉴定特异性分子/细胞 OC-S抗结肠炎作用的改善。我们预计提出的研究将提供一个 OC-S作为一种局部疗法减少IBD的结论性结果和支持未来临床评估的决定 严重程度和相关癌症。

Inflammatory Bowel Disease (IBD) is a debilitating disease that affects ~70,000 new people every year in the USA. Additionally, IBD increases the risk of developing colon cancer. Due to the chronicity of the disease and inconsistent treatment outcomes of current anti-IBD drugs (e.g. ~30% non-responders to anti-TNFα agents), and related deadly side effects (such as sepsis), the majority of IBD patients (in millions) turn to complementary and alternative medicines (CAMs). Thus, it is imperative that in addition to the pursuit of “safe precision medicine”, there is an unmet need to advance safe CAMs with strong anti-inflammatory properties. In this regard, the anti-inflammatory role of the safe dietary component curcumin is widely recognized due to its multiple targets in the inflammation pathways, which may be beneficial in managing the inflammatory flares induced by a wide range of mechanisms in IBD that may include non-responders to precision medicine. Recently, the enthusiasm for curcumin has been diminished due to its failure in several clinical trials for other diseases, mainly due to its poor bioavailability. Improving the curcumin bioavailability consistently for clinical advancement has been challenging because of its very high metabolic rate. In contrast to existing strategies, our working hypothesis is by delivering soluble and bioactive curcumin locally to the inflammation site (without systemic exposure), the road-blocks could be circumvented in advancing curcumin for long-term complementary therapy for IBD and associated cancer. To this end, a uniquely engineered polymer-based technology, Ora-Curcumin-S (OC-S), was invented by molecular complexation of curcumin with a group of polymers called Eudragits®. Strong published preliminary data showed that OC-S is >2000 times water- soluble than curcumin and delivered high proportions of soluble curcumin to the colon lumen without detectable absorption in both healthy and colitis mice. Further, it inhibited TLR4 activity on immune cells, which interferes with multiple pathways related to immune dysregulation in IBD and epithelial transition to cancer. Importantly, OC-S effectively inhibited colitis-associated immune deregulations and mucosal injury in a mouse model of colitis at doses 3-60 times lower than reported curcumin studies. The OC-S complexes are the first reported colon-targeted curcumin delivery systems that are highly soluble and stable in water. Therefore, OC-S, for the first time, will enable us to test curcumin for local therapy for IBD. The overall goal of this proposal is to perform a thorough preclinical evaluation and examine the cellular mechanisms of inflammation-targeted OC- S complexes in inhibiting the ulcerative colitis (UC). The specific aims of the proposal include 1) To establish the safety and targeted delivery of OC-S to the inflamed colon, 2) To identify specific molecular/cellular functions ameliorated by the OC-S for its anti-colitis activity. We anticipate proposed studies to provide a conclusive outcome and support the decision for future clinical evaluation of OC-S as a local therapy to reduce IBD severity and associated cancer.