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

炎症性肠病的安全结肠靶向局部治疗策略

• 批准号: 10202303
• 负责人: HEMACHAND TUMMALA
• 金额: $ 44.11万
• 依托单位: SOUTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202303
• 关键词: 3-Dimensional; Adjuvant Therapy; Affect; Anti-Inflammatory Agents; Autoimmune Diseases; Award; Biological Availability; Blood; Blood Circulation; Cell physiology; Cells; Chronic; Chronic Disease; Clinical; Clinical Management; Clinical Trials; Colitis; Colon; Colon Carcinoma; Complement; Complementary and alternative medicine; Complementary therapies; Complex; Consumption; Crohn' s disease; Curcumin; Data; Dendritic Cells; Dietary Component; Disease; Disease remission; Dose; Drug toxicity; Engineering; Enzymes; Epithelial; Epithelial Cells; Eudragit; Failure; Flare; Food; Future; Goals; Human; Immune; Immunotherapeutic agent; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Injury; Intervention; Lead; Life Style; Local Therapy; Malignant Neoplasms; Metabolic; Molecular; Mucous Membrane; Mus; Oral; Organoids; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Polymers; Property; Publishing; Reaction Time; Relapse; Reporting; Research; Risk; Role; Safety; Sepsis; Severity of illness; Site; System; TLR4 gene; TNF gene; Technology; Testing; Therapeutic; Time; Toxin; Transitional Epithelium; Treatment outcome; Tumeric; Ulcerative Colitis; Water; absorption; base; cancer cell; cancer risk; clinical translation; colitis associated cancer; colorectal cancer risk; design; drug discovery; drug distribution; efficacy validation; efflux pump; healing; high risk; improved; in vivo; metabolic rate; mouse model; novel therapeutics; pathogen; patient population; precision medicine; preclinical evaluation; preclinical study; prevent; protective effect; research clinical testing; response; side effect; systemic toxicity; targeted delivery; therapy outcome

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.

炎症性肠病（IBD）是一种使人衰弱的疾病，在美国每年影响约70，000新患者。 USA.此外，IBD会增加患结肠癌的风险。由于疾病的长期性， 当前抗IBD药物的治疗结局不一致（例如，约30%的抗TNF α药物无应答）， 和相关的致命副作用（如败血症），大多数IBD患者（数百万）转向补充 替代药物（CAM）。因此，除了追求“安全精确”外， 由于“药物”的概念，对开发具有强抗炎特性的安全CAM的需求尚未得到满足。在这 关于这一点，安全的膳食成分姜黄素的抗炎作用由于其 炎症通路中的多个靶点，这可能有助于控制炎症发作 由IBD中的广泛机制引起，可能包括对精确药物的无应答者。 最近，由于姜黄素在其他一些临床试验中的失败，对姜黄素的热情已经减弱。 疾病，主要是由于其生物利用度差。持续提高姜黄素的生物利用度，用于临床 由于其非常高的代谢率，其发展一直具有挑战性。相比于现有 策略，我们的工作假设是通过提供可溶性和生物活性姜黄素局部炎症 在没有全身暴露的情况下，可以绕过长期推进姜黄素的障碍 IBD和相关癌症的补充疗法。为此，一种独特的聚合物基 技术，Ora-Curcumin-S（OC-S），是通过姜黄素与一组 聚合物称为Eudragits®。强有力的公布的初步数据显示，OC-S是水的2000倍以上。 比姜黄素可溶，并将高比例的可溶性姜黄素递送至结肠腔， 在健康和结肠炎小鼠中的吸收。此外，它抑制了免疫细胞上的TLR 4活性，这干扰了免疫细胞的免疫功能。 与IBD中免疫失调和上皮向癌症转变相关的多种途径。重要的是， OC-S有效地抑制结肠炎相关的免疫失调和粘膜损伤的小鼠模型， 剂量比报道的姜黄素研究低3-60倍。OC-S配合物为首次报道 结肠靶向姜黄素递送系统，其在水中高度可溶且稳定。因此，OC-S，对于 这是第一次，将使我们能够测试姜黄素用于IBD的局部治疗。本提案的总体目标是 进行彻底的临床前评估，并检查炎症靶向OC的细胞机制， S配合物抑制溃疡性结肠炎（UC）的作用。该提案的具体目标包括：（1）建立 OC-S向发炎结肠的安全性和靶向递送，2）鉴定特异性分子/细胞 OC-S因其抗结肠炎活性而改善的功能。我们预计拟议的研究将提供一个 结论性结果，并支持未来将OC-S作为减少IBD的局部治疗进行临床评价的决定 严重程度和相关癌症。