2020-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/653555摘要：發炎性腸道疾病(IBD)是腸道持續性或反覆性發炎，單株抗體(mAb)藥物的出現，顯著改善IBD治療效果。Infliximab是第一個被FDA核准用於治療的anti-TNF-α mAb，然而全身性的給予infliximab產生不良反應。因此開發一個口服大腸標的劑型來遞送infliximab，不僅增加局部的藥品濃度，也降低了全身性副作用的機會。mAb應用於口服遞送系統上，主要的限制為胃液強酸環境下易造成物理化學特性的不安定及其不易穿透腸壁。在本研究計畫中，我們將結合高分子材料及一段具有胞吞轉送特性之胜肽遞送infliximab至大腸以達到治療IBD的效果。結合pH應答(pH-responsive)高分子(Eudragit®)及持續釋放特性高分子(poly(lactic-co-glycolic acid) (PLGA))或酵素可降解性高分子(chitosan)是一個合適的大腸標遞送設計。另一方面，肝素結合凝血附著素c (HBHAc) 在體外腸道細胞試驗中發現具有胞吞轉送的特性，且已應用於腦中風的動物模型中，來增加紅血球生成素的血腦障壁穿透性，因此當蛋白質藥品成功遞送至大腸後HBHAc能夠進一步幫助其通過生理性屏蔽。三年計劃的目標如下:1. 建立及優化具大腸標的之抗體藥物遞送劑型 2. 評估此劑型之療效及分佈 3. 於IBD小鼠內評估具大腸標的遞送劑型修飾之HBHAc-infliximab其治療效果及安全性研究。透過此新的藥品遞送系統使anti-TNF-α mAb有效的遞送至發炎的大腸部位並穿透表皮細胞，進而達到有效的抗發炎，且降低全身性的不良反應。<br> Abstract: The inflammatory bowel disease (IBD) is characterized by chronic remittent or progressive inflammatory conditions of the intestine and includes Crohn’s disease (CD) and ulcerative colitis (UC). Moreover, the effect of IBD on health-care systems rises rapidly because the majority of patients are diagnosed early in life and the incidence continues to increase. The emergence of monoclonal antibodies as the treatment for IBD significantly improves the therapeutic efficacy. Infliximab is first FDA approved anti-TNF-α antibody for the treatment of CD, and later for the treatment of UC, and it binds to TNF-α molecules and following blocks the interaction between TNF-α and TNF-α receptor. However, the adverse side effects are observed as systemic administration of infliximab. Thus, the development of an orally colonic targeting formulation for infliximab is important, and it might not only increase the local drug concentration but also reduce the incident of systemic side effects. The chemical and physical instability under the harsh pH of the gastric fluid and the limited intestinal epithelium permeability are the major challenges while delivering therapeutic protein, such as infliximab, in oral administration. Thus, we would like to apply the polymers with colonic delivery activity and a peptide with transcytosis ability in oral delivery of infliximab for IBD in this study. The combination of the pH-responsive polymer, Eudragit®, and the sustained-releases polymer, poly(lactic-co-glycolic acid) (PLGA) or enzyme degradable polymer, chitosan, is a rational design for colonic delivery. On the other hand, HBHAc elicited the transcytosis activity on Caco-2 cell model in vitro, and it has been used as a carrier for enhancing BBB permeability of a protein drug (erythropoietin) on stroke model in vivo. Therefore, HBHAc is a potential carrier for protein drug across physical barrier after they are specifically delivered to colon. In this 3-year project, our goals are 1. Develop an optimal formulation of a colonic targeting delivery for model antibodies. 2. Evaluate the efficacy and distribution of the developed formulation. 3. Demonstrate the efficacy and safety and characterize formulated HBHAc-infliximab in IBD model in vivo. After this comprehensive study, formulated HBHAc-infliximab can be delivered efficiently to inflammatory colon site and further penetrate through epithelia barrier by the newly designed delivery system, and subsequently increase the efficacy in anti-inflammatory activity and minimize the systemic adverse effects.發炎性腸道疾病抗腫瘤壞死因子單株抗體抗體藥物口服大腸標的遞送穿胞胜肽inflammatory bowel diseaseanti-TNF monoclonal antibodyantibody drug orally colonic targetingcell-penetrating peptide