TNF-α靶向治疗克罗恩病的单抗纳米药物制备及效应研究

克罗恩病是一种慢性肠道炎症，目前尚无根治的方法。抗TNF-α单抗治疗虽有较好的临床效果，但仍存在许多问题，如患者对治疗的应答比例仅约50%，因抑制全身免疫功能可能导致的感染、过敏、自身免疫疾病等副作用甚至罹患肿瘤。如何建立一种早期预测、实时在体监测TNF-α疗效的评价方法？如何降低抗TNF-α治疗带来的全身毒副作用？本项目针对这两难题，拟构建新型英夫利昔单抗口服纳米药物，发挥天然多酚单宁酸的抑酶活性、刺激响应性等特色，实现定位释放，减少系统性药物暴露，减少消化系统蛋白酶的降解；同时引入89Zr示踪技术，结合PET影像，系统、连续、无创地评价单抗及纳米药物在体内的吸收、分布、代谢及排泄，为纳米药物的设计、抗炎效应及安全性评价提供客观依据。本项目多学科交叉，若成功，将为肠道疾病治疗提供一种增效、减毒的新策略，同时核素示踪评价方法易临床转化，有助于患者的筛选、治疗方案决策及调整，实现精准治疗。

Crohn's disease is a chronic intestinal inflammation and there is currently no cure. Anti-TNF-α monoclonal antibody has a good clinical effect in the treatment of moderate to severe Crohn's disease, but there are still many problems, such as the patient's response rate to treatment is only about 50%, the inhibition of systemic immune function may lead to infection, allergies, autoimmune diseases and even cancer. How to establish an early prediction and real-time evaluation method for the treatment of anti-TNF-α? How to reduce the systemic side effects caused by anti-TNF-α treatment? In order to solve these two problems, this project plans to construct a new infliximab nanodrugs for oral delivery. This nanodrugs exert the characteristics of natural polyphenol tannic acid such as enzyme inhibition activity and stimuli responsiveness, to achieve fixed localization release, reduce systemic drug exposure and digestion of proteases. By introduction of radionuclide (89Zr) tracer technology and PET imaging, in vivo systematic, continuous,noninvasive evaluation of the absorption, distribution, metabolism and excretion of monoclonal antibodies and nanodrugs can be achieved. This will provide an objective basis for the design, anti-inflammatory effects and safety evaluation of nanomedicine. If this project is successful, it will provide a new strategy for increasing efficacy and reducing toxicity in the treatment of intestinal diseases. At the same time, the radionuclide tracing method is easy for clinically translation, which is helpful for patients screening and precise treatment.