UST@SGC靶向抑制IL-12/23介导的免疫反应的机制及其在中重度克罗恩病诊疗中的作用研究

对TNF-α抑制剂无应答及失应答已成为克罗恩病（CD）治疗中亟需解决的问题，故探寻新治疗方式意义重大。研究表明，人源化乌斯奴单抗（Ustekinumab, UST）对治疗此类CD效果显著。我们前期对炎性微环境及多功能复合物的构建进行了研究，本项目拟在此基础上构建携载UST、过氧化氢酶（CAT）和超顺磁氧化铁（SPIO）的多功能复合物，靶向炎性微环境催化生成O2并释放SPIO促进US/MR成像，同时释放UST到炎症处，特异性结合白细胞介素IL-12/23 p40亚基，从上游阻断具有促炎作用的Th1及Th2细胞分化，起到免疫治疗作用。首先，拟通过搭载UST多功能复合物的构建及体外实验进行生物相容性、药物搭载及释放能力的研究。其次，建立大鼠模型进行分组诊疗实验，通过动物生存曲线、病理学及药代动力学研究，结合US/MR成像监控病情及免疫治疗效果。本项目有望为CD的诊疗一体化提供新思路。

Primary nonresponse and secondary loss of response has been a pain point in anti-TNF-α treatment, therefore exploring new immunotherapy is of great significance. It was reported that efficacy of the human monoclonal antibody Ustekinumab (UST) in patients with Crohn’s disease (CD) refractory to anti-TNF-α treatment has been confirmed. In previous researches, we studied inflammatory microenvironment and construction of multifunctional composites. Herein we propose to construct a multifunctional composite system encapsulating superparamagnetic iron oxide (SPIO), catalase (CAT) and UST. The composite will target the inflammatory microenvironment to generate oxygen(O2) microbubbles promoting enhancement of ultrasound and release SPIO to also facilitate MR enhancement. UST will simultaneously be released to targeted lesions for inhibiting heterodimeric cytokines IL-12/13 mediated response by binding with p40 subunits of IL-12/13 to hamper T cells from proliferating Th1 and Th2 cells that lead to pro-inflammatory responses. Firstly, construction of UST loaded composite and in-vitro experiments will be conducted to study biological compatibility, capacity of loading and releasing UST. Secondly, studies of animal survival curves, histopathology and pharmacokinetics will be integrated with results of US/MR imaging for evaluating CD severity and efficacy. This research will potentially provide novel insights for integrated diagnosis and treatment of CD in future.