基于SNF及GX1优化探针结合近红外成像用于早期胃癌精准诊断的研究

内镜下早期胃癌的精确诊断依旧是临床难点。近红外内镜因具有成像敏感性强和组织穿透力强等优点，其结合多肽靶向探针已被成功地运用于肠道腺瘤的精确诊断。表面微结构及微血管的异常是早期胃癌的典型特征，前期我们筛选获得了靶向胃癌表面微结构的多肽SNF及靶向微血管结构的多肽GX1，并鉴定SNF和GX1的受体分子分别为EpCAM和TGM2，但多肽与受体结合亲和力尚需提升。本课题拟通过多肽与受体蛋白三维结合位点预测，对SNF及GX1进行结构优化以提高其结合亲和力，并构建联合二种优化多肽的异价二聚体进一步提高结合亲和力和特异性，进而通过近红外荧光剂标记SNF优化肽、GX1优化肽及其异价二聚体制备近红外探针；结合近红外成像技术在细胞、动物和临床早期胃癌离体标本验证它们的生物活性及探讨其用于早期胃癌诊断的应用价值，筛选出高亲和力、高特异性和高肿瘤/背景比的探针，为早期胃癌近红外内镜分子精准诊断提供良好的候选探针。

The accurate diagnosis of early gastric cancer (EGC) under endoscopy is still a clinical problem. The advantages of near infrared (NIR) endoscopy includes high imaging sensitivity and tissue penetration. NIR endoscopy in combination with target probe have been applied to the accurate diagnosis of colorectal adenomas in a clinical trial. Abnormal microsurface and microvascular patterns are typical characteristics of EGC. In our previous study, we screened peptide SNF and GX1, which were demonstrated to target the microsurface and microvascular patterns of gastric cancer, respectively and we found the target proteins of SNF and GX1 were EpCAM and TGM2, respectively. However, the binding affinity of the peptides still needed to be improved. Our research plans to modify and optimize the peptides to improve the binding affinity of peptides to proteins based on three dimensional structures of peptides and receptor proteins. Besides, a heterodimer peptide were developed by combining optimized SNF and optimized GX1 in a heterodimer configuration to improve the binding affinity and specificity. Furthermore, we conducted NIR probes using NIR dyes conjugated with optimized SNF, optimized GX1 and heterodimer peptide and evaluated the biological activities and application value for detection of EGC with help of NIR imaging. We aim to screen a NIR probe with higher sensitivity, higher specificity and higher tumor background ratio, which would serve as a suitable candidate molecule for accurate diagnosis of EGC under NIR molecular endoscopy.