耐药相关稀土Gd纳米探针在胃癌耐药及逆转中的分子影像研究

Multi-drug resistance (MDR) is the important cause of the failure of the gastric cancer chemotherapy, dynamic monitoring drug resistance status and setting indiidualized treatment is the key to improve the effect of chemotherapy.Molecular imaging technology has brought an opportunity for us.In recent years, rare earth nanomaterials become hot in the field of OI-MRI duel-mode imaging because of its good and magnetic characteristics. In our previous work, after coupling duplicate MGb2 clone antibody and successfully gain the gastric cancer targeting rare earth Gd nanoprober, then tiny tumor was detected by dual-modal imaging.Peptide GMBP1 that specific combinates with gastric cancer resistant cells was development by ourselves, it was confirmed that GMBP1 and its receptor GRP78 may be the key molecular targets for gastric cancer detection and reversal .The project intends to use GMBP1 as targeting molecules, make tumor drug resisitance targeting preparation of Gd nanoprobes; Identify its physical and chemical properties of diameter and stability as well as its biological activity of binding specificity and affinity. After established subcutaneous model of gastric carcinoma in nude mice, to evaluate the gastric cancer diagnosis and effect of drug resistance reversal resistant by OI, MRI dual-mode imaging in vivo. The main purpose of our study is to research and develop a potential clinical transforming tumor targeting of Gd nanoprobes, providing new methods of molecular imaging for the evaluation of gastric cancer diagnosis and drug resistance reversal resistant effect in gastric cancer.

多药耐药（MDR）是导致胃癌化疗失败的重要原因，如何动态监测耐药状态，制定个体化治疗方案，是提高化疗效果的关键。分子影像技术给我们这种设想带来了契机。近年来，稀土纳米材料因兼具优良的上转换发光和磁学特性，成为OI-MRI双模态分子影像研究的一个热点。前期工作中，我们通过耦联MGb2抗体，制备纳米探针，通过双模态成像实现荷瘤鼠微小瘤灶的检测。我们自主研发获得胃癌耐药细胞特异结合肽GMBP1，并证实GMBP1及其受体GRP78有可能为胃癌耐药检测及逆转的关键分子靶点。本项目拟以GMBP1为靶点，制备胃癌耐药相关稀土Gd纳米探针；通过体内外实验，对探针的结合特异性、亲和力等生物学活性进行鉴定；建立皮下胃癌耐药荷瘤鼠模型，通过OI-MRI双模态成像，评价探针在胃癌耐药诊断与逆转治疗在体可视化中的价值。旨在研发有临床转化潜力的胃癌耐药相关稀土Gd纳米探针，为胃癌耐药诊断与逆转治疗提供分子影像新方法。

多药耐药是导致胃癌化疗失败的重要原因，如何动态监测耐药状态，制定个体化治疗方案，是提高化疗效果的关键。分子影像技术给我们这种设想带来了契机。不同成像技术各有其优劣势和适用性，联合MRI优良的空间分辨率与OI的高灵敏度，光学-磁共振双模态成像的研究与进展引人注目，基于纳米技术的“一体化”成像探针得到快速发展。前期工作中，我们自主研发获得胃癌耐药细胞特异结合肽GMBP1，并证实GMBP1及其受体GRP78有可能为胃癌耐药检测及逆转的关键分子靶点。基于此，本项目主要联合胃癌靶向分子和荧光染料、磁共振纳米材料制备光-磁双模态探针，用于评估OI-MRI双模态成像在胃癌耐药逆转治疗效果监测中潜在应用价值的探索。开展了核壳结构的NaGdF4:Yb3+,Er3+ UCNPs纳米晶体的制备及优化研究，终因合作者及合作单位的实际情况，原计划的稀土Gd纳米探针无法继续，最终选用了胃癌靶向分子GEBP11，同时连接磁性纳米颗粒与光学信号分子，成功制备了满足实验目的的OI-MRI双模态分子影像探针。体内外实验验证了该OI-MRI双模态分子影像探针，保留了特异性结合的生物学特性，具有良好的生物组织相容性，能在体内靶向结合聚集于肿瘤部位，并成功进行了光学、磁共振两种模态的分子成像。基于上述成果，通过建立荷耐药胃癌裸鼠移植瘤模型，顺利完成了胃癌耐药逆转治疗实验，采用OI-MRI双模态活体成像评估了GMBP1治疗对耐药胃癌的化疗增敏作用。本项目研究成果进一步证实，光-磁双模态分子成像在监测胃癌耐药逆转治疗效果评估中具有重要的潜在应用价值，为实体肿瘤的活体监测与疗效评估提供了新策略与新方法。本项目资助研究成果，发表学术研究论文5篇，其中SCIE收录论文1篇；获奖1项；参编译专著1部。培养研究生3名，美国克利夫兰医学中心访问学者1名。课题研究人员多次参加国际、国内学术会议，进行大会报告、壁报展示或书面交流。