卵巢癌发病率在女性生殖系统肿瘤中次于宫颈癌和子宫内膜癌，但死亡率居首,主要是由于其部位隐匿早期症状不明显，且缺乏简便灵敏的影像学诊断手段，75%患者诊断时已属晚期。而现有标志物CA125在敏感性和特异性上均不能令人满意，所以开发新的早期诊断的生物标志物非常必要。人附睾蛋白4（HE4）是近年发现的特异性显著高于CA125的卵巢癌相关蛋白，其表达与肿瘤大小成正相关。但是现有ELISA法检测HE4在早期诊断中的灵敏度并不高，有待提高检测方法的灵敏度以发现更小的肿瘤。本研究拟利用课题组前期开发的二氧化硅包磁纳米颗粒偶联HE4单抗形成纳米复合颗粒，高效快速富集血液和尿液中HE4蛋白；并分别通过人卵巢癌裸鼠皮下移植瘤模型和队列对照研究,比较纳米复合颗粒与现有ELISA法检测HE4的敏感性和特异性，进一步确定纳米复合颗粒在卵巢癌早期筛查中的价值和诊断分界点，以期为发展卵巢癌的早期诊断新方法提供依据。

Ovarian cancer, the incidence of which is lower than cervical cancer and endometrial carcinoma, has the highest mortality in all female reproductive system tumors. The current diagnostic methods including symptoms, imaging examinations, tumor markers are unsatisfactory, which accouted for poor diagnosis in early stage. Cancer antigen 125 (CA125) is a common tumor marker of ovarian cancer, however, the senstivity and the specificity of CA125 are limited. Therefore, novel biological markers for early diagnosis are needed to further study. Human epididymis protein 4 (HE4), a new marker for ovarian cancer, has higher specificity than CA125 and is positively correlated with tumor size. According to the ELISA methods, the sensitivity of HE4 is not still high; thus, the detection technologies need to be improved to raise the sensitivity of HE4 to find smaller cancers in earlier stage. In the study, we are to improve the SiO2 magnetic nanoparticles coupling with HE4 monoclonal antibody (nanocomposites) developed by ourselves to efficiently, rapidly capture and accumulate HE4 in blood and urine. And the sensitivity and the specificity of HE4 between the ELISA methods and the novel method (nanocomposites) will be compared by subcutaneously transplanting human ovarian cancer into nude mice, and furthermore, the cut-off point of HE4 for ovarian cancer screening and diagnosis value in early stage by means of the novel method (nanocomposites) will be explored.

我们应用前期合成的二氧化硅包磁Fe3O4纳米颗粒，与传统ELISA试剂盒进行比较验证，发现新材料的敏感性虽有提高，但稳定性不足以应用于临床。后期变更为液态芯片技术，显著提高了检测的敏感性与稳定性，将HE4最低检测水平由0.15ng/ml提高至0.07ng/ml。应用改进后的方法进行应用前景评价：荷瘤小鼠模型进行动物试验显示结果为阴性，卵巢癌细胞株HEY并不分泌HE4；随后进行了人群大样本的临床验证，提示该方法具有一定的临床应用价值（诊断ROC曲线下面积0.6124）。