面向乳腺癌特征物检测的多参量SERS微通道芯片及其探测技术研究

Breast cancer is the most frequent malignancy among women, and it is the forth to fifth leading cause of death among malignant tumors. To satisfy the grandiose demands of early diagnosis and personalized treatment of breast cancer, a multi-parameter micro total analysis system based on SERS is proposed in this project, which enables on-site detection of breast cancer biomarkers in human blood. In essence, a typical approach is to combine multi-dimensional SERS encoding based characterization method with microfluidic chip technology. The chip integrates the pre-treatment and further analysis of blood samples and achieves joint detection of breast cancer biomarkers ranging from circulating tumor cells (CTCs), protein to DNA and RNA with a high sensitivity, high throughput and high specificity. This approach avoids the weakness of single biomarker detection and improves accuracy of state diagnosis (including molecule subtypes) and prognosis evaluation, which provides a powerful technical support for quick formulation of personalized treatment. The main research contents of this project include the basic theory, design and manufacture of novel SERS detection chip and their applications in breast cancer biomarker detection. This project has the following two main goals: to develop multi-dimensional SERS encoding and imaging methods based on spatial/spectral encoding tools and to overcome technical difficulties in design, manufacture and utility of SERS-based breast cancer biomarker detection microchip. SERS microchip technology with independent intellectual property rights would be achieved, which will provide a design solution and technical support for minitype, portable and personalized real-time diagnosis platform of major diseases in the future.

乳腺癌是女性发病率最高的癌症，列所有癌症死因第4~5位。本项目面向乳腺癌早期诊断和个性化治疗的重大需求，提出将SERS光谱多维编码表征方法与微流控芯片技术结合，研制用于血液乳腺癌特征物on-site检测的多参量SERS微流控芯片。该芯片集血液样品处理和分析于一体，可从循环肿瘤细胞、蛋白质、核酸多个层面实现乳腺癌特征物的高灵敏、高通量和高特异性的联合检测，克服单一特征物检测的不足，提高乳腺癌诊断（含分子亚型鉴别）和预后评估的准确性，为快速制定个性化治疗方案提供有力支撑。项目拟围绕该新型SERS检测芯片的基本理论、设计制备和在乳腺癌特征物检测中的应用展开研究。发展基于空间/光谱编码等手段的多维SERS编码及成像方法，解决基于SERS的乳腺癌特征物检测芯片的设计、制作与检测的技术难点，发展具有自主知识产权的SERS微芯片，为小型、便携、个体化的重大疾病实时诊断平台提供设计思路和技术支持。

本项目围绕新型SERS生物检测芯片的基本理论、设计制备及其在乳腺癌特征物检测中的应用展开研究，取得了一系列成果。项目研究在Chemical Reviews、ACS Nano等国际刊物上发表SCI论文45篇（标注45篇），其中影响因子IF > 10.0的8篇，影响因子IF > 5.0的26篇；申请发明专利24项，已授权发明专利8项；培养国家优秀青年科学基金获得者1名、博士研究生5名、硕士研究生23名。项目主要成果包括：（1）提出并制备了一组高灵敏、高重复性的新型SERS纳米探针和基底；（2）发展了基于SERS的多维编码方法，将SERS波数、强度编码和微通道芯片空间编码相结合，极大地提高了光谱编码能力；（3）设计了一系列基于SERS技术的乳腺癌肿瘤标志物检测芯片，从细胞、蛋白、DNA/RNA、外泌体多个层面实现对乳腺癌特征物的高通量、高灵敏度、宽动态范围的联合检测。上述研究成果为乳腺癌的早期诊断、个性化治疗和预后评估提供了一个强有力的工具，同时为发展重大疾病实时诊断平台提供了设计思路和技术支持。