新型高灵敏近红外SERS探针合成及其活体多元成像应用研究

As novel imaging technique and optical nanoprobe,Raman in vivo imaging technique and surface-enhanced Raman scattering (SERS) tags draw a lot of attention owing to the high sensitivity, high spatial resolution and multiplex labeling ability. So far, the study on SERS tags has been mainly focused on the noble metal nanosubstrate. However, the development of Raman reporter, which is another key factor affect the optical quality of SERS tags, is far lagged behind. In this program, we aim to resolve the problem of limit of types and random selection of Raman reporter during the SERS tag synthesis.Novel near infrared (NIR) reporters that suitable for in vivo SERS tag will be designed and screened. Libraries of molecules will be synthesized based on NIR dye core structures of squaraine and cyanine with the aid of combinational chemical synthesis technique, and subject to further reporter screening and preparation of NIR SERS tags with various fingerprt spectra for multiplex in vivo Raman imaging. Furthermore, liposomes with different surface charges will be labeled with SERS tags with various optical fingerprints. Taking advantages of laser Raman system, it will be realized that the simultaneous detection of various types liposomes in tumor node mouse by analyzing the characteristic Raman information of each tag. The acquisition of their tumor targeting features and in vivo pharmacokinetics information will also be achieved. Our investigation will greatly improve the optical performance of SERS tags and promote development of Raman imaging technique toward the direction of high throughput screening and real application.

表面增强拉曼散射 (SERS) 探针具有高灵敏度、高空间分辨率和多元标记等优势，在活体拉曼成像领域引起了极大关注。目前SERS探针研究主要集中于贵金属纳米基底，对其光学品质同样具有重要影响的拉曼报告分子(RR)的开发则严重滞后。本研究拟解决近红外（NIR）SERS探针制备中RR种类局限的根本问题，从SERS机理、探针组装和活体应用所需求的化学结构出发，利用组合化学手段，设计、合成和筛选基于方酸菁和花菁两类荧光染料母核的全新RR，开发具有多种光谱指纹特征、适用于活体多元标记的NIR SERS探针组合。进一步实现对不同电荷脂质体模型纳米药物的标记。通过解析活体小鼠特征组织部位各SERS探针的特征峰信号，实现不同靶向性质脂质体的体内同时监测，进一步获取其体内药动学参数信息。课题的实现将极大提升SERS探针的光学品质，推动拉曼活体成像技术向高通量筛选和实际应用方向发展。

本项目主要研究工作包括新型内标化SERS探针和荧光-SERS二元纳米光学探针的设计和制备；SERS探针标记脂质体方法和报告分子释放行为研究；基于SERS探针的多功能纳米诊-疗平台构建和性能评价。主要成果包括：（1）发展一种新型AuNR@reporter@Ag内标化SERS纳米探针并深入探讨了信号增强机制，该内标化探针展示了优良的体内信号稳定性。（2）探索了Au@Ag/AuSERS探针标记脂质体方法，研究了脂质体内不同报告分子标记SERS探针的环境刺激响应行为，验证了在脂质体内，报告分子的保留依赖于与金属表面和磷脂双层两方面的相互作用。（3）制备了以NaYF4:Yb,Er为上转换发光纳米材料为荧光母核的荧光-SERS二元纳米光学探针，展示了良好的细胞和活体标记能力，在生物组织的检测深度可达7 mm。（4）制备的Ag@SiO2@mTiO2壳核结构荧光-SERS复合探针探同时担载药物阿霉素用于癌症治疗，在肿瘤细胞实验中展现了二元标记和肿瘤治疗的潜在用途；合成的新型卵壳结构的纳米材料AuNR@void@mTiO2同时具有SERS成像和光热-化学复合治疗功能，是一个有实际应用潜力的治疗诊断平台。本项目结果为SERS探针技术在生物医药领域中的应用提供了有意义的实验依据和新的研究思路。发表SCI论文5篇，影响因子均大于7。协助培养研究生5名。