近红外二区增强拉曼探针及其组织穿透深度研究

In vivo biomedical imaging in the second near-infrared window (NIR-II) of 1000-1700 nm can enormously improve the imaging depth and spatial resolution by reducing scattering, absorption, and autofluorescence of biological tissues, showing great significance in the biomedical studies and clinical applications. Surface-enhanced Raman spectroscopy (SERS) tags are featured by high sensitivity and fingerprint spectroscopy, which are promising optical probes for in vivo bioimaging. However, studies of SERS imaging in NIR-II region and its applications are underdeveloped due to lack of suitable NIR-II SERS tags. In this project, we aim to design the NIR-II SERS tags named as gap-enhanced Raman tags (GERTs). By embedding Raman-active molecules in internal metallic nanogaps, and precisely adjusting nanogap sizes in the range of 3-5 nm, the longer wavelength resonance peak of GERTs can be tuned to NIR-II and thus induce the strong enhanced Raman signal in this region. GERTs also show advantages including high sensitivity, high photostability and reproducibility, good biocompatibility and targeting ability, which are expected to achieve Raman imaging with deeper tissue penetration and higher spatial resolution. Furthermore, in this work GERTs will serve as promising tags to study the attenuation and penetration of NIR-II SERS signal through biological tissues, which can promote the fundamental researches and translational medicine of Raman-based imaging.

近红外二区的在体光学成像由于降低了生物组织的散射、吸收及自发荧光，能够极大提升成像深度和空间分辨率，对于生物医学研究和临床应用有重要意义。表面增强拉曼光谱（SERS）探针具有高灵敏度和特征指纹光谱，是理想的光学成像探针。但目前基于近红外二区SERS的研究和成像应用较少，重要原因是缺乏适合的近红外二区SERS探针。本课题拟设计和开发一种基于缝隙增强拉曼探针的近红外二区SERS探针。将拉曼分子包埋在金属纳米探针的内部缝隙中，精确调节缝隙尺寸为3-5纳米，使探针的长波共振峰调谐至近红外二区，从而在该波长范围获得显著信号增强；探针具有高灵敏度、高光稳定性和重复性、良好靶向性和生物安全性等优势，有望实现深穿透和高分辨率的拉曼成像。同时，缝隙增强拉曼探针能够作为可靠材料，用于本课题来研究近红外二区SERS在生物组织中的穿透深度和衰减规律，这对拉曼成像技术的基础研究和临床转化均有显著参考价值。

本项目聚焦于近红外二区拉曼探针的开发及其信号组织穿透深度研究，拟通过新的思路来设计一种在近红外二区波长窗口内具有较高灵敏度的宽内隙结构缝隙增强拉曼探针，并探索近红外拉曼光谱信号在生物组织内的传播和衰减规律。主要研究内容包括：（1）通过理论验证了宽内隙结构的缝隙增强拉曼探针的生长机理，并利用金银电化学置换反应制备出宽内隙结构的缝隙增强拉曼探针纳米颗粒，证实其在近红外二区波长窗口内具有较高灵敏度。（2）定量研究了基于共振策略（即采用共振基底和共振信号分子）制备的近红外二区拉曼探针的性能和增强因子。此外也开发了非共振的金银合金结构探针，在提升信号强度的同时降低颗粒光热效果，从而提高信号的光稳定性，为基于近红外二区拉曼探针的在体生物医学成像应用奠定基础。（3）对近红外拉曼光谱信号在生物组织中衰减规律和穿透深度进行了系统研究，揭示了穿透深度与信号源原始信噪比之间的线性对数关系，为基于拉曼光谱的体内生物检测应用提供了关键标准和新见解。项目共发表期刊文章10篇，总影响因子>60分，其中影响因子10分以上的高水平SCI文章3篇。申请中国发明专利2项。参与国内外学术会议4人次。项目取得了理想的科研成果，达到了预期目标。

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