近红外II区可代谢表面增强拉曼探针的构建及其肿瘤精准术中导航研究

Precise positioning and complete resection of malignant tumors is a great challenge for tumor surgery. Effective intraoperative navigation technology can improve the accuracy and safety of surgery greatly. Surface-enhanced Raman scattering (SERS) imaging with the advantages of high sensitivity, high resolution, fingerprint spectrum, and low photobleaching has excellent prospects in the field of tumor intraoperative navigation. However, the reported SERS imaging usually use SERS probes in visible and near infrared I window, which has limited imaging penetration depth and unable to detect deep tumors. In addition, the probes are difficult to metabolize after entering the body, resulting in a long-term toxicity risk. To solve the above two problems, this project proposes to construct a kind of degradable SERS tags in near-infrared II (1000-1700nm) window, which has deeper imaging penetration depth, better biocompatibility and can be used for intraoperative image navigation of deep tumors and then metabolized out of the body. We intend to use the hydrophobic-hydrophobic self-assembly method to construct the degradable SERS probes in near-infrared II window with Raman molecules modified ultra-small gold nanorods and degradable biocompatible macromolecules. Then the SERS performance and biosafety of SERS tags are studied and optimized, and passively target tumors by intravenous injection to achieve intraoperative imaging navigation of deep tumor margins and microscopic lesions. This project is of great significance for promoting the clinical transformation research of SERS intraoperative imaging navigation.

恶性肿瘤的精准定位和完全切除是肿瘤手术面临的巨大挑战。有效的术中影像导航可以提高手术的精准性和安全性。表面增强拉曼散射（SERS）成像具有灵敏度高、分辨率高、指纹图谱、不易光漂白等优点，在肿瘤术中导航领域有极佳的前景。然而已报道的肿瘤SERS成像使用的多是可见光及近红外I区SERS探针，其成像穿透深度有限，难以探测深层肿瘤。并且探针进入体内后难以代谢，存在长期毒性风险。针对以上两个问题，本项目提出构建近红外II区（1000～1700nm）、可降解代谢SERS探针，其具备更深成像穿透深度和更好生物相容性，可用于深层肿瘤术中影像导航，并可代谢出体外。项目拟采用亲疏水自组装方法，通过修饰拉曼信号分子的超小金纳米棒和可降解的生物相容性高分子自组装，构建近红外II区可降解的组装体SERS探针，研究并优化其SERS性能和生物安全性，进而经静脉注射被动靶向肿瘤，实现深层肿瘤边缘及微小病灶的术中导航。

恶性肿瘤的精准定位和完全切除是肿瘤手术面临的巨大挑战。表面增强拉曼散射（SERS）成像具有灵敏度高、分辨率高、指纹图谱、不易光漂白等优点，叠加近红外二区激光的大穿透深度，在肿瘤术中导航领域有极佳的前景。本项目定位基于近红外二区SERS探针的肿瘤组织和前哨淋巴结的术中精准导航，聚焦SERS探针的构建与性能研究。经过3年时间的研究，我们基本上验证了本项目的研究设想的理论基础和实验可行性，构建了不同形貌的SERS探针，并用于肿瘤组织和转移前哨淋巴结的精准显影。主要工作包括：（1）用于术前和术中成像的多模态缝隙增强拉曼探针的设计、制备与应用；（2）超小金纳米棒组装体的构建与SERS性能研究；（3）比率表面增强拉曼探针用于转移前哨淋巴结的术中检测。（4）多功能纳米组装载药微球的构建及载药/释药性能研究。项目主要成果包括：（1）发展了一种可实现CT/MR/SERS多模态成像的探针，探针具有良好的生物相容性和生物安全性，在精确的术前CT/MRI诊断和术中拉曼成像指导下的癌症切除术方面具有巨大潜力。（2）构建了一系列基于金纳米棒和金纳米星的近红外二区共振SERS探针，实现了良好的信号增强和细胞成像效果，并扩展了载药微球研究体系。（3）开发了一种新的“双拉曼探针比率法”用于转移性前哨淋巴结的可视化和术中快速诊断，使用叶酸功能化的靶向和非靶向探针，基于拉曼成像结合经典的最小二乘数据处理方法来检测转移性SLN。该方法可以在术中快速诊断转移前哨淋巴结，并有望在未来指导外科手术。本项目的研究对于近红外二区SERS探针的制备和性能优化提供科学参考依据，对术中影像导航具有重要科学意义和应用潜力。