基于近红外LSPR活性星形纳米金的新型多功能SERS探针构建及其在癌症诊疗中的应用研究

Breast cancer is the most commonly diagnosed cancer among Chinese women, and the human epidermal growth factor receptor 2 (HER2, also called ERBB2) is a critical biomarker overexpressed in breast cancer, the status of which has important implications for prognosis and therapeutic decision-making of breast cancer. Considering excellent near-infrared photothermal effect from plasmonic gold nanostar and excellent specificity of Herceptin toward HER2, this proposal is to develop a novel multifunctional surface-enhanced Raman scattering (SERS) probe that is integrated with light-triggered photothermal/Herceptin dual-modal therapy for breast cancer. In this design, the SERS detection result can be used to decide if the light controllable dual modal therapy is implemented, which thus improves the controllability of therapy and reduces the side effect. First, we will develop a near-infrared multifunctional SERS probe of both photothermal therapy and Herceptin therapy, optimize the photon-to-heat conversion efficiency and investigate light controllable release of Herceptin drug, to achieve optimal synergistic therapy parameters. Then, we will investigate the cell-to-cell heterogeneity of HER2 expression in single live cells of different breast cancer cell lines, and elucidate the effect of therapy on HER2 expression. Finally, we will evaluate the in vivo detection of cancer cells and tumor, examine the dual modal therapeutic efficacy, and assess its application in intraoperative guide for removal of residual cancer cells in a breast cancer tumor xenograft mouse model. Therefore, expectedly, this proposal will provide a new avenue for early diagnosis and personalized therapy of breast cancer, which is of fundamental and applicable significance for breast cancer care.

乳腺癌是威胁中国女性健康的第一大恶性肿瘤，而HER2是乳腺癌异常表达的重要生物分子，其状态是预后判断和制定治疗方案的重要参考指标。利用星形纳米金优异的近红外光热效应和赫赛汀对HER2的特异性识别，本课题拟研制兼具光热-药物双模式治疗功能的新型表面增强拉曼散射（SERS）探针，实现乳腺癌超灵敏检测和光控双模式治疗。SERS检测结果可用来决策是否实施近红外光诱导的双模式治疗，增强治疗的可控性和减少副作用。首先，研制兼具近红外光热-赫赛汀药物双模式治疗的多功能SERS探针，优化光热转换效率和揭示赫赛汀药物光控释放动力学规律，获得双模式协同治疗优化参数。然后，研究乳腺癌活细胞HER2表达的异质性及治疗时HER2表达的动态变化规律。最后，评估多功能SERS探针对体内癌细胞和肿瘤组织的检测性能及双模式治疗疗效。本课题的完成将为乳腺癌早期检测和靶向精确治疗提供一种新思路和新技术，具有重要的实际意义。

乳腺癌是中国女性第一大恶性肿瘤，早期诊断和高效靶向治疗是提高乳腺癌治愈率以及改善患者治疗后生存质量的关键。本项目旨在探索面向乳腺早期诊断的高性能SERS传感技术和构建新型乳腺癌光学诊疗平台，实现乳腺癌精准分型和HER2+乳腺癌靶向治疗，以及构建乳腺癌多模态治疗可视化平台。主要研究成果包括：（1）开发了高性能近红外一区（NIR-I）多刺状Au纳米结构、近红外二区（NIR-II）框架和多孔Au-Ag结构以及NIR-II活性Au-Cu2-xSe异质结，建立了可控合成方法学，阐明了结构与表面等离激元性质的关系；（2）发展了SERS-垂直流纸基检测技术，实现外泌体蛋白多重定量剖析，从而可对乳腺癌无创诊断和分型；将深度学习和SERS检测技术结合发展了基于外泌体谱学剖析的乳腺癌分型方法，亦可对乳腺癌术后效果进行无创评估；此外，我们将机器学习与SERS结合实现了在细胞水平上乳腺癌治疗过程中HER2表达的动态连续监测；（3）开发了高性能多功能近红外SERS探针，实现了乳腺肿瘤活体SERS成像、术中微肿瘤高灵敏SERS检测以及术中实时清除，显著提高了乳腺癌治疗效果；（4）发展了高性能光学诊疗一体化平台，我们研制了一种集成NIR-II表面等离激元材料的三酶级联MOF诊疗平台，实现了光控饥饿治疗、化学动力学治疗和光热治疗高效联合乳腺癌治疗；还开发了基于Au-Cu2-xSe异质结的NIR-II光学诊疗平台，实现了单一波长光下成像指导的光热/光催化/化学动力学多模态治疗。相关研究成果在Nature Communications、Advanced Materials、Angewandte Chemie International Edition、Advanced Functional Materials和Nano Letters等本领域主流学术期刊上发表学术论文26篇，其中IF>10的论文16篇，授权国家发明专利1项，培养了博士生2名，硕士生8名。完成了项目预期目标。