pH-ROS双级响应近红外二区纳米探针用于乳腺癌及其肺转移的诊疗研究

Lung metastasis, as one of the most common metastatic sites in breast cancer, is highly lethal and located in deep tissue, which is difficult to detect breast cancer in early stage and micro-metastases. Optical nanoprobes in near-infrared II (NIR-II) region, with advantages of high tissue penetration depth and sensitivity, are suitable for molecular imaging of micro-metastases in deep tissue and the combination of photothermal/photodynamic therapy (PTT/PDT) for breast cancer. In this research, ROS-responsive NIR-II fluorescent prodrugs for tumor microenvironment will be developed and then encapsulated in pH-responsive metal-organic framework to construct pH-ROS dual-responsive NIR nanoprobes. The nanoprobes can be used as NIR-II fluorescence/photoacoustic (FL/PA) contrast agent, with specific activatable NIR-II FL/PA signals in tumor microenvironment for the localization of breast cancer tumors and lung metastases, as well as monitoring release of drugs. In addition, the nanoprobes can be used for PTT/PDT to enhance the treatment efficiency of targeted chemotherapy. Integrating tumor microenvironment-responsive imaging and treatments, the nanoprobes may realize the early detection, positioning and treatment of lung metastasis of breast cancer and provid a new strategy for the diagnosis and treatment of breast cancer, which has great significance in cancer research.

肺转移是乳腺癌转移的常见转移部位之一，致死率高且位于组织深部，早期乳腺癌和微小转移灶难以检出。近红外二区(NIR-II)光学纳米探针具有组织穿透深度高、灵敏度高等优势，适于深层组织中微小转移灶的分子成像，且具有良好的光热或单线态氧产生效率，可实现乳腺癌的光热-光动力联合治疗。本项目拟研制肿瘤微环境ROS响应性NIR-II荧光前药，并将其载入pH敏感的金属有机框架中，构建pH-ROS双级响应NIR-II纳米探针。该探针可作为NIR-II荧光/光声造影剂，在肿瘤微环境中特异性激活NIR-II荧光/光声信号，定位乳腺癌肿瘤及肺转移病灶，同时监控药物释放过程，并通过光热/光动力治疗增强靶向化疗效率，实现乳腺癌及其肺转移的特异性诊疗一体化。该探针集肿瘤微环境响应成像、肿瘤微环境响应治疗等协同诊疗于一体，实现乳腺癌肺转移的早期检出、定位、治疗监控，为乳腺癌诊疗提供全新策略，具有重要的研究意义。

乳腺癌是最常见的恶性肿瘤之一，其致死率在我国女性癌症患者中高居首位。乳腺癌肺转移是乳腺癌转移的常见转移部位之一，早期无特殊症状。传统影像学检查难以发现早期乳腺癌、微小转移灶及肿瘤治疗后基因和细胞水平发生的改变。近红外二区(NIR-II)光学纳米探针具有组织穿透深度高、灵敏度高等优势，适于深层组织中微小转移灶的分子成像，且具有良好的光热或单线态氧产生效率，可实现乳腺癌的光热-光动力联合治疗。本课题围绕肿瘤微环境特征、探针聚集状态、体内代谢过程等要素，设计构建了三种肿瘤微环境响应型纳米探针，并将其用于乳腺癌体内外模型的可视化光学诊疗，探索提升乳腺癌诊治准确率、有效性及安全性的新途径。本项目主要开展了以下三种肿瘤微环境响应型纳米探针的研究：1）pH-ROS级联响应型可视化纳米探针通过干扰细胞能量代谢增效三阴性乳腺癌光动力治疗（PDT）；2）纤连蛋白靶向的近红外二区（NIR-II）荧光/光声纳米探针，用于乳腺癌及其肺转移的NIR-II荧光/光声成像和光热治疗（PTT）；3）波长可调的蝶状分子与动态纳米组装体，用于三阴性乳腺近红外荧光/光声/CT成像和PTT/PDT联合治疗。本项目构建并评估了三种乳腺癌微环境响应型纳米探针的理化性能，体外验证了纳米探针与乳腺癌细胞靶向性能；体内完成了纳米探针在乳腺癌荷瘤小鼠的生物学分布评估，并在体验证了其在乳腺癌皮下移植瘤及肺转移小鼠体内靶向成像和治疗的功能。综上所述，本项目的研究表明乳腺癌微环境响应型纳米探针不仅有效提高了乳腺癌及其肺转移的诊断精准度和治疗效率，且有望为研发安全性高的乳腺癌诊疗一体化分子探针提供重要的科学依据和理论基础，具有重要的潜在临床价值。