基于共轭高分子的pHe敏感型NIR-II肿瘤光学成像探针及光热疗的研究

Compared to the conventional near-infrared (NIR, 750–900 nm) imaging, New NIR-II (1.0–1.7 mm) fluorescence image has attracted much interest recently owing to higher spatial resolution at deeper tissue penetration depths. However, shortcomings of existing NIR-II fluorophores include relatively weak 800 nm absorption，low optical stability and biocompatibility，Smart response of tumor microenvironment .According to the above requirements, our project proposed to develop novel NIR-II fluorescence image probes based on water soluble conjugated polymer with a rapid response intelligent diagnostic system for tumor microenvironment. Firstly, the tumor targeting based on pHe responsive functional groups-modified block conjugated polymers with native strong 800nm absorption and photostability are firstly prepared through controllable radical polymerization. Then the polyethylene glycol chains are introduced to endow good water-solubility and biocompatibility. Secondly, the NIR-II fluorescence signal and aggregation relationships are investigated under different tumor microenvironment. In the meantime, we capitalized on the acidic, tumour microenvironment pHe to achieve the detection of tumour tissues in a broad range of mouse cancer regardless of their genotypes and phenotypes. Besides, the development of photothermal therapy against cancer using our probes is conducted by investigating the photo-thermal conversion performance based on their strong NIR absorption properties.Finally, the performance of the probes will be evaluated through investigating the NIR-II fluorescence imaging and photothermal therapy in vivo. We hope this work will be beneficial to developing high-performance NIR-II fluorescence probes for applications in biomedical theranostics.

新型近红外II区（NIR-II, 1.0-1.7 um）荧光成像技术相较于传统近红外（650–950 nm）成像技术具有更高光学对比度、更深组织穿透深度等优势而在肿瘤诊疗方面迅速受到关注。但该类技术目前缺乏穿透深度深、生物相容和光稳定性好、肿瘤智能靶向的NIR-II成像探针。因此，本课题提出开发基于共轭高分子的pHe敏感型NIR-II成像探针，即利用共轭高分子光稳定性好、吸光性强等特性，开发800 nm吸收（穿透深度深）的共轭高分子链，通过可控自由基聚合引入肿瘤微环境pHe响应基团，继而连接聚乙二醇提高其水溶性和生物相容性；研究肿瘤pHe刺激下该探针聚集态及相关NIR-II信号的变化以及由此产生的对广谱肿瘤的识别能力；并利用探针近红外光吸收的能力用于光热疗；使用裸鼠模型评价探针肿瘤靶向成像和治疗能力，发展NIR-II成像指导光热疗于一体的肿瘤诊疗模式，推动相关光学技术在生物医学领域应用。

荧光成像凭借灵敏度高、特异性强等诸多优势在重大疾病的诊疗领域发挥着重要作用。然而传统的近红外一区(NIR-I，700～900 nm)荧光成像存在组织穿透性差等问题，限制了其临床应用。近红外二区(NIR-II, 1000～1700 nm)荧光成像可以极大地减弱生物组织对光的吸收、散射和自发荧光，从而显著提升成像深度及成像效果。由于荧光成像依赖于目标-背景信号比值，而现有的NIR-II 荧光探针大多为“always on”型探针，会严重影响成像信噪比。与 “always on” 型NIR-II荧光探针相比，可激活型NIR-II荧光探针对生物组织具有特异靶向性、更高的成像信噪比和更低的检测限，可以帮助医学工作者从分子水平来获取不同疾病的病理参数和体内病理机制。首先，我们利用“双锁钥匙”概念构筑了双重疾病参数协同激活的纳米探针HISSNPs用于肿瘤超高特异性NIR-II荧光成像。其次，构筑了一例生物可擦除的分子间供-受体相互作用用于可激活NIR-II荧光成像探针。最后，构筑了一例NO智能响应的 NIR-II荧光纳米探针用于药物诱导的肝毒性实时监测。