具有聚集诱导发光特征的高效肺癌双靶向放疗增敏剂系统的设计和临床前研究

The early diagnosis of lung cancer and the enhancement of radiotherapy are a difficult problem. It is urgent to construct radiosensitizers with strong targeting, good water solubility, low cytotoxicity and high radiosensitization efficiency. Aggregation-Induced Emission (AIE) materials have strong luminescence properties and a variety of potential biomedical values in the aggregate state; dual-target-specific nanoparticles have good performance and are ideal target carriers; Perfluorocarbon (PFC) is biosafety and can transport oxygen efficiently. We intend to use polyethylene glycol polymers (PEG) to encapsulate AIE molecules and PFC materials as nanoparticle cores, and outer terminals of the nanoparticles will be conjugated with two monoclonal antibodies which targeting EGFR and PD-L1 by covalent bond, finally construct dual-targeted radiosensitizer nano-systems for lung cancer cells. It can overcome many shotcomings of conventional radiosensitizers, such as the low targeting ability, poor biocompatibility, low radiosensitization efficiency and the inability to solve the radioresistance caused by hypoxia. The proposed AIE molecule has photothermal or photodynamic therapeutic effects, which can be synergistic with radiotherapy effects and verified by cell and lung cancer nude mouse models. Simultaneously combined with near-infrared imaging and photoacoustic imaging brought by AIE molecules, lung cancer early targeted imaging of tumor tissue in lung cancer nude mouse models can be achieved. This project mainly solves the key problem of poor radiotherapy for lung cancer, and provides a solid experimental basis and theoretical basis for improving the effect of radiotherapy for lung cancer.

肺癌的早期诊断和放射治疗效果增强是一项难题，构建靶向性强、水溶性好、细胞毒性低和放射增敏效率高的放射增敏剂迫在眉睫。聚集诱导发光（AIE）材料在聚集状态下具有强烈的发光性能和多种潜在的生物医学价值；双靶点特异性的纳米颗粒性能良好，是理想的靶向载体；PFC的生物安全性好，能高效运送氧气。我们拟应用PEG聚合物封装AIE分子和PFC为纳米颗粒核心，外侧偶联分别靶向EGFR和PD-L1的两种单抗，构建肺癌细胞双靶向的纳米放射增敏剂。它可以克服常规放射增敏剂靶向性低、生物相容性差、放射增敏效率低和乏氧导致的放射抵抗等不足。拟设计的AIE分子拥有光热或光动力治疗效应，可与放疗相协同，并经细胞和裸鼠模型验证；同时结合AIE分子所带来的近红外或光声成像，实现裸鼠肿瘤组织的早期靶向显像。本项目可解决肺癌难以早期诊断和放疗效果不佳的关键问题，为肺癌的临床早期诊断及放疗效果的增强提供坚实的实验基础和理论依据。

肿瘤的精准诊疗意义重大，基于光激活疗法的光热治疗和光动力治疗具有重要的科学价值和临床意义。同时设计具有肿瘤标志物靶向或细胞器靶向等的纳米探针，以及采用近红外或双光子激活以进行组织深层次激发的光敏剂、光热剂对于肿瘤的靶向诊疗作用显著。因此，我们设计了具有聚集诱导发光性质的高性能靶向治疗荧光探针，在光物理化学及细胞或活体层面上进行了验证工作，取得了一系列研究成果，构建了结构简单、性能优越的有机小分子探针并进行了深入研究。通过本项目的的实施，课题组取得了如下的科研进展：（1）构建了基于聚集诱导发光性质细胞器靶向探针，包括多种脂滴靶向探针，探讨了其细胞器靶向性、双光子吸收性能和细胞、冰冻切片和活体的双光子成像及光动力治疗应用，（2）设计了具有明亮红光发射的EGFR靶向性AIE纳米探针的构建及细胞层面研究，并明确了其细胞内吞途径，靶向部位和双光子吸收和双光子成像等性能，（3）开发具有聚集诱导发光性能或基于卟啉类小分子自组装纳米材料的诊疗一体化纳米探针，在体外测试中明确单重分子的双重效果，即光动力治疗与光热治疗相协同对肿瘤的精准诊疗应用研究，（4）设计具有简易化学结构的线粒体靶向荧光探针，以用于线粒体成像及光动力治疗研究，同时能够实现对抗生素金刚烷胺进行高灵敏度检测等方面的研究工作。本研究通过实验测试与理论探讨相结合，为肿瘤的精准诊疗及协同增强治疗提供了新的思路，进一步丰富了荧光探针的合成和纳米探针的设计策略。在本项目的资助下，项目主持人以第一作者或通讯作者在国际上知名或权威的学术期刊上发表高水平SCI论著7篇，获得河南省科技进步二等奖1项，指导博士研究生2名，硕士研究生2名。

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