HIF-1α特异性18FEt-cyclo-CLLFVY肽PET探针的设计及其在肿瘤乏氧显像中的研究

The hypoxia-inducible factor-1 (HIF-1) transcription factor is an important regulator of tumor response to hypoxia, inflammation and tumor growth. This project based on the modification of cyclo-CLLFVY, which identified from a library of 3.2 million cyclic hexapeptide and plays as an inhibitor of the HIF-1α/HIF-1β protein-protein interaction. FEt-cyclo-CLLFVY would be synthesized and evaluated as candidate ligands analysis of HIF-1α/β interaction. The radioactive tracer 18FEt-cyclo-CLLFVY would be prepared for positron emission tomography (PET) imaging. By means of PET/CT’s high-resolution, tissue localization, 18FEt-cyclo-CLLFVY could directly provide the oxygen content in hypoxic tissue/ hypoxic state/HIF-1α expression. In brief, its biological targeting and cellular uptake mechanisms will be revealed. By the precisely detect the oxygen state, it can prediction efficacy and prognostic evaluation for tumor hypoxia. In the aspect of clinical tumor hypoxia imaging, it will be used for tumor detection, guide target radiotherapy and prognostic evaluation.

缺氧诱导因子(HIF-1) 是一种具有转录活性的核蛋白，其在氧稳态调节及肿瘤生长等方面有重要作用。本项目以首个可特异性阻断HIF-1α/β蛋白相互作用的cyclo-CLLFVY肽为基础，进行化学修饰，获得FEt-cyclo-CLLFVY肽，分析其对HIF-1α/β蛋白的作用关系。而后进行18F的标记，获得可用于PET显像的18FEt-cyclo-CLLFVY探针。在细胞水平研究其HIF-1α靶向性、蛋白作用关系、细胞乏氧水平等。借助PET/CT 的高分辨率等能力，研究肿瘤发生发展过程中，HIF-1α表达情况与肿瘤乏氧的定量关系。总之，本项目提出的新型HIF-1α靶向的18FEt-cyclo-CLLFVY肽PET探针，从分子水平，可获得通过HIF-1α与细胞中氧含量的关系及与相关受体蛋白的作用机制；从肿瘤临床乏氧显像而言，可直接提供肿瘤区域乏氧信息，指导放疗靶区勾画、肿瘤乏氧增敏及评价预后。

缺氧诱导因子（HIF-1）是一种具有转录活性的核蛋白，其在氧稳态调节与肿瘤生长等方面有重要作用。本项目以首个可特异性阻断HIF-1α/β蛋白相互作用的cyclo-CLLFVY六元肽为基础，对其进行化学修饰并进行放射性标记得到了68Ga/64Cu/Al18F-NOTA-CLLFVY。研究了标记条件对放射化学纯度的影响，稳定性，药代动力学情况及动物水平的生物分布和micror-PET成像，并与研究最多的乏氧探针18F-FMISO进行了简单的对比。结果证实，新型分子探针Al18F-NOTA-CLLFVY有望用于肿瘤乏氧区域及乏氧水平的探测。