新型FSHR靶向探针18F-X-FSH33-53的研制及在前列腺癌诊断中的应用研究

Prostate cancer is one of the most common cancers in men. Traditional examination methods such as PSA screening, CT and invasive biopsy ,may result in overtreatment or undertreatment due to low specificity and sensitivity. PET plays an important role in diagnosis and prognosisin oncology. Developing specific PET probes is benefit for successful diagnosis and treatment of prostate cancer.Follicle-stimulating hormone receptor (FSHR) is a potential marker of tumor. FSHR is overexpressed at the tumor periphery and always negative in normal and benign tissues. In this project, the novel PET imaging agents targeting FSHR, 18F-Al-NOTA-MAL-GGGRDN-FSH33-53 and 18F-Al-NOTA-MAL-Rn-FSH33-53, were designed based on FSH33-53 after modification. Al18F complex method was used to simplify the labeling procedure. To our knowledge, it is the first report in the world.Through in vitro competitive cell binding assay and in vivo microPET imaging, the optimal FSHR probe with high specificity and good in vivo characters was obtained. Feasibility of prostate cancer imaging with the probe are evaluated at in situ and metastatic tumor models. The achievements will supply a novel strategy for design the probe and provide a new technology for differential diagnosis, assessment therapeutic effect and prognosis of prostate cancer.

前列腺癌是一种严重影响男性健康的恶性肿瘤。现有检查方法存在特异性、灵敏性低等缺陷，可致治疗过度或不足。PET在肿瘤诊断和预后方面具有重要价值，开发新型特异性PET探针将有利于前列腺癌的成功诊治。卵泡刺激素受体（FSHR）是潜在的前列腺癌靶向标志物，在肿瘤表层高表达，而正常和良性组织中不表达或低表达。本课题以FSHR为靶标，研制用于前列腺癌的靶向PET探针，国内外未见报道。拟以FSH33-53为载体，经亲水性连接剂(GGGRDN)或穿膜肽(Rn,n=0,5,7,9,11)修饰后,应用氟化铝标记新策略制得18F-GGGRDN-FSH33-53、18F-Rn-FSH33-53, microPET快速筛选出最佳探针18F-X-FSH33-53。建立肿瘤模型，考察此探针用于前列腺癌诊断的可行性。项目若成功，将为多肽探针的设计、合成提供新思路，为前列腺癌的诊断提供新技术，具有重要的学术价值和社会效益。

前列腺癌是一种严重影响男性健康的恶性肿瘤，卵泡刺激素受体（FSHR）是潜在的前列腺癌靶向标志物，本项目以FSHR为靶标，以FSH33-53为载体，研制用于前列腺癌早期诊断的靶向PET探针。本项目组用亲水性连接剂（GGGRDN）和穿膜肽(Rn,n=0,5,7,9,11)对FSH33-53进行修饰，用氟化铝标记策得到FSHR特异性PET探针。临床前研究表明，穿膜肽精氨酸连接剂未能明显提高肿瘤摄取值和延长瘤内滞留时间，而亲水性连接剂GGGRDN修饰的前体肽18FAl-NOTA-MAL-GGGRDN-FSH33-53（记作18FAl-FSH2）提高了肿瘤摄取值（2.68±0.50%ID/g），虽然瘤内滞留时间未能明显改善，但大大降低了动物腹腔显影，展现出了良好的显像性能。18FAl-FSH2标记率达到40%，且体内稳定，前列腺癌荷瘤鼠MicroPET显像证实18FAl-FSH2在所筛选的FSH33-53序列中，体内显像性能最优，特异性和靶向性良好，可以用来进行前列腺癌早期诊断。进一步研究，我们发现抑肽酶协同18F-Al-NOTA-MAL-FSH2注射能明显增强肿瘤摄取，大大延长瘤内滞留时间。尾静脉注射1h后，肿瘤摄取值达到了9.21%ID/g，。我们也尝试FSH33-53联合细胞穿膜肽IIKK用于肿瘤靶向诊疗，研究结果显示FSH33-53联合细胞穿膜肽IIKK能够抑制肿瘤的生长，且使用安全。这项研究可能为其它抗肿瘤、诊疗一体化靶向肽的设计提供新的见解。