FAP和α_(Ⅴ)β_(3)双靶向分子标记物的结构优化及其在荷瘤鼠体内的生物分布研究  

Structure Optimization and Their Biodistribution in Tumor-bearing Mice on FAP and α_Ⅴβ_(3) Dual Targeting Molecular Probes

作　　者：吴晓明 田国新 文雪君 何田 马福秋[1,3] 薛云 WU Xiaoming;TIAN Guoxin;WEN Xuejun;HE Tian;MA Fuqiu;XUE Yun(College of Nuclear Science and Technology,Harbin Engineering University,Harbin 150001,China;Yantai Lannacheng Biotechnology Co.,Ltd.,Yantai 264199,China;Yantai Research Institute,Harbin Engineering University,Yantai 264006,China;Yong Loo Lin School of Medicine,National University of Singapore,Singapore 119074,Singapore)

机构地区：[1]哈尔滨工程大学核科学与技术学院,黑龙江哈尔滨150001 [2]烟台蓝纳成生物技术有限公司,山东烟台264199 [3]哈尔滨工程大学烟台研究院,山东烟台264006 [4]新加坡国立大学杨潞龄医学院,新加坡119074

出　　处：《原子能科学技术》2025年第4期803-815,共13页Atomic Energy Science and Technology

基　　金：山东省重点研发计划“核动未来”科技示范工程项目(2023SFGC0101)。

摘　　要：为避免单靶标记物检测肿瘤时易出现误诊漏诊,本文设计并合成了能同时靶向FAP和α_(V)β_(3)受体的两种异源二聚体放射性显像剂^(68)Ga-FAPI-RGD-01和^(68)Ga-FAPI-RGD-02,并对其进行了microPET显像研究和初步U87MG荷瘤鼠生物分布研究。高效液相色谱分析结果表明,二者均具有良好的体外稳定性,无论是在生理盐水体系还是在胎牛血清体系中均可以维持大于95%的放化纯度。U87MG荷瘤鼠的microPET显像结果表明,相比于^(68)Ga-FAPI-RGD-01,^(68)Ga-FAPI-RGD-02具有更高的肿瘤摄取比,以及更低的心脏、肝脏、肾脏和肌肉组织摄取,表明其具有优异的药代动力学性能和肿瘤显像效果。以上结果表明,^(68)Ga-FAPI-RGD-02具有临床疾病诊断的巨大潜力。Fibroblast activation protein(FAP) is a crucial biomarker for the activation of tumor associated fibroblasts,served as an excellent target for both the diagnosis and treatment of cancer.In recent years,a variety of quinoline-based FAP inhibitors(FAPIs) have been developed,such as FAPI-02,FAPI-04 and FAPI-46,which were used to positron emission tomography(PET) imaging for clinical patients.However,high expression of FAP also occurs in chronic inflammation,fibrosis,arthritis,atherosclerotic plaques and cardiac fibrosis,which results in a compromised sensitivity/selectivity in distinguishing cancers from other FAP-positive diseases,such as chronic inflammation and fibrosis.Additionally,integrin receptor α_Vβ_(3) highly expresses on the surface of various tumor cells and neovascular endothelial cells,including those in lung cancer,glioblastoma,breast cancer,and osteosarcoma,but absent in resting endothelial cells of normal tissues.Integrin receptor α_Vβ_(3) plays an important role in regulating tumor growth,angiogenesis,local invasiveness,and metastatic potential.However,RGD-based radiotracers,including multimeric RGD peptides with enhanced integrintargeting efficiency have only moderate tumor uptake.Based on this,in this paper two heterologous dimeric radiotracers,^(68)Ga-FAPI-RGD-01 and ^(68)Ga-FAPI-RGD-02,were designed and synthesized,which are based on the quinoline-based FAPI-02 for targeting FAP,a cyclic RGD peptide for targetingα_(V)β_(3),a 1,4,7-triazacyclononanetriacetic acid(NOTA) group for radionuclide labeling,and poly(ethylene glycol) linker.And then,the two radiotracers were used to study the microPET imaging and preliminary biodistribution in U87MG tumor-bearing mice.The excellent in vitro stability of both 68GaFAPI-RGD-01 and ^(68)Ga-FAPI-RGD-02 was confirmed through high-performance liquid chromatography analysis,which could maintain radiochemical purity over 95% in PBS buffer solution or in serum medium for at least 4 h.The radiotracers also show favorable binding affinity and specificity thro

关 键 词：放射性标记物 成纤维细胞 整合素受体α_Vβ_3 FAPI-RGD 

分 类 号：TL923[核科学技术—核燃料循环与材料]