摘要
为探究氟铝[^(18)F]AlF标记的靶向成纤维细胞激活蛋白(FAP)和整合素α_(Ⅴ)β_(3)受体的异源二聚体探针1,4,7-三氮杂环壬烷-1,4,7-三乙酸-FAP抑制剂精氨酸-甘氨酸-天冬氨酸(NOTA-FAPI-RGD),评价其在FAP表达阳性荷瘤裸鼠模型中的小动物PET显像研究和初步临床应用,本研究采用先前研究优化的氟铝标记方法进行[^(18)F]AlF-NOTA-FAPI-RGD标记,并将[^(18)F]AlF-NOTA-FAPI-RGD在HT1080-FAP肿瘤细胞中完成细胞摄取和抑制实验及体外特异性摄取评估,通过荷瘤鼠的PET显像,观察[^(18)F]AlF-NOTA-FAPI-RGD在HT1080-FAP肿瘤模型中的分布。同时分别进行NOTA-FAPI-02、NOTA-RGD和NOTA-FAPI-RGD三种抑制剂与放射性探针共同注射后的PET显像,及[^(18)F]AlF-NOTA-FAPI-02和[^(18)F]AlF-NOTA-RGD的PET显像,以评估体内双靶向特异性。此外,还进行了临床患者的初步PET显像研究,以评估其临床诊断效果。结果显示,本研究成功合成了FAP和α_(Ⅴ)β_(3)受体双靶向放射性探针[^(18)F]AlF-NOTA-FAPI-RGD,其在HT1080-FAP肿瘤细胞内120 min时总摄取率达44.66%±0.26%,在用NOTA-FAPI-02、NOTA-RGD、NOTA-FAPI-RGD分别进行抑制时,放射性摄取降低为0.46%±0.04%、37.61%±1.21%和0.16%±0.02%,P<0.01,证明了其双靶向特异性。荷瘤鼠PET显像结果显示,[^(18)F]AlF-NOTA-FAPI-RGD在体内表现出优异的药代动力学特征,肿瘤摄取在0.5 h可达(9.67±1.23)%ID/g,滞留时间长,给药后6 h肿瘤摄取仍有(8.10±1.35)%ID/g,且肿瘤摄取可以分别被NOTA-FAPI-02、NOTA-RGD和NOTA-FAPI-RGD所抑制。对照组示踪剂[^(18)F]AlF-NOTA-FAPI-02和[^(18)F]AlF-NOTA-RGD展现出更低的肿瘤摄取和滞留。此外,[^(18)F]AlF-NOTA-FAPI-RGD在临床乳腺癌患者的PET图像也展示出更高的病灶放射性摄取(SUVmax=12.41),显著高于[^(18)F]F-FDG(SUVmax=7.45),P<0.01。[^(18)F]AlF-NOTA-FAPI-RGD在体内外实验中均展示了双靶向特异性摄取,相比于单靶点示踪剂具有明显优势,该示踪剂不仅在临床前研究中呈现出良好的成像质量,在初步临床实验中也展现出优异的肿瘤病灶检出率,表明[^(18)F]AlF-NOTA-FAPI-RGD有望成为一种用于检测FAP和/或α_(Ⅴ)β_(3)受体高表达肿瘤的放射性示踪剂,且具有临床应用前景。
This study aims to investigate the heterodimeric probe[^(18)F]AlF-labeled targeting both fibroblast activation protein(FAP)and integrin receptorα_(Ⅴ)β_(3):1,4,7-triazacyclononane-1,4,7-triacetic acid-FAP inhibitor-arginine-glycine-aspartic acid(NOTA-FAPI-RGD)for its potential application in small-animal PET imaging of FAP-positive tumor-bearing nude mouse models and its preliminary clinical application.[^(18)F]AlF-NOTA-FAPI-RGD was synthesized using an optimized[^(18)F]AlF-labeling method developed in previous studies.Cellular uptake and blocking experiments were performed in HT1080-FAP tumor cells to evaluate specific uptake in vitro.PET imaging was conducted in HT1080-FAP tumor-bearing mice to observe the distribution of[^(18)F]AlF-NOTA-FAPI-RGD in the HT1080-FAP tumor model.Competitive PET imaging was performed by co-injection of NOTA-FAPI-02,NOTARGD,and NOTA-FAPI-RGD inhibitors,respectively,alongside imaging using[^(18)F]AlF-NOTA-FAPI-02 and[^(18)F]AlF-NOTA-RGD,to assess dual-target specificity in vivo.In addition,preliminary clinical PET imaging was also performed in breast cancer patients to evaluate its diagnostic performance.The dual-target radiotracer[^(18)F]AlF-NOTA-FAPI-RGD is successfully synthesized and evaluated in this study.It exhibites significant uptake in HT1080-FAP tumor cells;Cell uptake can reach up to 44.66%±0.26%.After being blocked with NOTA-FAPI-02,NOTA-RGD,and NOTA-FAPI-RGD inhibitors,the cell uptake decreases to 0.46%±0.04%,37.61%±1.21%,and 0.16%±0.02%,with P<0.01,which confirms the dual-target specificity of[^(18)F]AlF-NOTA-FAPI-RGD.In HT1080-FAP tumorbearing mice,PET imaging demonstrates that[^(18)F]AlF-NOTA-FAPI-RGD displays excellent pharmacokinetics,with high tumor uptake and prolonged retention time:Tumor uptake can reach up to(9.67±1.23)%ID/g at 0.5 h,and 6 h post-injection,tumor uptake still retains(8.10±1.35)%ID/g.Tumor uptake is effectively inhibited by NOTA-FAPI-02,NOTA-RGD,and NOTA-FAPI-RGD inhibitors,which demonstrates the dual-targeting specificity for both FAP and integrin receptorα_(Ⅴ)β_(3).In contrast,the control radiotracers[^(18)F]AlF-NOTA-FAPI-02 and[^(18)F]AlF-NOTA-RGD show lower HT1080-FAP tumor uptake and retention,which indicates the superiority of[^(18)F]AlF-NOTA-FAPI-RGD.Furthermore,clinical PET imaging in breast cancer patients demonstrates a greater lesion uptake value for[^(18)F]AlF-NOTA-FAPI-RGD(SUVmax=12.41)compared to[^(18)F]FDG(SUVmax=7.45).[^(18)F]AlFNOTA-FAPI-RGD demonstrates dual-targeting specificity for both FAP and integrin receptorα_(Ⅴ)β_(3),as well as high tumor uptake and prolonged tumor retention in both preclinical and clinical studies.Compared to single-targeting tracers,it shows superior imaging quality and lesion detection.These results highlight the potential of[^(18)F]AlF-NOTA-FAPI-RGD as a radiotracer for diagnosing tumors with high FAP and/or integrinα_(Ⅴ)β_(3)expression,which offers promising prospects for clinical application.
作者
吴晓明
文雪君
薛云
田国新
林敏
唐铭泽
马福秋
WU Xiaoming;WEN Xuejun;XUE Yun;TIAN Guoxin;LIN Min;TANG Mingze;MA Fuqiu(College of Nuclear Science and Technology,Harbin Engineering University,Harbin 150001,China;Yantai Lannacheng Biotechnology Co.,Ltd.,Yantai 264199,China;Yong Loo Lin School of Medicine,National University of Singapore,Singapore 119074,Singapore;Yantai Research Institute,Harbin Engineering University,Yantai 264006,China)
出处
《原子能科学技术》
2026年第1期247-256,共10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)。
