Synthesis, Preclinical Evaluation, and a Pilot Clinical PET Imaging Study of (68)Ga-Labeled FAPI Dimer.
Synthesis, Preclinical Evaluation, and a Pilot Clinical PET Imaging Study of (68)Ga-Labeled FAPI Dimer.
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68Ga 标记的 FAPI 二聚体的合成、临床前评估和初步临床 PET 成像研究
DOI：
10.2967/jnumed.121.263016
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发表时间：
2022-06
影响因子：
9.3
通讯作者：
Chen, Haojun
中科院分区：
文献类型：
--
作者：
Zhao, Liang;Niu, Bo;Fang, Jianyang;Pang, Yizhen;Li, Siyang;Xie, Chengrong;Sun, Long;Zhang, Xianzhong;Guo, Zhide;Lin, Qin;Chen, Haojun
关键词：
视觉摘要肿瘤相关成纤维细胞(CAF)是肿瘤微环境的重要组成部分。成纤维细胞激活蛋白(FAP)在CAF中高表达。FAP靶向分子显像剂，包括FAP抑制剂(FAPIs)04和46，在肿瘤诊断中显示出良好的结果。然而，对于多肽靶向放射性核素治疗应用来说，这些分子具有相对较短的肿瘤保留时间。我们的目标是设计一种68Ga标记的FAPI二聚体68Ga-DOTA-2P(FAPI)2，以优化药物动力学，并评价这种形式是否比其单体类似物更有效。方法：在喹啉类FAPI突变体(FAPI-46)的基础上合成68Ga-DOTA-2P(FAPI)2，并测定其在CAF中的结合性能。用小动物PET和生物分布实验测定FAP阳性患者来源的异种移植物的临床前药代动力学。对3名健康志愿者进行了~(68)Ga-DOTA-2P(FAPI)_2的有效剂量学评价，并对3例癌症患者进行了~(68)Ga-FAPI-46和~(68)Ga-DOTA-2P(FAPI)_2的PET/CT显像。结果：68Ga-DOTA-2P(FAPI)2在磷酸盐缓冲液和胎牛血清中稳定4h，FAPI二聚体在体内外对FAP具有较高的亲和力和特异性。在患者来源的异种移植中，68Ga-DOTA-2P(FAPI)2的肿瘤摄取大约是68Ga-FAPI-46的2倍，而健康器官显示出低的示踪剂摄取和快速的体内清除。用Olinda计算，68Ga-DOTA-2P(Fapi)2的有效剂量为1.19E−02mSv/mBq。最后，3名癌症患者的正电子发射计算机断层扫描显示，在所有肿瘤病变中，68Ga-DOTA-2P(Fapi)2的摄取高于68Ga-Fapi-46(SUVmax，分别为8.1-39.0vs.1.7-24.0P<；0.001)。结论：与68Ga-FAPI-46相比，68Ga-DOTA-2P(FAPI)2具有更强的肿瘤摄取和滞留特性，有望成为FAP阳性表达的恶性肿瘤的诊断显像剂和靶向治疗的示踪剂。
Visual Abstract Cancer-associated fibroblasts (CAFs) are crucial components of the tumor microenvironment. Fibroblast activation protein (FAP) is overexpressed in CAFs. FAP-targeted molecular imaging agents, including the FAP inhibitors (FAPIs) 04 and 46, have shown promising results in tumor diagnosis. However, these molecules have a relatively short tumor-retention time for peptide-targeted radionuclide therapy applications. We aimed to design a 68Ga-labeled FAPI dimer, 68Ga-DOTA-2P(FAPI)2, to optimize the pharmacokinetics and evaluate whether this form is more effective than its monomeric analogs. Methods: 68Ga-DOTA-2P(FAPI)2 was synthesized on the basis of the quinoline-based FAPI variant (FAPI-46), and its binding properties were assayed in CAFs. Preclinical pharmacokinetics were determined in FAP-positive patient-derived xenografts using small-animal PET and biodistribution experiments. The effective dosimetry of 68Ga-DOTA-2P(FAPI)2 was evaluated in 3 healthy volunteers, and PET/CT imaging of 68Ga-FAPI-46 and 68Ga-DOTA-2P(FAPI)2 was performed on 3 cancer patients. Results: 68Ga-DOTA-2P(FAPI)2 was stable in phosphate-buffered saline and fetal bovine serum for 4 h. The FAPI dimer showed high affinity and specificity for FAP in vitro and in vivo. The tumor uptake of 68Ga-DOTA-2P(FAPI)2 was approximately 2-fold stronger than that of 68Ga-FAPI-46 in patient-derived xenografts, whereas healthy organs showed low tracer uptake and fast body clearance. The effective dose of 68Ga-DOTA-2P(FAPI)2 was 1.19E−02 mSv/MBq, calculated using OLINDA. Finally, the PET/CT scans of the 3 cancer patients revealed higher intratumoral uptake of 68Ga-DOTA-2P(FAPI)2 than of 68Ga-FAPI-46 in all tumor lesions (SUVmax, 8.1–39.0 vs. 1.7–24.0, respectively; P < 0.001). Conclusion: 68Ga-DOTA-2P(FAPI)2 has increased tumor uptake and retention properties compared with 68Ga-FAPI-46, and it could be a promising tracer for both diagnostic imaging and targeted therapy of malignant tumors with positive expression of FAP.
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DOI：
10.1007/s00259-021-05273-8
发表时间：
2021-08
影响因子：
9.1
作者：
Kratochwil C;Giesel FL;Rathke H;Fink R;Dendl K;Debus J;Mier W;Jäger D;Lindner T;Haberkorn U
通讯作者：
Haberkorn U
影响因子：
4.7
作者：
Liu S
通讯作者：
Liu S
整合素αvβ3靶向放射性核素治疗联合免疫检查点阻断免疫治疗可协同增强抗肿瘤疗效。
影响因子：
12.4
作者：
Chen, Haojun;Zhao, Liang;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan
影响因子：
4.7
作者：
Lang, Lixin;Li, Weihua;Guo, Ning;Ma, Ying;Zhu, Lei;Kiesewetter, Dale O.;Shen, Baozhong;Niu, Gang;Chen, Xiaoyuan
通讯作者：
Chen, Xiaoyuan
靶向癌症相关成纤维细胞的一种肿瘤模仿方法。
DOI：
10.2967/jnumed.118.210435
发表时间：
2018-09
期刊：
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
影响因子：
--
作者：
Loktev A;Lindner T;Mier W;Debus J;Altmann A;Jäger D;Giesel F;Kratochwil C;Barthe P;Roumestand C;Haberkorn U
通讯作者：
Haberkorn U