State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou , 510060, Guangdong, People's Republic of China.
Department of Nuclear Medicine, Affiliated Hospital of Jiangnan University, Wuxi, 214000, China.
Eur J Nucl Med Mol Imaging. 2023 Jun;50(7):2100-2113. doi: 10.1007/s00259-023-06147-x. Epub 2023 Feb 18.
Extradomain B of fibronectin (EDB-FN) is a promising diagnostic and therapeutic biomarker for thyroid cancer (TC). Here, we identified a high-affinity EDB-FN targeted peptide named EDBp (AVRTSAD) and developed three EDBp-based probes, Cy5-PEG4-EDBp(Cy5-EDBp), [F]-NOTA-PEG4-EDBp([F]-EDBp), and [Lu]-DOTA-PEG4-EDBp ([Lu]-EDBp), for the surgical navigation, radionuclide imaging, and therapy of TC.
Based on the previously identified EDB-FN targeted peptide ZD2, the optimized EDB-FN targeted peptide EDBp was identified by using the alanine scan strategy. Three EDBp-based probes, Cy5-EDBp, [F]-EDBp, and [Lu]-EDBp, were developed for fluorescence imaging, positron emission tomography (PET) imaging, and radiotherapy in TC tumor-bearing mice, respectively. Additionally, [F]-EDBp was evaluated in two TC patients.
The binding affinity of EDBp to the EDB fragment protein (Kd = 14.4 ± 1.4 nM, n = 3) was approximately 336-fold greater than that of the ZD2 (Kd = 4839.7 ± 361.7 nM, n = 3). Fluorescence imaging with Cy5-EDBp facilitated the complete removal of TC tumors. [F]-EDBp PET imaging clearly delineated TC tumors, with high tumor uptake (16.43 ± 1.008%ID/g, n = 6, at 1-h postinjection). Radiotherapy with [Lu]-EDBp inhibited tumor growth and prolonged survival in TC tumor-bearing mice (survival time of different treatment groups: saline vs. EDBp vs. ABRAXANE vs. [Lu]-EDBp = 8.00 d vs. 8.00 d vs. 11.67 d vs. 22.33 d, ***p < 0.001). Importantly, the first-in-human evaluation of [F]-EDBp demonstrated that it had specific targeting properties (SUVmax value of 3.6) and safety.
Cy5-EDBp, [F]-EDBp, and [Lu]-EDBp are promising candidates for the surgical navigation, radionuclide imaging, and radionuclide therapy of TC, respectively.
纤连蛋白外结构域 B（EDB-FN）是甲状腺癌（TC）有前途的诊断和治疗生物标志物。在这里，我们鉴定了一种高亲和力的 EDB-FN 靶向肽，命名为 EDBp（AVRTSAD），并开发了三种基于 EDBp 的探针，Cy5-PEG4-EDBp（Cy5-EDBp）、[F]-NOTA-PEG4-EDBp([F]-EDBp) 和 [Lu]-DOTA-PEG4-EDBp([Lu]-EDBp)，用于 TC 的手术导航、放射性核素成像和治疗。
基于先前鉴定的 EDB-FN 靶向肽 ZD2，我们使用丙氨酸扫描策略鉴定了优化的 EDB-FN 靶向肽 EDBp。为了在 TC 荷瘤小鼠中进行荧光成像、正电子发射断层扫描（PET）成像和放射治疗，分别开发了三种基于 EDBp 的探针 Cy5-EDBp、[F]-EDBp 和 [Lu]-EDBp。此外，还在两名 TC 患者中评估了 [F]-EDBp。
EDBp 与 EDB 片段蛋白的结合亲和力（Kd=14.4±1.4 nM，n=3）约为 ZD2（Kd=4839.7±361.7 nM，n=3）的 336 倍。Cy5-EDBp 的荧光成像有助于完全切除 TC 肿瘤。[F]-EDBp PET 成像清晰地描绘了 TC 肿瘤，具有高肿瘤摄取（16.43±1.008%ID/g，n=6，在注射后 1 小时）。[Lu]-EDBp 放射治疗抑制了 TC 荷瘤小鼠的肿瘤生长并延长了其存活时间（不同治疗组的存活时间：生理盐水 vs. EDBp vs. ABRAXANE vs. [Lu]-EDBp=8.00 d vs. 8.00 d vs. 11.67 d vs. 22.33 d，***p<0.001）。重要的是，[F]-EDBp 的首次人体评估表明其具有特异性靶向特性（SUVmax 值为 3.6）和安全性。
Cy5-EDBp、[F]-EDBp 和 [Lu]-EDBp 分别是 TC 手术导航、放射性核素成像和放射性核素治疗的有前途的候选物。
