甲状腺癌是最常见的内分泌癌症，其中分化型甲状腺癌 (DTC) 占诊断的 95%。虽然大多数 DTC 患者均采用放射性碘 (RAI) 进行诊断和治疗，但高达 20% 的 DTC 患者会出现 RAI 难治性 (RAI-R)。与仍然热衷于 RAI 的患者相比，RAI-R 患者的生存率显着降低。本研究探索 [89Zr]Zr-TR1402 作为一种针对 DTC 的促甲状腺激素受体 (TSHR) 靶向 PET 放射性药物。通过将重组人 TSH (rhTSH) 类似物 TR1402 与螯合剂 p-SCN-Bn-去铁胺 (DFO) 以 3:1 (DFO/ TR1402) 和 89Zr 放射性标记 (t1/2 = 78.4 h, β = 22.7%)。由于 TSHR 在常见的 DTC 衍生细胞系中不存在，因此通过稳定转导，通过递送含有人 TSHR 基因全长编码区的慢病毒，重新引入 TSHR。 [89Zr]Zr-TR1402 的受体介导的摄取在稳定转导的 TSHR 和野生型 TSHR-DTC 细胞系中进行了体外评估。在注射后第1-3天对携带TSHR和TSHR异种移植物的雄性和雌性无胸腺裸鼠进行体内PET成像，并在注射后第3天进行离体生物分布。 TSHR THJ529T (P < 0.0001) 和 FTC133 (P < 0.01) 细胞对 1 nM [89Zr]Zr-TR1402 的体外摄取显着高于 TSHR-THJ529T 和 FTC133 细胞。通过用 250 nm DFO-TR1402 阻断摄取，这种摄取在 TSHR THJ529T (P < 0.0001) 和 TSHR FTC133 (P < 0.0001) 细胞中具有特异性。体内PET成像显示TSHR肿瘤中[89Zr]Zr-TR1402的积累，在第1天达到最高。在男性FTC133异种移植模型中，离体生物分布证实FTC133（1.3）之间的摄取存在显着差异（P <0.001）。 ± 0.1%ID/g) 和 FTC133- (0.8 ± 0.1%ID/g) 肿瘤。在雄性 THJ529T 异种移植模型中，THJ529T (1.8 ± 0.6%ID/g) 和 THJ529T- (0.8 ± 0.4%ID/g) 肿瘤之间的摄取也存在显着差异 (P < 0.05)。 [89Zr]Zr-TR1402 在表达 TSHR 的 DTC 细胞系中的体外和体内积累支持了该方法的持续临床前优化。

Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [89Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [89Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with 89Zr (t1/2 = 78.4 h, β+ = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [89Zr]Zr-TR1402 was evaluated in vitro in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. In vivo PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with ex vivo biodistribution on Day 3 postinjection. In vitro uptake of 1 nM [89Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T (P < 0.0001) and FTC133 (P < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T (P < 0.0001) and TSHR+ FTC133 (P < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. In vivo PET imaging showed accumulation of [89Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, ex vivo biodistribution confirmed a significant difference (P < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference (P < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T- (0.8 ± 0.4%ID/g) tumors. The in vitro and in vivo accumulation of [89Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.