Department of Radiology, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
Department of Surgery, University of Alabama at Birmingham, Birmingham, Alabama 35294, United States.
Mol Pharm. 2024 Aug 5;21(8):3889-3896. doi: 10.1021/acs.molpharmaceut.4c00224. Epub 2024 Jul 8.
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 [Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [Zr]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 Zr ( = 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 [Zr]Zr-TR1402 was evaluated in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with biodistribution on Day 3 postinjection. uptake of 1 nM [Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T ( < 0.0001) and FTC133 ( < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T ( < 0.0001) and TSHR+ FTC133 ( < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. PET imaging showed accumulation of [Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, biodistribution confirmed a significant difference ( < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference ( < 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 and accumulation of [Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.
甲状腺癌是最常见的内分泌癌，其中分化型甲状腺癌（DTC）占诊断病例的 95%。虽然大多数 DTC 患者在诊断和治疗时使用放射性碘（RAI），但仍有高达 20%的 DTC 患者对 RAI 产生耐药（RAI-R）。与仍对 RAI 敏感的患者相比，RAI-R 患者的生存率明显降低。本研究探讨了[Zr]Zr-TR1402 作为一种针对甲状腺刺激激素受体（TSHR）的 PET 放射性药物，用于 DTC。[Zr]Zr-TR1402 通过将重组人 TSH（rhTSH）类似物 TR1402 与螯合剂 p-SCN-Bn-去铁胺（DFO）以摩尔比 3:1（DFO/TR1402）偶联，并与 Zr（ = 78.4 h，β = 22.7%）进行放射性标记，以摩尔活性 25.9 MBq/nmol 的方式合成。由于 TSHR 在常用的 DTC 衍生细胞系中不存在，因此通过递送含有人类 TSHR 基因全长编码区的慢病毒，将 TSHR 重新引入稳定转导中。在稳定转导的 TSHR+和野生型 TSHR- DTC 细胞系中评估了[Zr]Zr-TR1402 的受体介导摄取。在携带 TSHR+和 TSHR-异种移植物的雄性和雌性无胸腺裸鼠中，在注射后第 1-3 天进行 PET 成像，并在第 3 天进行生物分布。1 nM [Zr]Zr-TR1402 的摄取在 TSHR+THJ529T（<0.0001）和 FTC133（<0.01）细胞中明显高于 TSHR-THJ529T 和 FTC133 细胞。在 TSHR+THJ529T（<0.0001）和 TSHR+FTC133（<0.0001）细胞中，通过用 250nm DFO-TR1402 阻断摄取，证明这种摄取是特异性的。PET 成像显示[Zr]Zr-TR1402 在 TSHR+肿瘤中的积累，在第 1 天最高。在雄性 FTC133 异种移植模型中，生物分布证实 FTC133+（1.3±0.1%ID/g）和 FTC133-（0.8±0.1%ID/g）肿瘤之间存在显著差异（<0.001）。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）肿瘤之间也观察到摄取的显著差异（<0.05）。[Zr]Zr-TR1402 在 TSHR 表达的 DTC 细胞系中的积累支持该方法的进一步临床前优化。
