MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom; and.
J Nucl Med. 2023 Dec 1;64(12):1965-1971. doi: 10.2967/jnumed.123.265429.
Poly(adenosine diphosphate ribose) polymerase (PARP) has emerged as an effective therapeutic strategy against cancer that targets the DNA damage repair enzyme. PARP-targeting compounds radiolabeled with an Auger electron-emitting radionuclide can be trapped close to damaged DNA in tumor tissue, where high ionizing potential and short range lead Auger electrons to kill cancer cells through the creation of complex DNA damage, with minimal damage to surrounding normal tissue. Here, we report on [I]CC1, an I-labeled PARP inhibitor for radioligand therapy of cancer. Copper-mediated I iododeboronation of a boronic pinacol ester precursor afforded [I]CC1. The level and specificity of cell uptake and the therapeutic efficacy of [I]CC1 were determined in human breast carcinoma, pancreatic adenocarcinoma, and glioblastoma cells. Tumor uptake and tumor growth inhibition of [I]CC1 were assessed in mice bearing human cancer xenografts (MDA-MB-231, PSN1, and U87MG). In vitro and in vivo studies showed selective uptake of [I]CC1 in all models. Significantly reduced clonogenicity, a proxy for tumor growth inhibition by ionizing radiation in vivo, was observed in vitro after treatment with as little as 10 Bq [I]CC1. Biodistribution at 1 h after intravenous administration showed PSN1 tumor xenograft uptake of 0.9 ± 0.06 percentage injected dose per gram of tissue. Intravenous administration of a relatively low amount of [I]CC1 (3 MBq) was able to significantly inhibit PSN1 xenograft tumor growth but was less effective in xenografts that expressed less PARP. [I]CC1 did not cause significant toxicity to normal tissues. Taken together, these results show the potential of [I]CC1 as a radioligand therapy for PARP-expressing cancers.
聚（二磷酸腺苷核糖）聚合酶（PARP）已成为一种针对靶向 DNA 损伤修复酶的癌症治疗的有效策略。用发射俄歇电子的放射性核素标记的 PARP 靶向化合物可以被捕获到肿瘤组织中受损的 DNA 附近，在那里高电离势和短射程的俄歇电子会通过产生复杂的 DNA 损伤来杀死癌细胞，而对周围正常组织的损伤最小。在这里，我们报告了一种用于癌症放射性配体治疗的 I 标记的 PARP 抑制剂 [I]CC1。铜介导的硼酸盐 PINACOL 酯前体的 I 碘代脱硼化提供了 [I]CC1。在人乳腺癌、胰腺腺癌和神经胶质瘤细胞中，测定了 [I]CC1 的细胞摄取水平和特异性以及治疗效果。在携带人癌异种移植瘤（MDA-MB-231、PSN1 和 U87MG）的小鼠中评估了 [I]CC1 的肿瘤摄取和肿瘤生长抑制作用。体外和体内研究表明，所有模型中均有 [I]CC1 的选择性摄取。在体外，用 10 Bq 以下的 [I]CC1 处理后，观察到对克隆形成的显著抑制，这是体内电离辐射抑制肿瘤生长的一个替代指标。静脉注射后 1 小时的生物分布显示 PSN1 肿瘤异种移植摄取 0.9±0.06 每克组织注射剂量的百分比。静脉给予相对较低量的 [I]CC1（3 MBq）能够显著抑制 PSN1 异种移植肿瘤的生长，但在表达较少 PARP 的异种移植中效果较差。[I]CC1 对正常组织没有引起明显的毒性。总之，这些结果表明 [I]CC1 作为 PARP 表达癌症的放射性配体治疗具有潜力。
