聚(二磷酸腺苷核糖)聚合酶(PARP)已经成为针对靶向DNA损伤修复酶的癌症的有效治疗策略。用俄歇电子发射放射性核素放射性标记的PARP靶向化合物可以被捕获在肿瘤组织中受损的DNA附近,高电离电势和短程导致俄歇电子通过产生复杂的DNA损伤来杀死癌细胞,对周围正常组织的损伤最小。这里,我们报道了[123I]CC1,一种123I标记的PARP抑制剂,用于癌症的放射性配体治疗.方法:铜介导的硼频哪醇酯前体的123I碘化得到[123I]CC1。在人乳腺癌中确定了细胞摄取的水平和特异性以及[123I]CC1的治疗效果,胰腺腺癌,和胶质母细胞瘤细胞。在携带人类癌症异种移植物(MDA-MB-231、PSN1和U87MG)的小鼠中评估[123I]CC1的肿瘤摄取和肿瘤生长抑制。结果:体外和体内研究显示在所有模型中选择性摄取[123I]CC1。显著降低克隆性,体内电离辐射抑制肿瘤生长的代表,在用低至10Bq[123I]CC1处理后在体外观察到。静脉内给药后1小时的生物分布显示PSN1肿瘤异种移植物摄取每克组织0.9±0.06百分比注射剂量。静脉内施用相对低量的[123I]CC1(3MBq)能够显著抑制PSN1异种移植物肿瘤生长,但在表达较少PARP的异种移植物中效果较差。[123I]CC1对正常组织无明显毒性。结论:综合来看,这些结果显示了[123I]CC1作为表达PARP的癌症的放射性配体治疗的潜力.
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 [
123I]CC1, an
123I-labeled PARP inhibitor for radioligand therapy of cancer. Methods: Copper-mediated
123I iododeboronation of a boronic pinacol ester precursor afforded [
123I]CC1. The level and specificity of cell uptake and the therapeutic efficacy of [
123I]CC1 were determined in human breast carcinoma, pancreatic adenocarcinoma, and glioblastoma cells. Tumor uptake and tumor growth inhibition of [123I]CC1 were assessed in mice bearing human cancer xenografts (MDA-MB-231, PSN1, and U87MG). Results: In vitro and in vivo studies showed selective uptake of [
123I]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 [123I]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 [
123I]CC1 (3 MBq) was able to significantly inhibit PSN1 xenograft tumor growth but was less effective in xenografts that expressed less PARP. [123I]CC1 did not cause significant toxicity to normal tissues. Conclusion: Taken together, these results show the potential of [123I]CC1 as a radioligand therapy for PARP-expressing cancers.