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用于三阴性乳腺癌治疗的俄歇发射体共轭聚（ADP-核糖）聚合酶抑制剂：一项体外比较研究

Auger Emitter Conjugated PARP Inhibitor for Therapy in Triple Negative Breast Cancers: A Comparative In-Vitro Study.

作者信息

Sankaranarayanan Ramya Ambur, Peil Jennifer, Vogg Andreas T J, Bolm Carsten, Terhorst Steven, Classen Arno, Bauwens Matthias, Maurer Jochen, Mottaghy Felix, Morgenroth Agnieszka

机构信息

Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen, Germany.

Institute of Organic Chemistry, RWTH Aachen University, 52056 Aachen, Germany.

出版信息

Cancers (Basel). 2022 Jan 4;14(1):230. doi: 10.3390/cancers14010230.

DOI:10.3390/cancers14010230
PMID:35008392
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8750932/
Abstract

PARP1 inhibitors (PARPi) are currently approved for BRCA metastatic breast cancer, but they have shown limited response in triple negative breast cancer (TNBC) patients. Combination of an Auger emitter with PARPis enables PARP inhibition and DNA strand break induction simultaneously. This will enhance cytotoxicity and additionally allow a theranostic approach. This study presents the radiosynthesis of the Auger emitter [I] coupled olaparib derivative: [I]-PARPi-01, and its therapeutic evaluation in a panel of TNBC cell lines. Specificity was tested by a blocking assay. DNA strand break induction was analysed by γH2AX immunofluorescence staining. Cell cycle analysis and apoptosis assays were studied using flow cytometry in TNBC cell lines (BRCA). Anchorage independent growth potential was evaluated using soft agar assay. [I]-PARPi-01 showed PARP1-specificity and higher cytotoxicity than olaparib in TNBC cell lines irrespective of BRCA their status. Cell lines harbouring DNA repair deficiency showed response to [I]-PARPi-01 monotherapy. Combined treatment with Dox-NP further enhanced therapeutic efficiency in metastatic resistant BRCA cell lines. The clonogenic survival was significantly reduced after treatment with [I]-PARPi-01 in all TNBC lines investigated. Therapeutic efficacy was further enhanced after combined treatment with chemotherapeutics. [I]-PARPi-01 is a promising radiotherapeutic agent for low radiation dosages, and mono/combined therapies of TNBC.

摘要

聚（ADP-核糖）聚合酶1抑制剂（PARP1i）目前已被批准用于治疗携带BRCA突变的转移性乳腺癌，但在三阴性乳腺癌（TNBC）患者中显示出的反应有限。将俄歇电子发射体与PARP1i联合使用能够同时抑制PARP并诱导DNA链断裂。这将增强细胞毒性，并额外提供一种诊疗方法。本研究展示了俄歇电子发射体[碘-125]偶联奥拉帕利衍生物：[碘-125]-PARPi-01的放射性合成，及其在一组TNBC细胞系中的治疗评估。通过阻断试验测试特异性。通过γH2AX免疫荧光染色分析DNA链断裂诱导情况。在TNBC细胞系（BRCA）中使用流式细胞术研究细胞周期分析和凋亡检测。使用软琼脂试验评估非锚定依赖性生长潜力。[碘-125]-PARPi-01在TNBC细胞系中显示出PARP1特异性，且无论BRCA状态如何，其细胞毒性均高于奥拉帕利。具有DNA修复缺陷的细胞系对[碘-125]-PARPi-01单一疗法有反应。与阿霉素纳米颗粒（Dox-NP）联合治疗进一步提高了转移性耐药BRCA细胞系的治疗效率。在所有研究的TNBC细胞系中，用[碘-125]-PARPi-01治疗后克隆形成存活率显著降低。与化疗药物联合治疗后治疗效果进一步增强。[碘-125]-PARPi-01是一种有望用于低辐射剂量以及TNBC单药/联合治疗的放射治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/6922515bfa97/cancers-14-00230-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/df60fe634421/cancers-14-00230-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/2c7b8ef07231/cancers-14-00230-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/d4232dd49aba/cancers-14-00230-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/56b118ca0b26/cancers-14-00230-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/231f9b0b2788/cancers-14-00230-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/6922515bfa97/cancers-14-00230-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/df60fe634421/cancers-14-00230-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/2c7b8ef07231/cancers-14-00230-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/d4232dd49aba/cancers-14-00230-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/56b118ca0b26/cancers-14-00230-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/231f9b0b2788/cancers-14-00230-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/874c/8750932/6922515bfa97/cancers-14-00230-g006.jpg

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