改进螺旋放射治疗剂 123I-MAPi 的放射合成。

IF 2.1 4区 医学 Q2 BIOLOGY International Journal of Radiation Biology Pub Date : 2023-01-01 Epub Date: 2020-07-02 DOI:10.1080/09553002.2020.1781283
Thomas C Wilson, Stephen A Jannetti, Navjot Guru, Nagavarakishore Pillarsetty, Thomas Reiner, Giacomo Pirovano
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引用次数: 9

摘要

目的:123I-MAPi 是一种新型 PARP1 靶向奥杰放射治疗药物,在临床前胶质瘤模型中显示出良好的效果。目前,123I-MAPi 采用多步合成法合成,产量不高,摩尔活性(MA)较低,限制了将这项技术转化为大剂量人体研究的能力。材料与方法:123I-MAPi 是通过 123I-iododetannylation 对相应的三丁基锡前体进行单步合成制备的。体外内化试验、亚细胞分馏和共聚焦显微镜用于评估 123I-MAPi 在小细胞肺癌模型中的性能:123I-MAPi 由相应的锡烷前体一步合成,AY 为 45 ± 2%,MA 为 11.8 ± 4.8 GBq µmol-1。体外 LX22 细胞显示出快速内化(5 分钟),经亚细胞分馏确定主要在细胞膜、细胞核和染色质中积累:在此,我们开发了一种改进的奥杰治疗剂 123I-MAPi 的放射合成方法。该工艺采用单步123I-碘代二烷酰化反应,从相应的锡烷前体中获得良好的AY和MA。在小细胞肺癌模型中对 123I-MAPi 进行了体外评估,结果表明它具有 PARP 高表达、快速内化和高核摄取等特点。
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Improved radiosynthesis of 123I-MAPi, an auger theranostic agent.

Purpose: 123I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently, 123I-MAPi is synthesized using multistep synthesis that results in modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize 123I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.

Materials and methods: 123I-MAPi was prepared in a single step via 123I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of 123I-MAPi in a small cell lung cancer model.

Results: 123I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq µmol-1. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation.

Conclusions: Here, we have developed an improved radiosynthesis of 123I-MAPi, an Auger theranostic agent. This process was achieved using a single step, 123I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA. 123I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.

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来源期刊
CiteScore
5.00
自引率
11.50%
发文量
142
审稿时长
3 months
期刊介绍: The International Journal of Radiation Biology publishes original papers, reviews, current topic articles, technical notes/reports, and meeting reports on the effects of ionizing, UV and visible radiation, accelerated particles, electromagnetic fields, ultrasound, heat and related modalities. The focus is on the biological effects of such radiations: from radiation chemistry to the spectrum of responses of living organisms and underlying mechanisms, including genetic abnormalities, repair phenomena, cell death, dose modifying agents and tissue responses. Application of basic studies to medical uses of radiation extends the coverage to practical problems such as physical and chemical adjuvants which improve the effectiveness of radiation in cancer therapy. Assessment of the hazards of low doses of radiation is also considered.
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