基于二吲哚的 MRI 对比剂的合成与评价及其在坏死组织体内可视化的研究。

Synthesis and Evaluation of Diindole-Based MRI Contrast Agent for In Vivo Visualization of Necrosis.

机构信息

Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No.100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People's Republic of China.

Department of TCMs Pharmaceuticals, School of TCM & State Key Laboratory of Natural Medicines, China Pharmaceutical University, No.24, Tongjiaxiang, Gulou District, Nanjing, 210009, Jiangsu Province, People's Republic of China.

出版信息

Mol Imaging Biol. 2020 Jun;22(3):593-601. doi: 10.1007/s11307-019-01399-2.

DOI:10.1007/s11307-019-01399-2

PMID:31332630

Abstract

PURPOSE

Noninvasive imaging of cell necrosis can provide an early evaluation of tumor response to treatments. Here, we aimed to design and synthesize a novel diindole-based magnetic resonance imaging (MRI) contrast agent (Gd-bis-DOTA-diindolylmethane, Gd-DIM) for assessment of tumor response to therapy at an early stage.

PROCEDURES

The oil-water partition coefficient (Log P) and relaxivity of Gd-DIM were determined in vitro. Then, its necrosis avidity was examined in necrotic cells in vitro and in rat models with microwave ablation-induced muscle necrosis (MAMN) and ischemia reperfusion-induced liver necrosis (IRLN) by MRI. Visualization of tumor necrosis induced by combretastatin A-4 disodium phosphate (CA4P) was evaluated in rats bearing W256 orthotopic liver tumor by MRI. Finally, DNA binding assay was performed to explore the possible necrosis-avidity mechanism of Gd-DIM.

RESULTS

The Log P value and T1 relaxivity of Gd-DIM is - 2.15 ± 0.01 and 6.61 mM s, respectively. Gd-DIM showed predominant necrosis avidity in vitro and in vivo. Clear visualization of the tumor necrosis induced by CA4P was achieved at 60 min after administration of Gd-DIM. DNA binding study indicated that the necrosis-avidity mechanism of Gd-DIM may be due to its binding to exposed DNA in necrotic cells.

CONCLUSION

Gd-DIM may serve as a promising necrosis-avid MRI contrast agent for early assessment of tumor response to therapy.

摘要

目的

细胞坏死的无创成像可以提供对肿瘤对治疗反应的早期评估。在这里，我们旨在设计和合成一种新型基于二吲哚的磁共振成像（MRI）造影剂（Gd-双-DOTA-二吲哚甲烷，Gd-DIM），用于早期评估肿瘤对治疗的反应。

程序

体外测定 Gd-DIM 的油水分配系数（Log P）和弛豫率。然后，通过 MRI 在体外坏死细胞以及微波消融诱导的肌肉坏死（MAMN）和缺血再灌注诱导的肝坏死（IRLN）大鼠模型中检测其坏死亲和力。通过 MRI 评估 Gd-DIM 诱导 CA4P 诱导的肿瘤坏死的能力。最后，进行 DNA 结合实验，以探讨 Gd-DIM 可能的坏死亲和力机制。

结果

Gd-DIM 的 Log P 值和 T1 弛豫率分别为-2.15±0.01 和 6.61 mM s。Gd-DIM 在体外和体内均表现出强烈的坏死亲和力。在给予 Gd-DIM 后 60 分钟即可实现对 CA4P 诱导的肿瘤坏死的清晰可视化。DNA 结合研究表明，Gd-DIM 的坏死亲和力机制可能是由于其与坏死细胞中暴露的 DNA 结合。