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First Evaluation of Radioiodinated Flavonoids as Necrosis-Avid Agents and Application in Early Assessment of Tumor Necrosis
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2017-12-20 00:00:00 , DOI: 10.1021/acs.molpharmaceut.7b00781
Jiajia Liang 1, 2, 3 , Ziping Sun 4 , Dongjian Zhang 2, 3 , Qiaomei Jin 2, 3 , Lingqiao Cai 2, 3 , Lin Ma 1, 2, 3 , Wei Liu 5 , Yicheng Ni 2, 3, 6 , Jian Zhang 2, 3 , Zhiqi Yin 1
Affiliation  

A rapid and accurate identification of necrotic tissues is of great importance to define disease severity, predict prognosis, and monitor responses to therapies. To seek necrosis-avid agents with clinically translational potential, we first evaluated the necrosis avidity of flavonoids in rodent models of muscular, myocardial, and tumoral necrosis. In this study, the necrosis avidity of eight radioiodinated 5,7-dihydroxyflavones was tested by ex vivo gamma counting, histochemical staining, and autoradiography in mouse models of ethanol-induced muscular necrosis. The necrosis avidity of a lead tracer, 131I-5, was further assessed in rat models of myocardial infarction and reperfusion. Therapy response was evaluated by 131I-5 single photon emission computed tomography/computed tomography imaging 24 h after combretastatin A-4 disodium phosphate (CA4P) therapy on rats bearing W256 breast carcinomas. The necrosis avidity mechanism for the tracers was studied by in vitro DNA binding experiments of 12 5,7-dihydroxyflavones and in vivo blocking experiments of 131I-5. In the results, all 131I-5,7-dihydroxyflavones showed intense uptake to necrotic muscles, and 131I-5 emerged as the most potential tracer among them. 131I-5 obtained a necrotic-viable myocardium ratio of 5.0 ± 0.9 in post-mortem biodistribution on reperfused myocardial infarction models and achieved necrosis imaging on CA4P-treated W256 tumors 4 h after tracer injection. DNA binding studies suggested that necrosis avidity was related to DNA binding to a certain extent. The uptake of 131I-5 in necrotic muscle was markedly blocked by excessive ethidium bromide and cold 5 with a 51.95% and 64.29% decline at 1 h after coinjection, respectively. In conclusion, flavonoids are necrosis-avid agents. Furthermore, 131I-5 can serve as a promising necrosis-avid diagnostic tracer for the rapid imaging of necrotic tissues, supporting the further molecular design of radiotracer based on 5.

中文翻译:

放射性碘黄酮类化合物作为坏死因子的首次评估及其在肿瘤坏死早期评估中的应用

快速准确地鉴定坏死组织对于确定疾病的严重程度,预测预后并监测对治疗的反应非常重要。为了寻找具有临床翻译潜力的坏死抗体,我们首先在肌肉,心肌和肿瘤坏死的啮齿动物模型中评估了类黄酮的坏死亲和力。在这项研究中,通过体外γ计数,组织化学染色和放射自显影在乙醇诱发的肌肉坏死的小鼠模型中测试了八个放射性碘化的5,7-二羟基黄酮的坏死亲和力。在心肌梗塞和再灌注的大鼠模型中进一步评估了铅示踪剂131 I- 5的坏死亲和力。通过131 I-评价治疗反应康维他汀A-4磷酸二钠(CA4P)治疗后24小时对患有W256乳腺癌的大鼠进行5次单光子发射计算机断层扫描/计算机断层扫描成像。通过12种5,7-二羟基黄酮的体外DNA结合实验和131 I- 5的体内阻断实验研究了示踪剂的坏死亲和力机制。结果中,所有131 I-5,7-二羟基黄酮均显示出对坏死肌的强烈摄取,而131 I- 5成为其中最有潜力的示踪剂。131 I- 5在再灌注心肌梗死模型的死后生物分布中获得了5.0±0.9的坏死存活心肌比率,并在示踪剂注射后4 h对CA4P治疗的W256肿瘤实现了坏死成像。DNA结合研究表明,坏死亲和力在一定程度上与DNA结合有关。共注射后1小时,过量的溴化乙锭和冷5显着阻断了坏死肌中131 I- 5的摄取,分别降低了51.95%和64.29%。总之,类黄酮是一种坏死抗药剂。此外,131 I- 5可以作为坏死组织快速成像的坏死诊断诊断示踪剂,支持基于5的放射性示踪剂的进一步分子设计。
更新日期:2017-12-20
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