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是时候转变范式了:非αvβ3整合素靶向放射性药物的翻译与临床应用

It's Time to Shift the Paradigm: Translation and Clinical Application of Non-αvβ3 Integrin Targeting Radiopharmaceuticals.

作者信息

Kossatz Susanne, Beer Ambros Johannes, Notni Johannes

机构信息

Department of Nuclear Medicine, School of Medicine, Technical University of Munich, 81675 Munich, Germany.

Central Institute for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, 81675 Munich, Germany.

出版信息

Cancers (Basel). 2021 Nov 26;13(23):5958. doi: 10.3390/cancers13235958.

Abstract

For almost the entire period of the last two decades, translational research in the area of integrin-targeting radiopharmaceuticals was strongly focused on the subtype αvβ3, owing to its expression on endothelial cells and its well-established role as a biomarker for, and promoter of, angiogenesis. Despite a large number of translated tracers and clinical studies, a clinical value of αvβ3-integrin imaging could not be defined yet. The focus of research has, thus, been moving slowly but steadily towards other integrin subtypes which are involved in a large variety of tumorigenic pathways. Peptidic and non-peptidic radioligands for the integrins α5β1, αvβ6, αvβ8, α6β1, α6β4, α3β1, α4β1, and αMβ2 were first synthesized and characterized preclinically. Some of these compounds, targeting the subtypes αvβ6, αvβ8, and α6β1/β4, were subsequently translated into humans during the last few years. αvβ6-Integrin has arguably attracted most attention because it is expressed by some of the cancers with the worst prognosis (above all, pancreatic ductal adenocarcinoma), which substantiates a clinical need for the respective theranostic agents. The receptor furthermore represents a biomarker for malignancy and invasiveness of carcinomas, as well as for fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF), and probably even for Sars-CoV-2 (COVID-19) related syndromes. Accordingly, the largest number of recent first-in-human applications has been reported for radiolabeled compounds targeting αvβ6-integrin. The results indicate a substantial clinical value, which might lead to a paradigm change and trigger the replacement of αvβ3 by αvβ6 as the most popular integrin in theranostics.

摘要

在过去二十年的几乎整个时期,整合素靶向放射性药物领域的转化研究都高度集中在αvβ3亚型上,这是由于其在内皮细胞上的表达以及作为血管生成的生物标志物和促进剂的明确作用。尽管有大量的转化示踪剂和临床研究,但αvβ3整合素成像的临床价值尚未确定。因此,研究重点一直在缓慢但稳步地转向其他整合素亚型,这些亚型参与了多种肿瘤发生途径。整合素α5β1、αvβ6、αvβ8、α6β1、α6β4、α3β1、α4β1和αMβ2的肽类和非肽类放射性配体首先在临床前进行了合成和表征。其中一些靶向αvβ6、αvβ8和α6β1/β4亚型的化合物随后在过去几年中进入人体试验阶段。αvβ6整合素可能最受关注,因为它在一些预后最差的癌症(尤其是胰腺导管腺癌)中表达,这证实了对相应治疗诊断药物的临床需求。此外,该受体还代表了癌的恶性和侵袭性的生物标志物,以及纤维化疾病(如特发性肺纤维化(IPF))甚至可能是与严重急性呼吸综合征冠状病毒2(SARS-CoV-2,新冠病毒)相关综合征的生物标志物。因此,最近针对靶向αvβ6整合素的放射性标记化合物报道了最多的首次人体应用。结果表明其具有重大的临床价值,这可能导致范式转变,并引发αvβ6取代αvβ3成为治疗诊断学中最受欢迎的整合素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/99ef/8657165/f16dd00642e2/cancers-13-05958-g001.jpg

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