Radiolabeled cyclic RGD peptides as radiotracers for tumor imaging.
Radiolabeled cyclic RGD peptides as radiotracers for tumor imaging.
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DOI：
10.1007/s41048-016-0021-8
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发表时间：
2016
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整联蛋白家族包括24种跨膜受体，每种受体是18种α亚基之一和8种β亚基之一的异二聚体组合。它们的主要功能是通过与配体结合后跨膜传递信号，将细胞与细胞外微环境的粘附和相互作用与细胞内信号传导和细胞骨架重排整合在一起。整合素αvβ3是一种含有精氨酸-甘氨酸-天冬氨酸（RGD）三肽序列的细胞外基质蛋白受体。αvβ3通常在上皮细胞和成熟内皮细胞上以低水平表达，但在许多实体瘤中高度表达。αvβ3水平与肿瘤转移和侵袭性的可能性密切相关，这使其成为开发抗血管生成药物的重要生物靶标，以及用于早期肿瘤诊断的分子成像探针。在过去的十年中，许多放射性标记的环RGD肽已被评价为放射性示踪剂，用于通过SPECT或PET成像肿瘤。尽管它们被称为“αvβ3靶向”放射性示踪剂，但放射性标记的环状RGD肽也能够结合αvβ5、α5β1、α6β4、α4β1和αvβ6整联蛋白，这可能有助于增强它们的肿瘤摄取，因为“受体群体增加”。本文将使用多聚体环RGD肽作为例子来说明整合素靶向放射性示踪剂的发展的基本原则，并侧重于不同的方法，以最大限度地提高其肿瘤摄取和T/B比。它还将讨论整合素靶向放射性示踪剂的临床前评价的重要测定，以及它们作为分子成像工具的潜在应用，用于非侵入性监测肿瘤转移和早期检测肿瘤对抗血管生成治疗的反应。
The integrin family comprises 24 transmembrane receptors, each a heterodimeric combination of one of 18α and one of 8β subunits. Their main function is to integrate the cell adhesion and interaction with the extracellular microenvironment with the intracellular signaling and cytoskeletal rearrangement through transmitting signals across the cell membrane upon ligand binding. Integrin αvβ3 is a receptor for the extracellular matrix proteins containing arginine–glycine–aspartic (RGD) tripeptide sequence. The αvβ3 is generally expressed in low levels on the epithelial cells and mature endothelial cells, but it is highly expressed in many solid tumors. The αvβ3 levels correlate well with the potential for tumor metastasis and aggressiveness, which make it an important biological target for development of antiangiogenic drugs, and molecular imaging probes for early tumor diagnosis. Over the last decade, many radiolabeled cyclic RGD peptides have been evaluated as radiotracers for imaging tumors by SPECT or PET. Even though they are called “αvβ3-targeted” radiotracers, the radiolabeled cyclic RGD peptides are also able to bind αvβ5, α5β1, α6β4, α4β1, and αvβ6 integrins, which may help enhance their tumor uptake due to the “increased receptor population.” This article will use the multimeric cyclic RGD peptides as examples to illustrate basic principles for development of integrin-targeted radiotracers and focus on different approaches to maximize their tumor uptake and T/B ratios. It will also discuss important assays for pre-clinical evaluations of the integrin-targeted radiotracers, and their potential applications as molecular imaging tools for noninvasive monitoring of tumor metastasis and early detection of the tumor response to antiangiogenic therapy.