Radiolabeled cyclic RGD peptides as integrin alpha(v)beta(3)-targeted radiotracers: maximizing binding affinity via bivalency.
Radiolabeled cyclic RGD peptides as integrin alpha(v)beta(3)-targeted radiotracers: maximizing binding affinity via bivalency.
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DOI：
10.1021/bc900167c
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发表时间：
2009-12
影响因子：
4.7
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Liu S
整合素αvβ3在肿瘤血管生成中起重要作用，是具有暴露的精氨酸-甘氨酸-天冬氨酸（RGD）三肽序列的细胞外基质蛋白的受体。这些包括玻连蛋白、纤连蛋白、纤维蛋白原、核纤层蛋白、胶原、冯·威利布兰德因子、骨桥蛋白和腺病毒颗粒。整合素αvβ3在上皮细胞和成熟内皮细胞上低水平表达，但在肿瘤新生血管的活化内皮细胞和一些肿瘤细胞上过表达。整合素αvβ3在肿瘤生长、侵袭和转移过程中的有限表达为快速生长的实体瘤的早期检测和治疗提供了一个有趣的分子靶点。在过去的十年中，许多放射性标记的线性和环状RGD肽拮抗剂已被评价为整合素αvβ3靶向放射性示踪剂。在通过SPECT或PET对整合素αvβ3阳性肿瘤进行成像方面已取得重大进展。在临床前荷瘤模型中评价的放射性示踪剂中，[18 F]半乳糖-RGD（2-[18 F]氟丙酰胺c（RGDfK（SAA）; SAA = 7-氨基-L-甘油-L-半乳糖-2，6-脱水-7-脱氧庚酰胺）和[18 F]-AH 111585目前正在临床研究中用于可视化癌症患者中的整合素αvβ3表达。然而，它们的低肿瘤摄取、高成本和缺乏用于常规放射合成的制备模块将限制它们的继续临床应用。因此，持续需要更有效的整联蛋白αvβ3靶向放射性示踪剂，其易于从试剂盒制剂制备而无需进一步的标记后纯化。本文将重点介绍不同的方法，以最大限度地提高环RGD肽的靶向能力，并提高非癌器官的放射性示踪剂排泄动力学。肿瘤摄取和肿瘤与背景比值的改善对于早期检测整合素αvβ3阳性肿瘤和/或非侵入性监测抗血管生成治疗的疗效非常重要。
Integrin αvβ3 plays a significant role in tumor angiogenesis, and is a receptor for the extracellular matrix proteins with the exposed arginine-glycine-aspartic (RGD) tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, lamin, collagen, Von Willibrand’s factor, osteoponin, and adenovirus particles. Integrin αvβ3 is expressed at low levels on epithelial cells and mature endothelial cells, but it is overexpressed on the activated endothelial cells of tumor neovasculature and some tumor cells. The restricted expression of integrin αvβ3 during tumor growth, invasion and metastasis present an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. Over the last decade, many radiolabeled linear and cyclic RGD peptide antagonists have been evaluated as the integrin αvβ3-targeted radiotracers. Significant progress has been made on their use for imaging integrin αvβ3-positive tumors by SPECT or PET. Among the radiotracers evaluated in pre-clinical tumor-bearing models, [18F]Galacto-RGD (2-[18F]fluoropropanamide c(RGDfK(SAA); SAA = 7-amino-L-glyero-L-galacto-2,6-anhydro-7-deoxyheptanamide) and [18F]-AH111585 are currently under clinical investigation for visualization of integrin αvβ3 expression in cancer patients. However, their low tumor uptake, high cost and lack of preparative modules for routine radiosynthesis will limit their continued clinical applications. Thus, there is a continuing need for more efficient integrin αvβ3-targeted radiotracers that are readily prepared from a kit formulation without further post-labeling purification. This article will focus on different approaches to maximize the targeting capability of cyclic RGD peptides and to improve the radiotracer excretion kinetics from non-cancerous organs. Improvement of tumor uptake and tumor-to-background ratios is important for early detection of integrin αvβ3-positive tumors and/or noninvasive monitoring of therapeutic efficacy of antiangiogenic therapy.
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