Liu Shuang
School of Health Sciences, Purdue University, Civil Engineering Building Room 1275, 550 Stadium Mall Drive, West Lafayette, Indiana 47907, USA.
Mol Pharm. 2006 Sep-Oct;3(5):472-87. doi: 10.1021/mp060049x.
Integrin alphavbeta3 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 alphavbeta3 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 highly restricted expression of integrin alphavbeta3 during tumor growth, invasion, and metastasis presents an interesting molecular target for both early detection and treatment of rapidly growing solid tumors. In the past decade, many radiolabeled linear and cyclic RGD peptide antagonists have been evaluated as the integrin alphavbeta3 targeted radiotracers. Significant progress has been made on their use for imaging tumors of different origin by single photon emission computed tomography (SPECT) or positron emission tomography (PET) in several tumor-bearing animal models. [18F]Galacto-RGD is under clinical investigation as the first integrin alphavbeta3 targeted radiotracer for noninvasive visualization of the activated integrin alphavbeta3 in cancer patients. This review will focus on the radiolabeled multimeric cyclic RGD peptides (dimers and tetramers) useful as radiotracers to image the tumor integrin alphavbeta3 expression by SPECT and PET, and some fundamental aspects for the development of integrin alphavbeta3 targeted radiotracers. These include the choice of radionuclide and bifunctional chelators, selection of targeting biomolecules, and factors influencing the integrin alphavbeta3 binding affinity and tumor uptake, as well as different approaches for modification of radiotracer pharmacokinetics.
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。这些蛋白包括玻连蛋白、纤连蛋白、纤维蛋白原、层粘连蛋白、胶原蛋白、血管性血友病因子、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度表达。整合素αvβ3在肿瘤生长、侵袭和转移过程中的高度受限表达为快速生长实体瘤的早期检测和治疗提供了一个有趣的分子靶点。在过去十年中，许多放射性标记的线性和环状RGD肽拮抗剂已被评估为整合素αvβ3靶向放射性示踪剂。通过单光子发射计算机断层扫描（SPECT）或正电子发射断层扫描（PET）在几种荷瘤动物模型中，它们用于不同起源肿瘤成像方面已取得了显著进展。[18F]半乳糖 - RGD作为首个用于无创可视化癌症患者活化整合素αvβ3的整合素αvβ3靶向放射性示踪剂正在进行临床研究。本综述将聚焦于用作放射性示踪剂通过SPECT和PET成像肿瘤整合素αvβ3表达的放射性标记多聚体环状RGD肽（二聚体和四聚体），以及整合素αvβ3靶向放射性示踪剂开发的一些基本方面。这些方面包括放射性核素和双功能螯合剂的选择、靶向生物分子的选择、影响整合素αvβ3结合亲和力和肿瘤摄取的因素，以及放射性示踪剂药代动力学修饰方法。
