Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors
Design, synthesis, and evaluation of near infrared fluorescent multimeric RGD peptides for targeting tumors
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DOI：
10.1021/jm050947h
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发表时间：
2006-04-06
影响因子：
7.3
通讯作者：
Achilefu, S
中科院分区：
文献类型：
--
作者：
Ye, YP;Bloch, S;Achilefu, S
已知RGD肽和整合素之间的分子相互作用介导许多生物学和病理学过程。这使得人们对开发具有高亲和力和改善的对整联蛋白受体的选择性的RGD化合物的兴趣增加。在这项研究中，我们合成和评估了一系列的多聚体的RGD化合物构建在一个含二羧酸的近红外（NIR）荧光染料（cypate）的肿瘤靶向。高效地制备了一系列NIR荧光RGD化合物，包括一种RGD单体（cypate-（RGD）（2）-NH 2）、两种RGD二聚体（cypate-（RGD）（2）-NH 2和cypate-（RGD-NH 2）（2））、一种三聚体（cypate-（RGD）3-NH 2）、两种四聚体（cypate-（RGD）（4）-NH 2和cypate（2）]（2）和一种八聚体（cypate-[（RGD）（4）-NH 2]（2））。结合[（RGD）（2）-NH 2]（2）），一种六聚体（cypate-[（RGD）3-NH 1C），多聚体RGD化合物对α（v）β（3）整联蛋白受体（ABIR）的亲和力相对于单体cypate-RGD-NH 2显示出显著增加。通常，多聚体RGD单元的二价线性阵列以比其单价类似物略高的亲和力结合ABIR。这些结果表明，受体结合亲和力不仅依赖于RGD部分的数量，但也对侧肽的空间排列。通过NIR荧光显微镜监测化合物被ABIR阳性肿瘤细胞（A549）内化。数据显示，与本研究中的其他化合物相比，八聚体RGD衍生物的内吞作用显著更高。体内非侵入性光学成像和生物分布数据表明，化合物保留在A549肿瘤组织中。这些结果清楚地表明，在NIR荧光染料核心上的简单RGD三肽阵列可以被ABIR识别。通过仔细的en分子设计和文库构建优化的RGD部分的空间排列可以诱导多价配体-受体相互作用，用于体内肿瘤成像和肿瘤靶向治疗。
Molecular interactions between RGD peptides and integrins are known to mediate many biological and pathological processes. This has led to an increased interest in the development of RGD compounds with high affinity and improved selectivity for integrin receptors. In this study, we synthesized and evaluated a series of multimeric RGD compounds constructed on a dicarboxylic acid-containing near-infrared (NIR) fluorescent dye (cypate) for tumor targeting. An array of NIR fluorescent RGD compounds was prepared efficiently, including one RGD monomer (cypate-(RGD)(2)-NH2), two RGD dimers (cypate-(RGD)(2)-NH2 and cypate-(RGD-NH2)(2)), one trimer (cypate-(RGD)3-NH2), two tetramers (cypate-(RGD)(4)-NH2 and cypate(2)](2)), and one octamer (cypate-[(RGD)(4)-NH2](2)). The binding [(RGD)(2)-NH2](2)), one hexamer (cypate-[(RGD)3-NHI C, affinity of the multimeric RGD compounds for alpha(v)beta(3) integrin receptor (ABIR) showed a remarkable increase relative to the monomer cypate-RGD-NH2. Generally, the divalent linear arrays of the multimeric RGD units bound the ABIR with slightly higher affinity than their monovalent analogues. These results suggest that the receptor binding affinity was not only dependent on the number of RGD moieties but also on the spatial alignments of the pendant peptides. Internalization of the compounds by ABIR-positive tumor cells (A549) was monitored by NIR fluorescence microscopy. The data showed that endocytosis of the octameric RGD derivative was significantly higher by comparison to other compounds in this study. In vivo noninvasive optical imaging and biodistribution data showed that the compounds were retained in A549 tumor tissue. These results clearly demonstrated that an array of simple RGD tripeptides on a NIR fluorescent dye core can be recognized by ABIR. Optimization of the spatial alignment of the RGD moieties through careful en molecular design and library construction could induce multivalent ligand-receptor interactions useful for in vivo tumor imaging and tumor-targeted therapy.