Dual In Vivo Quantification of Integrin-targeted and Protease-activated Agents in Cancer Using Fluorescence Molecular Tomography (FMT)
Dual In Vivo Quantification of Integrin-targeted and Protease-activated Agents in Cancer Using Fluorescence Molecular Tomography (FMT)
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DOI：
10.1007/s11307-009-0279-z
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发表时间：
2010-10-01
影响因子：
3.1
通讯作者：
Bednar, Bohumil
中科院分区：
文献类型：
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作者：
Kossodo, Sylvie;Pickarski, Maureen;Bednar, Bohumil
整合素，特别是α（v）β（3）和α（v）β（5），在肿瘤细胞和活化的内皮细胞中上调，因此，作为癌症生物标志物。我们开发了一种新的近红外标记的光学试剂，用于体内检测和定量α（v）β（3）/α（v）β（5）。合成了一种小肽模拟物α（v）β（3）拮抗剂，与近红外荧光（NIRF）染料偶联，并在整合素过表达细胞中检测结合特异性，抑制玻连蛋白介导的细胞粘附，体外与肿瘤和内皮细胞结合，竞争研究。在体内对药物动力学、生物分布、肿瘤靶向特异性和抗血管生成治疗的效果进行了评估。整合素NIRF试剂在体外对α（v）β（3/）α（v）β（5）显示出很强的选择性，在体内主要分布于肿瘤，从而可以无创和实时定量肿瘤中的整合素信号。抗血管生成治疗显着抑制体内整合素信号，但对组织蛋白酶可裂解的NIR试剂没有影响。同时成像揭示了不同的分布模式，反映了肿瘤进展过程中整合素和组织蛋白酶生物学的潜在差异。NIRF标记的整合素拮抗剂可以在体内对肿瘤进行非侵入性分子荧光成像和定量，改善并提供更精确的癌症检测和治疗监测方法。
Integrins, especially alpha(v)beta(3) and alpha(v)beta(5), are upregulated in tumor cells and activated endothelial cells and as such, serve as cancer biomarkers. We developed a novel near-infrared-labeled optical agent for the in vivo detection and quantification of alpha(v)beta(3)/alpha(v)beta(5).A small peptidomimetic alpha(v)beta(3) antagonist was synthesized, coupled to a near-infrared fluorescent (NIRF) dye, and tested for binding specificity using integrin-overexpressing cells, inhibition of vitronectin-mediated cell attachment, binding to tumor and endothelial cells in vitro, and competition studies. Pharmacokinetics, biodistribution, specificity of tumor targeting, and the effect of an antiangiogenic treatment were assessed in vivo.The integrin NIRF agent showed strong selectivity towards alpha(v)beta(3/)alpha(v)beta(5) in vitro and predominant tumor distribution in vivo, allowing noninvasive and real-time quantification of integrin signal in tumors. Antiangiogenic treatment significantly inhibited integrin signal in vivo but had no effect on a cathepsin-cleavable NIR agent. Simultaneous imaging revealed different patterns of distribution reflecting the underlying differences in integrin and cathepsin biology during tumor progression.NIRF-labeled integrin antagonists allow noninvasive molecular fluorescent imaging and quantification of tumors in vivo, improving and providing more refined approaches for cancer detection and treatment monitoring.