Near-Infrared Neodymium Tag for Quantifying Targeted Biomarker and Counting Its Host Circulating Tumor Cells
Near-Infrared Neodymium Tag for Quantifying Targeted Biomarker and Counting Its Host Circulating Tumor Cells
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近红外钕标签用于量化目标生物标志物并对其宿主循环肿瘤细胞进行计数
DOI：
10.1021/acs.analchem.7b02016
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发表时间：
2017
影响因子：
7.4
通讯作者：
Wang Qiuquan
中科院分区：
文献类型：
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作者：
Liu Chunlan;Lu Shu;Yang Limin;Chen Peijie;Bai Peiming;Wang Qiuquan
复杂生物系统中目标分析物的定量信息是理解其相关机制的最基本前提，如果它是所谓的生物标志物，那么精确诊断疾病也是如此。在这里，我们设计并合成了带有双工信号、第二近红外（NIR）窗口的钕（Nd）核心标签[1,4,7,10-四氮杂环十二烷-1,4,7-三乙酸（DOTA）-Nd复合物以及光捕获天线氨基荧光素（AMF，λex/em= 494/520 nm），AMF-DOTA-Nd]发光（λem= 1065 nm，2.5 μs）和稳定同位素质量（142Nd）。 AMF-DOTA-Nd 与基于尿素的拟肽靶向基团 2-[3-(1,3-二羧丙基)-脲基]戊二酸 (DUPA)-8-Aoc-Phe-Phe-Cys (DUPAaFFC) (DUPAaFFC-AMF-DOTA-Nd) 共价连接，使我们能够检测和定量前列腺特异性膜抗原 (PSMA) 及其剪接变体（总 PSMA、tPSMA），在本研究中被设置为目标生物标志物的示例，使用 NIR 和电感耦合等离子体质谱 (ICPMS)，检测限 (LOD) (3σ) 为 0.3 ng/mL。当将其应用于对前列腺癌（PCa）和良性前列腺增生（BPH）患者以及健康志愿者的80份血液样本进行分析时，我们发现320和600 ng/mLtPSMA可以推荐作为区分BPH和PCa以及诊断PCa的阈值。此外，使用 ICPMS 对 PSMA 阳性循环肿瘤细胞 (CTC) 进行计数，当标记细胞跨膜 mPSMA 时，格里森评分为 6 至 9 的 PCa 血样中的 CTC 为 134 至 773 个。当其他特定目标基团被修改为 NIR Nd 标签时，开发的这种方法有望适用于液体活检中其他具有临床意义的生物分子及其宿主 CTC。
Quantitative information on a targeted analyte in a complex biological system is the most basic premise for understanding its involved mechanisms, and thus precise diagnosis of a disease if it is a so-called biomarker. Here, we designed and synthesized a neodymium (Nd)-cored tag [1,4,7,10-tetraazacyclododecane-1,4,7-trisacetic acid (DOTA)–Nd complex together with a light-harvesting antenna aminofluorescein (AMF, λex/em= 494/520 nm), AMF–DOTA–Nd] with duplex signals, second near-infrared (NIR) window luminescence (λem= 1065 nm, 2.5 μs), and stable isotopic mass (142Nd). AMF–DOTA–Nd covalently linked with a urea-based peptidomimetic targeting group, 2-[3-(1,3-dicarboxypropyl)-ureido]pentanedioic acid (DUPA)-8-Aoc-Phe-Phe-Cys (DUPAaFFC) (DUPAaFFC–AMF–DOTA–Nd), allowing us to detect and quantify prostate-specific membrane antigen (PSMA) and its splice variants (total PSMA,tPSMA), which was set as an example of targeted biomarkers in this study, using NIR and inductively coupled plasma mass spectrometry (ICPMS) with the limit of detection (LOD) (3σ) of 0.3 ng/mL. When it was applied to the analysis of 80 blood samples from prostate cancer (PCa) and benign prostatic hyperplasia (BPH) patients as well as healthy volunteers, we found that 320 and 600 ng/mLtPSMA could be recommended as the threshold values to differentiate BPH from PCa and for the diagnosis of PCa. Moreover, PSMA-positive circulating tumor cells (CTCs) were counted using ICPMS being from 134 to 773 CTCs in the PCa blood samples of the Gleason score from 6 to 9 when the cell membrane-spanningmPSMA was tagged. Such a methodology developed could be expected to be applicable to other clinic-meaningful biomolecules and their host CTCs in liquid biopsy, when other specific targeting groups are modified to the NIR Nd tag.