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Paired Agent Fluorescence Imaging of Cancer in a Living Mouse Using Preassembled Squaraine Molecular Probes with Emission Wavelengths of 690 and 830 nm.
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2019-12-06 , DOI: 10.1021/acs.bioconjchem.9b00750
Cynthia L Schreiber 1 , Canjia Zhai 1 , Janel M Dempsey 1 , Hannah H McGarraugh 1 , Braden P Matthews 1 , Caroline R Christmann 1 , Bradley D Smith 1
Affiliation  

New methods are described for the construction of targeted fluorescence probes for imaging cancer and the assessment of tumor targeting performance in a living mouse model. A novel noncovalent assembly process was used to fabricate a set of structurally related targeted fluorescent probes with modular differences in three critical assembly components: the emission wavelength of the squaraine fluorochrome, the number of cRGDfK peptide units that target the cancer cells, and the length of the polyethylene glycol chains as pharmacokinetic controllers. Selective targeting of cancer cells was proven by a series of cell microscopy experiments followed by in vivo imaging of subcutaneous tumors in living mice. The mouse imaging studies included a mock surgery that completely removed a fluorescently labeled tumor. Enhanced tumor accumulation due to probe targeting was first evaluated by conducting Single Agent Imaging (SAI) experiments that compared tumor imaging performance of a targeted probe and untargeted probe in separate mouse cohorts. Although there was imaging evidence for enhanced tumor accumulation of the targeted probe, there was moderate scatter in the data due to tumor-to-tumor variability of the vasculature structure and interstitial pressure. A subsequent Paired Agent Imaging (PAI) study coinjected a binary mixture of targeted probe (with emission at 690 nm) and untargeted probe (with emission at 830 nm) into the same tumor-burdened animal. The conclusion of the PAI experiment also indicated enhanced tumor accumulation of the targeted probe, but the statistical significance was much higher, even though the experiment required a much smaller cohort of mice. The imaging data from the PAI experiment was analyzed to determine the targeted probe's Binding Potential (BP) for available integrin receptors within the tumor tissue. In addition, pixelated maps of BP within each tumor indicated a heterogeneous spatial distribution of BP values. The results of this study show that the combination of fluorescent probe preassembly and PAI is a promising new way to rapidly develop targeted fluorescent probes for tumors with high BP and eventual use in clinical applications such as targeted therapy, image guided surgery, and personalized medicine.

中文翻译:

使用预装配的690和830 nm发射波长的Squaraine分子探针在活体小鼠中对癌症进行配对药剂荧光成像。

描述了构建用于成像癌症的靶向荧光探针和评估活小鼠模型中肿瘤靶向性能的新方法。一种新颖的非共价组装工艺用于制造一组结构相关的靶向荧光探针,其在三个关键组装组件中具有模块差异:方酸荧光染料的发射波长,靶向癌细胞的cRGDfK肽单元的数量以及聚乙二醇链作为药代动力学的控制因子。一系列细胞显微镜实验证明了对癌细胞的选择性靶向,随后对活体小鼠的皮下肿瘤进行了体内成像。小鼠影像学研究包括模拟手术,该手术完全去除了荧光标记的肿瘤。首先通过进行单剂成像(SAI)实验评估由于探针靶向引起的增强的肿瘤积累,该实验比较了在单独的小鼠队列中靶向探针和非靶向探针的肿瘤成像性能。尽管有影像学证据显示靶向探针的肿瘤积累增强,但由于脉管系统结构和间质压力在肿瘤之间的变异性,数据中存在中等程度的分散。后续的配对剂成像(PAI)研究将目标探针(在690 nm处发射)和非目标探针(在830 nm处发射)的二元混合物共同注射到同一肿瘤负荷大的动物中。PAI实验的结论还表明目标探针的肿瘤蓄积增强,但统计学意义要高得多,即使实验要求的小鼠群要小得多。分析来自PAI实验的成像数据,以确定肿瘤组织内可用的整​​联蛋白受体的目标探针结合电位(BP)。此外,每个肿瘤内的BP像素化图谱表明BP值的空间分布不均。这项研究的结果表明,荧光探针预组装和PAI的结合是一种有前途的新方法,可以快速开发针对具有高BP肿瘤的靶向荧光探针,并最终在诸如靶向治疗,图像引导手术和个性化医学等临床应用中使用。每个肿瘤内的BP像素化图表明BP值的空间分布不均。这项研究的结果表明,荧光探针预组装和PAI的结合是一种有前途的新方法,可以快速开发针对具有高BP肿瘤的靶向荧光探针,并最终在诸如靶向治疗,图像引导手术和个性化医学等临床应用中使用。每个肿瘤内的BP像素化图表明BP值的空间分布不均。这项研究的结果表明,荧光探针预组装和PAI的结合是一种有前途的新方法,可以快速开发具有高BP的肿瘤靶向荧光探针,并最终用于诸如靶向治疗,图像引导手术和个性化医学等临床应用。
更新日期:2019-12-07
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