Unlabeled aspirin as an activatable theranostic MRI agent for breast cancer.
Unlabeled aspirin as an activatable theranostic MRI agent for breast cancer.
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DOI：
10.7150/thno.53147
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
McMahon MT
中科院分区：
文献类型：
--
作者：
Pavuluri K;Yang E;Ayyappan V;Sonkar K;Tan Z;Tressler CM;Bo S;Bibic A;Glunde K;McMahon MT
基本原理：化学交换饱和转移（CEST）磁共振成像（MRI）正在成为钆对比MRI的替代方案。我们评估了原位乳腺肿瘤异种移植物CEST MRI的可能性，未标记的阿司匹林通过各种酶活性转化为水杨酸（SA），最显著的是抑制环氧合酶（考克斯）-1/-2酶。研究方法：我们用Western Blot分析检测了考克斯-1/-2在四种乳腺癌细胞系中的表达，并选择了表达最高和最低的细胞系。然后，我们在阿司匹林治疗后进行CEST MRI以检测SA水平，并进行ELISA以测量下游前列腺素E2（PGE 2）的水平。我们还将阿司匹林注射到生长原位肿瘤异种移植物的小鼠的尾静脉中，所述原位肿瘤异种移植物表达高和低考克斯-1/-2，并且获得这些肿瘤异种移植物的SA CEST MR图像长达70分钟。然后收获肿瘤进行Western印迹和ELISA实验，分别测量考克斯-1/-2表达和PGE 2水平。结果如下：蛋白质印迹法确定SUM 159细胞含有比MDA-MB-231细胞显著更高的考克斯-1/-2表达水平，与更高水平的下游PGE 2一致。SA CEST MRI对两种细胞系产生了相似的对比度，约为3%，与考克斯-1/-2表达水平无关。阿司匹林治疗后，PGE 2水平下降约50%。来自我们的小鼠研究的结果与培养的细胞一致，在注射后1小时，MDA-MB-231和SUM 159肿瘤异种移植物模型中的总体SA CEST MRI对比度为5~8%。SUM 159中的PGE 2水平比MDA-MB-231高10倍，并且降低了50%。CEST对比度直接取决于注射剂量，注射100 µL 300 mM、200 mM和150 mM阿司匹林后分别观察到约6%、约3%和约1.5%的对比度。结论：我们的数据表明，使用阿司匹林作为非侵入性可激活CEST MRI造影剂用于乳腺肿瘤检测的可行性。
Rationale: Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is emerging as an alternative to gadolinium-based contrast MRI. We have evaluated the possibility of CEST MRI of orthotopic breast tumor xenografts with unlabeled aspirin's conversion to salicylic acid (SA) through various enzymatic activities, most notably inhibition of cyclooxygenase (COX)-1/-2 enzymes. Methods: We measured the COX-1/-2 expression in four breast cancer cell lines by Western Blot analysis and selected the highest and lowest expressing cell lines. We then performed CEST MRI following aspirin treatment to detect SA levels and ELISA to measure levels of downstream prostaglandin E2 (PGE2). We also injected aspirin into the tail vein of mice growing orthotopic tumor xenografts which expressed high and low COX-1/-2 and acquired SA CEST MR images of these tumor xenografts for up to 70 minutes. Tumors were then harvested to perform Western Blot and ELISA experiments to measure COX-1/-2 expression and PGE2 levels, respectively. Results: Western Blots determined that SUM159 cells contained significantly higher COX-1/-2 expression levels than MDA-MB-231 cells, in line with higher levels of downstream PGE2. SA CEST MRI yielded similar contrast at approximately 3% for both cell lines, independent of COX-1/-2 expression level. PGE2 levels decreased by about 50% following aspirin treatment. Results from our mouse study aligned with cultured cells, the overall SA CEST MRI contrast in both MDA-MB-231 and SUM159 tumor xenograft models was 5~8% at one hour post injection. PGE2 levels were ten times higher in SUM159 than MDA-MB-231 and decreased by 50%. The CEST contrast directly depended on the injected dose, with ~6%, ~3% and ~1.5% contrast observed following injection of 100 µL of 300 mM, 200 mM and 150 mM aspirin, respectively. Conclusions: Our data demonstrate the feasibility of using aspirin as a noninvasive activatable CEST MRI contrast agent for breast tumor detection.