Accelerated 19F·MRI Detection of Matrix Metalloproteinase-2/-9 through Responsive Deactivation of Paramagnetic Relaxation Enhancement.
Accelerated 19F·MRI Detection of Matrix Metalloproteinase-2/-9 through Responsive Deactivation of Paramagnetic Relaxation Enhancement.
复制标题
通过顺磁弛豫增强的响应失活加速 19F·MRI 检测基质金属蛋白酶-2/-9。
DOI：
10.1155/2019/4826520
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发表时间：
2019
影响因子：
--
通讯作者：
Faas HM
中科院分区：
文献类型：
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作者：
Faas HM
顺磁性钆离子（Gd III）与DOTA基螯合物复合，已成为增加感兴趣组织中磁共振成像（MRI）对比度的有用工具。最近，“开/关”探针作为靶酶的19 F·MRI生物传感器已经出现，其利用顺磁性Gd III中心裂解后横向（或T2）弛豫时间的增加。分子19 F·MRI由于缺乏背景信号而具有高特异性的优点，但信号强度低，导致空间分辨率低和记录时间长。在这项工作中，一个“开/关”探头的概念，利用顺磁弛豫增强（PRE）的响应失活产生19 F纵向（T1）弛豫对比加速分子MRI。探针概念应用于基质金属蛋白酶（MMP），这是一类与许多炎症性疾病和癌症相关的酶，可修饰生物活性细胞外底物。细胞外空间中这些生物标志物的存在使得MMP成为响应性PRE失活探针的可接近的靶标。在19 F生物传感器探针中的响应性PRE失活，对MMP-2和MMP-9具有选择性，与以前的方法相比，能够以显著减少的实验时间实现分子MRI对比。PRE失活由MMP通过蛋白酶底物的切割引起，所述蛋白酶底物充当含氟部分与顺磁性Gd III结合的DOTA复合物之间的接头。采用超短回波时间（UTE）MRI和标准梯度回波（GE）MRI中的短回波时间来科普PRE有源探头在其“开启状态”下的快速19 F横向弛豫。在响应性PRE失活后，来自“关闭状态”探针的19 F·MRI信号减弱，从而通过相关的阴性MRI对比度指示靶酶的存在。使用在短时间内获得的19 F·MRI，识别造影剂稀释引起的假阳性19 F·MRI反应。
Paramagnetic gadolinium ions (GdIII), complexed within DOTA‐based chelates, have become useful tools to increase the magnetic resonance imaging (MRI) contrast in tissues of interest. Recently, “on/off” probes serving as19F·MRI biosensors for target enzymes have emerged that utilize the increase in transverse (orT2) relaxation times upon cleavage of the paramagnetic GdIIIcentre. Molecular19F·MRI has the advantage of high specificity due to the lack of background signal but suffers from low signal intensity that leads to low spatial resolution and long recording times. In this work, an “on/off” probe concept is introduced that utilizes responsive deactivation of paramagnetic relaxation enhancement (PRE) to generate19F longitudinal (T1) relaxation contrast for accelerated molecular MRI. The probe concept is applied to matrix metalloproteinases (MMPs), a class of enzymes linked with many inflammatory diseases and cancer that modify bioactive extracellular substrates. The presence of these biomarkers in extracellular space makes MMPs an accessible target for responsive PRE deactivation probes. Responsive PRE deactivation in a19F biosensor probe, selective for MMP‐2 and MMP‐9, is shown to enable molecular MRI contrast at significantly reduced experimental times compared to previous methods. PRE deactivation was caused by MMP through cleavage of a protease substrate that served as a linker between the fluorine‐containing moiety and a paramagnetic GdIII‐bound DOTA complex. Ultrashort echo time (UTE) MRI and, alternatively, short echo times in standard gradient echo (GE) MRI were employed to cope with the fast19F transverse relaxation of the PRE active probe in its “on‐state.” Upon responsive PRE deactivation, the19F·MRI signal from the “off‐state” probe diminished, thereby indicating the presence of the target enzyme through the associated negative MRI contrast. Null point1H·MRI, obtainable within a short time course, was employed to identify false‐positive19F·MRI responses caused by dilution of the contrast agent.