The liver targeting of Mn-BnO-TyrEDTA and its preliminary application in a mouse liver cancer model
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摘要:
目的 评价锰苄基酪氨酸乙二胺四乙酸（Mn-BnO-TyrEDTA）MRI对比剂的肝靶向性及其在小鼠肝癌模型上的初步运用。 方法 经尾静脉注射相同剂量的Mn-BnO-TyrEDTA和钆塞酸二钠（Gd-EOB-DTPA），并对小鼠进行MRI动态增强扫描，持续1 h，以监测对比剂的分布和清除情况。同时在小鼠肝脏上注射肝癌细胞H22（1×105/30 μL）和基质胶（25 μL）的混合液以建立肝癌模型，并对上述模型进行MRI。将钆喷葡胺作为对照组。 结果 注射Mn-BnO-TyrEDTA 1 min后肝脏开始强化，信号强度在3 min时达到峰值并持续至30 min；1 min后血液和肾脏信号强度开始明显降低，3 min后可见对比剂进入膀胱。通过比较3 min归一化信噪比和对比噪声比，判断两种对比剂肝靶向的强弱：Mn-BnO-TyrEDTA的归一化信噪比和对比噪声比分别为3.07±0.38和11±4.0，Gd-EOB-DTPA的归一化信噪比和对比噪声比分别为2.06±0.11和4.4±0.4，差异有统计学意义（P<0.05）。与正常肝实质比较，小鼠肝癌模型的肝内病灶呈明显低信号。 结论 Mn-BnO-TyrEDTA具有肝靶向性，并且经肝脏和肾脏双重途径清除，其在1~5 min的肝靶向性明显强于Gd-EOB-DTPA。小鼠肝癌模型的肝内病灶与周围正常肝实质具有较好的信号差异。 -
关键词:
- 锰苄基酪氨酸乙二胺四乙酸 /
- 肝靶向MRI对比剂 /
- 钆塞酸二钠 /
- 钆喷葡胺 /
- 肝癌模型
Abstract:Objective To evaluate the liver targeting of manganese benzyltyrosine ethylenediamine tetraacetic acid (Mn-BnO-TyrEDTA) MRI contrast agent and its preliminary application in mouse liver cancer model. Methods Mice were given by the same dose of Mn-BnO-TyrEDTA and disodium gadolinium serate (Gd-EOB-DTPA) via a caudal vein, and dynamic enhanced MRI scans were performed for 1 h to monitor the distribution and clearance of contrast agents. Simultaneously injecting liver cancer cell H22 (1×105/30 μL) into mouse liver and matrix adhesive (25 μL) using a mixed solution to establish a liver cancer model and perform MRI imaging. Gd-DTPA was used as the control group. Results After injecting Mn-BnO-TyrEDTA for 1 min, the liver began to strengthen, and the signal intensity reached its peak at 3 min and continued until 30 min; After 1 min, the blood and kidney signal intensity began to significantly decrease, and after 3 min, the contrast agent entered the bladder. By comparing the normalized signal‑to‑noise ratio and contrast‑to‑noise ratio for 3 min, it was determined that the liver targeting values of the two contrast agents were 3.07±0.38 and 11±4.0 for Mn-BnO-TyrEDTA and 2.06±0.11 and 4.4±0.4 for Gd-EOB-DTPA, respectively, with statistical differences (P<0.05). Compared with normal liver parenchyma, the intrahepatic lesions in the mouse liver cancer model showed significantly low signal intensity. Conclusion Mn-BnO-TyrEDTA has liver targeting, and it is cleared through both liver and kidney pathways. Its liver targeting is significantly stronger than Gd-EOB-DTPA at 1-5 min. There is a good signal difference between the intrahepatic lesions of the mouse liver cancer model and the surrounding normal liver parenchyma. -
图 1 小鼠MRI
Figure 1. Mouse MRI. A, G: Plain MRI images of mice; B-F: Images of mice injected with contrast agent Mn-BnO-TyrEDTA; H-L: Images of mice injected with contrast agent Gd-EOB-DTPA.
图 2 注射相同剂量的Mn-BnO-TyrEDTA与Gd-EOB-DTPA以后，小鼠肝脏、血液、肾脏的MRI nSNR-Time曲线图和∆CNR柱状图
Figure 2. Comparison of MRI nSNR-Time curves and ∆CNR histograms of mouse liver, blood, and kidneys after injection of the same dose of Mn-BnO-TyrEDTA and Gd-EOB-DTPA. A: MRI nSNR-Time curve of mouse liver; B: MRI nSNR-Time curve of mouse blood; C: MRI nSNR-Time curve of the kidney; D: Histogram of ∆CNR in the liver of mice in the first 5 min.
图 3 测量小鼠各组织Mn浓度含量
Figure 3. Measurement of Mn concentration in various tissues of mice. ICP-MS measurement of Mn concentration in various tissues of mice 24 h after injection of Mn-BnO-TyrEDTA (n=3), and the control group was mice without injection of contrast agent (n=3).
图 4 小鼠肝癌模型MRI
Figure 4. Mouse liver cancer model MRI. A: T1WI plain scan images of mouse liver cancer; B-D: Image of mice injected with contrast agent Gd-DTPA; E: Mouse liver cancer T2WI; F-H: Injection contrast agent Mn-BnO-TyrEDTA mouse image. ST: Stomach; L: Liver; T: Tumor.
表 1 注射相同剂量的两种对比剂在小鼠肝脏中的MRI信号强度
Table 1. MRI signal intensity of two contrast agents injected with the same dose in mouse liver (n=5)
Injection time SI Mn-BnO-TyrEDTA Gd-EOB-DTPA t P 3 min nSNR 3.07±0.38 2.06±0.11 4.354 0.004 CNR 11±4.0 4.4±0.4 2.79 0.03 SI: Signal intensity. 
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