Diagnostic Significance of pH-Responsive Gd³⁺-Based T₁ MR Contrast Agents

We discuss recent advances in Gd-based T₁-weighted MR contrast agents for the mapping of cellular pH. The pH plays a critical role in various biological processes. During the past two decades, several MR contrast agents of strategic importance for pH-mapping have been developed. Some of these agents shed light on the pH fluctuation in the tumor microenvironment. A pH-responsive self-assembled contrast agent facilitates the visualization of tumor size as small as 3 mm³. Optimization of various parameters is crucial for the development of pH-responsive contrast agents. In due course, the new contrast agents may provide significant insight into pH fluctuations in the human body.

Visualization of Tumor Angiogenesis Using MR Imaging Contrast Agent Gd-DTPA-anti-VEGF Receptor 2 Antibody Conjugate in a Mouse Tumor Model

OBJECTIVE: To visualize tumor angiogenesis using the MRI contrast agent, Gd-DTPA-anti-VEGF receptor 2 antibody conjugate, with a 4.7-Tesla MRI instrument in a mouse model. MATERIALS AND METHODS: We designed a tumor angiogenesis-targeting T1 contrast agent that was prepared by the bioconjugation of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and an anti-vascular endothelial growth factor receptor-2 (VEGFR2) antibody. The specific binding of the agent complex to cells that express VEGFR2 was examined in cultured murine endothelial cells (MS-1 cells) with a 4.7-Tesla magnetic resonance imaging scanner. Angiogenesis-specific T1 enhancement was imaged with the Gd-DTPA-anti-VEGFR2 antibody conjugate using a CT-26 adenocarcinoma tumor model in eight mice. As a control, the use of the Gd-DTPA-anti-rat immunoglobulin G (Gd-DTPA-anti-rat IgG) was imaged with a tumor model in eight mice. Statistical significance was assessed using the Mann-Whitney test. Tumor tissue was examined by immunohistochemical analysis. RESULTS: The Gd-DTPA-anti-VEGFR2 antibody conjugate showed predominant binding to cultured endothelial cells that expressed a high level of VEGFR2. Signal enhancement was approximately three-fold for in vivo T1-weighted MR imaging with the use of the Gd-DTPA-anti-VEGFR2 antibody conjugate as compared with the Gd-DTPA-rat IgG in the mouse tumor model (p < 0.05). VEGFR2 expression in CT-26 tumor vessels was demonstrated using immunohistochemical staining. CONCLUSION: MR imaging using the Gd-DTPA-anti-VEGFR2 antibody conjugate as a contrast agent is useful in visualizing noninvasively tumor angiogenesis in a murine tumor model.

Evaluation by Contrast-Enhanced MR Imaging of the Lateral Border Zone in Reperfused Myocardial Infarction in a Cat Model

OBJECTIVE: To identify and evaluate the lateral border zone by comparing the size and distribution of the abnormal signal area demonstrated by MR imaging with the infarct area revealed by pathological examination in a reperfused myocardial infarction cat model. MATERIALS AND METHODS: In eight cats, the left anterior descending coronary artery was occluded for 90 minutes, and this was followed by 90 minutes of reper-fusion. ECG-triggered breath-hold turbo spin-echo T2-weighted MR images were initially obtained along the short axis of the heart before the administration of contrast media. After the injection of Gadomer-17 and Gadophrin-2, contrast-enhanced T1-weighted MR images were obtained for three hours. The size of the abnormal signal area seen on each image was compared with that of the infarct area after TTC staining. To assess ultrastructural changes in the myocardium at the infarct area, lateral border zone and normal myocardium, electron microscopic examination was performed. RESULTS: The high signal area seen on T2-weighted images and the enhanced area seen on Gadomer-17-enhanced T1WI were larger than the enhanced area on Gadophrin-2-enhanced T1WI and the infarct area revealed by TTC staining; the difference was expressed as a percentage of the size of the total left ventricle mass (T2= 39.2 %; Gadomer-17 =37.25 % vs Gadophrin-2 = 29.6 %; TTC staining = 28.2 %; p < 0.05). The ultrastructural changes seen at the lateral border zone were compatible with reversible myocardial damage. CONCLUSION: In a reperfused myocardial infarction cat model, the presence and size of the lateral border zone can be determined by means of Gadomer-17- and Gadophrin-2-enhanced MR imaging.

Gadomer-17 in Contrast Enhanced MR Imaging of Reperfused Myocardial Infarction in a Cat Model

PURPOSE: To evaluate in reperfused myocardial infarction in a cat model, the time-course of signal enhancement as seen on Gadomer-17 enhanced MRI, and to correlate the size of the enhanced area with that of the infarct area as revealed by on histochemical examination. MATERIALS AND METHODS: Five cats which had undergone occlusion of the LAD followed by reperfusion underwent MR imaging. After T2-weighted imaging, Gadomer-17 enhanced T1-weighted images were obtained in four cats during a six-hour period, and in one during a three-hour period. Signal intensities were measured in the enhanced and non-enhanced areas of enhanced T1-weighted images. and using 2,3,5-triphenyl tetrazolium chloride (TTC) histochemical staining, the size of the abnormal signal area on each image was compared with that of the infarct area. RESULT: The enhanced area seen on enhanced T1-weighted images showed rapidly increased signal intensity following the administration of Gadomer-17. Maximum enhancement was detected during a 40 -60 minutes period, with an average enhancement of 168 +/-9.9% of normal myocardium. TTC staining revealed that the size of the high signal area on T2-weighted images and of the enhanced area on enhanced T1-weighted images was greater than that of the infarct area (p<0.05). CONCLUSION: In reperfused myocardial infarction in a cat model, Gadomer-17 enhanced MR imaging delineates both reversibly and irreversibly damaged myocardium, with strong enhancement and a broad temporal window. We may therefore expect that Gadomer-17 is useful for demonstrating myocardial injury.