A novel molecular magnetic resonance imaging agent targeting activated leukocyte cell adhesion molecule as demonstrated in mouse brain metastasis models

Abstract

Molecular magnetic resonance imaging (MRI) allows visualization of biological processes at the molecular level. Upregulation of endothelial ALCAM (activated leukocyte cell adhesion molecule) is a key element for leukocyte recruitment in neurological disease. The aim of this study, therefore, was to develop a novel molecular MRI contrast agent, by conjugating anti-ALCAM antibodies to microparticles of iron oxide (MPIO), for detection of endothelial ALCAM expression in vivo. Binding specificity of ALCAM-MPIO was demonstrated in vitro under static and flow conditions. Subsequently, in a proof-of-concept study, mouse models of brain metastasis were induced by intracardial injection of brain-tropic human breast carcinoma, lung adenocarcinoma or melanoma cells to upregulate endothelial ALCAM. At selected time-points, mice were injected intravenously with ALCAM-MPIO, and ALCAM-MPIO induced hypointensities were observed on T2*-weighted images in all three models. Post-gadolinium MRI confirmed an intact blood-brain barrier, indicating endoluminal binding. Correlation between endothelial ALCAM expression and ALCAM-MPIO binding was confirmed histologically. Statistical analysis indicated high sensitivity (80–90%) and specificity (79–83%) for detection of endothelial ALCAM in vivo with ALCAM-MPIO. Given reports of endothelial ALCAM upregulation in numerous neurological diseases, this advance in our ability to image ALCAM in vivo may yield substantial improvements for both diagnosis and targeted therapy.

The Clinical and Theranostic Values of Activated Leukocyte Cell Adhesion Molecule (ALCAM)/CD166 in Human Solid Cancers

“…It appears that the main source of ALCAM in brain imaging and histology analyses is likely to be endothelial cells, and normal brain tissue appears to be negative, emphasising the relatively exclusive nature of ALCAM in the cell type. The other interesting finding is that the blood-brain barrier appears to be intact as the metastatic legion had virtually no trace from the conjugate [137]. This is a very interesting finding, however, with some limitations.…”

“…Brain metastases in selenoglycoprotein fed mice had markedly reduced brain metastasis and tumour intra-and extravasation in brain vasculatures, which appears to be a result of reduction in ALCAM and PECAM1 in the mice [122]. Other work has shown that an antibody to ALCAM can recognise well endothelial cells surrounding metastatic tumours of the brain [137], indicating a cell-based targeting possibility, namely targeting tumourassociated endothelium. However, a great deal has yet to be learned here.…”

“…Other work using ALCAM as an imaging target tool has been recently attempted. Zarghami and colleagues have conjugated iron oxide microparticles to anti-ALCAM (mouse) antibody and used the conjugate as an imaging tool to detect brain metastasis from various tumour types [137]. The conjugate injection has resulted in the detection of small metastatic foci from the breast, melanoma, and lung cancers on MRI, as hypodensity regions.…”

Radioimmunotherapy for Brain Metastases: The Potential for Inflammation as a Target of Choice

“…In preclinical studies, blocking VLA-4 or ALCAM on tumour cells ( via incubation with neutralizing antibodies) resulted in a significant decrease in the number and volume of BM in comparison to the unblocked cells ( 19 ). Importantly, endothelial CAM overexpression has been observed in early BM in both preclinical studies and human tissue ( 20 , 21 ). VCAM-1, in particular, has been presented as a major biomarker of tumorigenesis in many types of cancers, further reinforcing its early biomarker status ( 22 ).…”

Current landscape and future perspectives in preclinical MR and PET imaging of brain metastasis

“…ALCAM-MPIO induced hypointensities were seen on T2* weighted MRI in all models, while post gadolinium MRI showed that the BBB was intact. 57 …”