Microbubbles coated with antibody to intracellular adhesion molecule-1

Excerpt

Ultrasound is widely used imaging modality (1) and is expanding its role in noninvasive molecular imaging with ligand-carrying microbubbles (2). Microbubbles are comprised of spherical cavities filled by a gas encapsulated in a shell. The shells are made of phospholipids, surfactant, denatured human serum albumin or synthetic polymer. Ligands and antibodies can be incorporated into the shell surface of microbubbles. Microbubbles are usually 2 to 8 μm in size. They provide a strongly reflective interface and resonate to ultrasound waves. They are used as ultrasound contrast agents in imaging of inflammation, angiogenesis, intravascular thrombus, and tumors (3-5). They are also potentially used for drug and gene delivery (6).

Endothelial cells are important cells in inflammatory responses (7, 8). Bacterial lipopolysaccharide, virus, inflammation, and tissue injury increase tumor necrosis factor α (TNFα), interleukin-1 (IL-1) and other cytokine and chemokine secretion. Leukocyte emigration from blood is dependent on their rolling along endothelial cell surfaces and subsequently adherence to endothelial cell surfaces. Inflammatory mediators and cytokines induce chemokine secretion from endothelial cells and other vascular cells and increase their expression of cell surface adhesion molecules, such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), integrins and selectins. Chemokines are chemotactic to leukocytes to sites of inflammation and tissue injury. The movements of leukocytes through endothelial junctions into the extravascular space are highly orchestrated through various interactions with different adhesion molecules on endothelial cells (9).

ICAM-1 is found on cell surface of endothelial cells and other vascular cells, such as smooth muscle cells and fibroblasts (10-14). It binds to counter-receptors on the cell-surface of leukocytes. IL-1 and TNFα increase ICAM-1 and other cell adhesion molecule expression on the vascular endothelial cells, leading to leukocyte adhesion to the activated endothelium. Microbubbles targeted with antibody against ICAM-1 are being developed as a noninvasive agent for ICAM-1 expression in vascular endothelial cells of dysfunctional endothelium (15-18).