Microbubble Contrast Agents for Molecular Ultrasound Imaging of Tumor Vasculature

Molecular ultrasound imaging was proposed more than two decades ago. The ultrasound contrast agents used for selective targeting of vascular biomarkers of disease are formulated as gas microbubbles surrounded by a thin shell.Microbubbles are decorated by the ligands that specifically bind to the biomarkers of disease overexpressed on the surface of vascular endothelium. The microbubble gas core is most often a poorly soluble perfluorinated gas (preferably C₄F₁₀ as the least soluble), to assure circulation lifetime for at least several minutes. The gas from circulating bubbles is exhaled via the lungs; bubbles collapse and lose echogenicity. As the circulating bubbles clear from the bloodstream, adherent targeted bubbles are still retained in the tumor microvasculature and provide strong acoustic backscatter and ultrasound detection capability. A critical feature that enables ultrasound use in molecular imaging, specifically in the oncology setting, is the detection sensitivity, already enabled in medical imaging equipment. Individual microbubbles, with sub-picogram mass, can be visualized in real time, many cm deep in the body. This chapter discusses microbubble preparation and attachment of targeting ligands to the microbubble shell. The logic of the performance of ultrasound molecular imaging is discussed, followed by an assessment of a number of imaging tools.