Abstract
ObjectiveTo prepare arginine-glycine-aspartate (RGD)-targeted ultrasound contrast microbubbles (MBs) and explore the feasibility of their use in assessing dynamic changes in αvβ3 integrin expression in a murine model of tumor angiogenesis.MethodsRGD peptides were conjugated to the surfaces of microbubbles via biotin-avidin linkage. Microbubbles bearing RADfK peptides were prepared as controls. The RGD-MBs were characterized using an Accusizer 780 and optical microscopy. The binding specificity of the RGD-MBs for ανβ3-expressing endothelial cells (bEnd.3) was demonstrated in vitro by a competitive inhibition experiment. In an in vivo study, mice bearing tumors of three different stages were intravenously injected with RGD-MBs and subjected to targeted, contrast-enhanced, high-frequency ultrasound. Subsequently, tumors were harvested and sectioned for immunofluorescence analysis of ανβ3 expression.ResultsThe mean size of the RGD-MBs was 2.36 ± 1.7 μm. The RGD-MBs showed significantly higher adhesion levels to bEnd.3 cells compared to control MBs (P < 0.01). There was rarely binding of RGD-MBs to αvβ3-negative MCF-7 cells. Adhesion of the RGD-MBs to the bEnd.3 cells was significantly inhibited following treatment with anti-alpha(v) antibodies. The quantitative acoustic video intensity for high-frequency, contrast-enhanced ultrasound imaging of subcutaneous human laryngeal carcinoma (Hep-2) tumor xenografts was significantly higher in small tumors (19.89 ± 2.49) than in medium tumors (11.25 ± 2.23) and large tumors (3.38 ± 0.67) (P < 0.01).ConclusionsRGD-MBs enable noninvasive in vivo visualization of changes in tumor angiogenesis during tumor growth in subcutaneous cancer xenografts.
Highlights
Angiogenesis, the process of blood vessel formation and recruitment, is directly associated with malignancy and necessary for cancer survival and progression [1,2]
The quantitative acoustic video intensity for high-frequency, contrast-enhanced ultrasound imaging of subcutaneous human laryngeal carcinoma (Hep-2) tumor xenografts was significantly higher in small tumors (19.89 ± 2.49) than in medium tumors (11.25 ± 2.23) and large tumors (3.38 ± 0.67) (P < 0.01)
RGD-MBs enable noninvasive in vivo visualization of changes in tumor angiogenesis during tumor growth in subcutaneous cancer xenografts
Summary
Angiogenesis, the process of blood vessel formation and recruitment, is directly associated with malignancy and necessary for cancer survival and progression [1,2] Various molecular markers, such as ανβ integrin, are selectively overexpressed on the surfaces of tumor vascular endothelial cells and play crucial roles in the angiogenic process by mediating the adhesion of circulating cells to blood vessel walls and the migration of endothelial cells [3,4]. Contrast-enhanced, high-frequency ultrasonography is an attractive imaging method for the characterization of tumor angiogenesis, arteriosclerosis, thrombosis, lymph nodes, and inflammation [4,6,7,8,9,10]. One molecular targeting strategy is the conjugation of specific ligands, such as peptides, monoclonal antibodies, glycoproteins, and other small molecules, to microbubble shell surfaces [1]
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