Vascular Endothelial Growth Factor Receptor 2-Specific Microbubbles for Molecular Ultrasound Detection of Prostate Cancer in a Rat Model

Abstract

To investigate whether rat prostate cancer can be detected by means of molecular ultrasound (US) using target-specific microbubbles versus a nonspecific contrast agent. A total of 20 Copenhagen rats were randomly examined 75 to 104 days after orthotopic implantation of G-Dunning rat prostatic tumor cells was using a high-end US system and either 1.2 mL/kg of the nonspecific agent A or 0.1 mL/kg of the target-specific agent B, containing vascular endothelial growth factor receptor 2 binding peptide. Contrast inflow (areas under the curve analysis) was determined during the first 30s, and all microbubbles were destroyed in the scan plane by means of the flash technique 20 minutes after intravenous administration to investigate specific accumulation of individual bubbles in tumors. Differences between normal prostate tissue and tumor were analyzed using luminance images. Sonographically determined tumor localization and extent were compared with magnetic resonance imaging and histology. The median tumor size in the 20 rats determined on US (2.3 mm) and magnetic resonance imaging (2.4 mm) showed a very high correlation (r = 0.92, P = 0.01). Both agent A and agent B demonstrated higher vascularization of tumor periphery compared with normal prostate (P < 0.05) based on contrast inflow and areas under the curve analysis. Twenty minutes after administration, luminance for agent B in the tumor was significantly higher (P = 0.003) compared with nonspecific agent A (11.8-0.1). In consensus reading, the increase in signal intensity of the tumor compared with normal prostate tissue was significantly higher for agent B (P = 0.005), whereas no significant difference was found for agent A (P = 0.180). The target-specific contrast agent was superior to the unspecific US contrast agent both with regard to early inflow analysis and specific accumulation in prostate cancer after 20 minutes.