Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma

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  • Tsuruta, James K.
    • Affiliation: School of Medicine, Department of Pediatrics
    • Other Affiliation: Joint Department of Biomedical Engineering; North Carolina State University; University of North Carolina at Chapel Hill
  • Schaub, Nicholas P.
    • Affiliation: School of Medicine, Department of Surgery
  • Rojas, Juan D.
    • Other Affiliation: Joint Department of Biomedical Engineering; North Carolina State University; University of North Carolina at Chapel Hill
  • Streeter, Jason
    • Other Affiliation: Engineering Science; Loyola University Chicago
  • Klauber-DeMore, Nancy
    • Other Affiliation: Engineering Science; Loyola University Chicago
  • Dayton, Paul
    • Affiliation: Eshelman School of Pharmacy, Division of Molecular Pharmaceutics
    • Other Affiliation: Joint Department of Biomedical Engineering; North Carolina State University; University of North Carolina at Chapel Hill
Abstract
  • Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. Previously, we showed ultrasound molecular imaging with SFRP2-targeted contrast increased average video pixel intensity (VI) of angiosarcoma vessels by 2.2 ± 0.6 VI versus streptavidin contrast. We hypothesized that redesigning our contrast agents would increase imaging performance. Improved molecular imaging reagents were created by combining NeutrAvidin™-functionalized microbubbles with biotinylated SFRP2 or IgY control antibodies. When angiosarcoma tumors in nude mice reached 8 mm, time-intensity, antibody loading, and microbubble dose experiments optimized molecular imaging. 10 minutes after injection, the control-subtracted time-intensity curve (TIC) for SFRP2-targeted contrast reached a maximum, after subtracting the contribution of free-flowing contrast. SFRP2 antibody-targeted VI was greater when contrast was formulated with 10-fold molar excess of maleimide-activated NeutrAvidin™ versus 3-fold (4.5 ± 0.18 vs. 0.32 ± 0.15, VI ± SEM, 5 x 106 dose, p < 0.001). Tumor vasculature returned greater average video pixel intensity using 5 x 107 versus 5 x 106 microbubbles (21.2 ± 2.5 vs. 4.5 ± 0.18, p = 0.0011). Specificity for tumor vasculature was confirmed by low VI for SFRP2-targeted, and control contrast in peri-tumoral vasculature (3.2 ± 0.52 vs. 1.6 ± 0.71, p = 0.92). After optimization, average video pixel intensity of tumor vasculature was 14.2 ± 3.0 VI units higher with SFRP2-targeted contrast versus IgY-targeted control (22.1 ± 2.5 vs. 7.9 ± 1.6, p < 0.001). After log decompression, 14.2 ΔVI was equal to ~70% higher signal, in arbitray acoustic units (AU), for SFRP2 versus IgY. This provided ~18- fold higher acoustic signal enhancement than provided previously by 2.2 ΔVI. Basing our targeted contrast on NeutrAvidin™-functionalized microbubbles, using IgY antibodies for our control contrast, and optimizing our imaging protocol significantly increased the SFRP2-specific signal returned from angiosarcoma vasculature, and may provide new opportunities for targeted molecular imaging.
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  • Article
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  • In Copyright
Journal title
  • PloS One
Journal volume
  • 12
Journal issue
  • 3
Page start
  • e0174281
Language
  • English
ISSN
  • 1932-6203

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