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Assessment of Molecular Acoustic Angiography for Combined Microvascular and Molecular Imaging in Preclinical Tumor Models

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Abstract

Purpose

The purposes of the present study is to evaluate a new ultrasound molecular imaging approach in its ability to image a preclinical tumor model and to investigate the capacity to visualize and quantify co-registered microvascular and molecular imaging volumes.

Procedures

Molecular imaging using the new technique was compared with a conventional ultrasound molecular imaging technique (multi-pulse imaging) by varying the injected microbubble dose and scanning each animal using both techniques. Each of the 14 animals was randomly assigned one of three doses; bolus dose was varied, and the animals were imaged for three consecutive days so that each animal received every dose. A microvascular scan was also acquired for each animal by administering an infusion of nontargeted microbubbles. These scans were paired with co-registered molecular images (VEGFR2-targeted microbubbles), the vessels were segmented, and the spatial relationships between vessels and VEGFR2 targeting locations were analyzed. In five animals, an additional scan was performed in which the animal received a bolus of microbubbles targeted to E- and P-selectins. Vessel tortuosity as a function of distance from VEGF and selectin targeting was analyzed in these animals.

Results

Although resulting differences in image intensity due to varying microbubble dose were not significant between the two lowest doses, superharmonic imaging had significantly higher contrast-to-tissue ratio (CTR) than multi-pulse imaging (mean across all doses 13.98 dB for molecular acoustic angiography vs. 0.53 dB for multi-pulse imaging; p = 4.9 × 10−10). Analysis of registered microvascular and molecular imaging volumes indicated that vessel tortuosity decreases with increasing distance from both VEGFR2- and selectin-targeting sites.

Conclusions

Molecular acoustic angiography (superharmonic molecular imaging) exhibited a significant increase in CTR at all doses tested due to superior rejection of tissue artifact signals. Due to the high resolution of acoustic angiography molecular imaging, it is possible to analyze spatial relationships in aligned microvascular and molecular superharmonic imaging volumes. Future studies are required to separate the effects of biomarker expression and blood flow kinetics in comparing local tortuosity differences between different endothelial markers such as VEGFR2, E-selectin, and P-selectin.

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Acknowledgments

This work was supported by grants R01CA170665, R01CA189479, U01CA189281, F32EB018715, and T32HL069768 from the National Institutes of Health. We thank Mike Lee and Emmanuel Cherin for their contributions to the design and fabrication of prototype transducers. Animal studies were performed within the Lineberger Comprehensive Cancer Center (LCCC) Animal Studies Core Facility at the University of North Carolina at Chapel Hill. The LCCC Animal Studies Core is supported in part by an NCI Center Core Support Grant (CA16086) to the UNC Lineberger Comprehensive Cancer Center.

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Authors and Affiliations

  1. Joint Department of Biomedical Engineering, University of North Carolina-Chapel Hill and North Carolina State University, Raleigh, NC, USA

    Brooks D. Lindsey, Sarah E. Shelton & Paul A. Dayton

  2. Sunnybrook Health Sciences Centre, Toronto, ON, Canada

    F. Stuart Foster

  3. Biomedical Research Imaging Center, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    Paul A. Dayton

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  1. Brooks D. Lindsey
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  2. Sarah E. Shelton
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  3. F. Stuart Foster
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  4. Paul A. Dayton
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Correspondence to Paul A. Dayton.

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Conflict of Interest

F. Stuart Foster is a consultant and receives research funding from VisualSonics, Inc. F. Stuart Foster and Paul A. Dayton are inventors on a pending patent describing the acoustic angiography technology. Paul A. Dayton is a co-founder of SonoVol, Inc., a company which has licensed the patent enabling acoustic angiography, and also was formerly on the scientific advisory board for Targeson, LLC. The authors declare that they have no conflict of interests with any other companies listed in this paper.

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Brooks D. Lindsey and Sarah E. Shelton contributed equally to this work

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Lindsey, B.D., Shelton, S.E., Foster, F.S. et al. Assessment of Molecular Acoustic Angiography for Combined Microvascular and Molecular Imaging in Preclinical Tumor Models. Mol Imaging Biol 19, 194–202 (2017). https://doi.org/10.1007/s11307-016-0991-4

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