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New macromolecular polymeric MRI contrast agents for application in the differentiation of cancer from benign soft tissues

Authors

  • Clemens C. Cyran MD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
    2. Department of Clinical Radiology, University Hospital Munich - Grosshadern, Ludwig-Maximilians-University, Munich, Germany
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  • Yanjun Fu PhD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
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  • Hans-Juergen Raatschen MD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
    2. Klinik und Hochschulambulanz für Radiologie und Nuklearmedizin Charité - Universitätsmedizin Berlin - Campus Benjamin Franklin, Berlin, Germany
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  • Victor Rogut MD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
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  • Bundit Chaopathomkul MD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
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  • David M. Shames MD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
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  • Michael F. Wendland PhD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
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  • Benjamin M. Yeh MD,

    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
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  • Robert C. Brasch MD

    Corresponding author
    1. Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, San Francisco, California
    • Center for Pharmaceutical and Molecular Imaging, Department of Radiology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0628
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Abstract

Purpose

To compare three new macromolecular polyethylene glycol (PEG) -core dendrimeric gadolinium(Gd)-based MRI contrast agents for their applicability in quantitative assays of endothelial leakiness and tissue vascular density for the differentiation of cancer from normal soft tissues.

Materials and Methods

Thirty-two athymic rats with human breast cancer xenografts (MDA-MB-435) were imaged by dynamic MRI following enhancement with one of three new (Gd-DOTA)-conjugated PEG-core dendrimer contrast agents (effective molecular weights 161 to 323 kDa). Results were compared with a prototype macromolecular contrast agent, albumin (Gd-DTPA). Assays of permeabilities (KPS; μL/min · 100 cm3) and tumor fractional plasma volumes (%) based on a two-compartment kinetic model were performed for skeletal muscle and tumors.

Results

The largest PEG-core contrast agent, PEG20,000-Gen4-(Gd-DOTA), leaked in breast tumors (KPS = 50 ± 23 μL/min · 100 cm3), while exhibiting no measurable transendothelial leak (KPS = 0 μL/min · 100 cm3) in normal soft tissue microvessels allowing successful differentiation (P < 0.05) of cancers from normal muscle. PEG12,000-Gen4-(Gd-DOTA) leaked in tumors and in normal muscle (KPS = 51 ± 26 and KPS = 21 ± 18μL/min · 100 cm3, respectively). The smallest agent, PEG12,000-Gen3-(Gd-DOTA) also showed a measurable leak in both normal and malignant microvessels.

Conclusion

MRI assays of vascular endothelial leakiness using new PEG-core, (Gd-DOTA)-conjugated macromolecular contrast agents proved applicable for the differentiation of human breast cancer from normal soft tissue. The apparent threshold in effective molecular weight for a clear differentiation of cancer from normal muscle with no measurable leak in the muscle is between 194 and 323 kDa. J. Magn. Reson. Imaging 2008. © 2008 Wiley-Liss, Inc.

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