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Characterizing Extravascular Fluid Transport of Macromolecules in the Tumor Interstitium by Magnetic Resonance Imaging

¹ Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; ² Department of Biophysics, Medical College of Wisconsin, Milwaukee, Wisconsin; ³ MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; and ⁴ Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

Requests for reprints: Zaver M. Bhujwalla, Department of Radiology, Johns Hopkins University School of Medicine, 208 Traylor Building, 720 Rutland Avenue, Baltimore, MD 21205. Phone: 410-955-9698; Fax: 410-614-1948; E-mail: zaver{at}mri.jhu.edu.

Noninvasive imaging techniques to image and characterize delivery and transport of macromolecules through the extracellular matrix (ECM) and supporting stroma of a tumor are necessary to develop treatments that alter the porosity and integrity of the ECM for improved delivery of therapeutic agents and to understand factors which influence and control delivery, movement, and clearance of macromolecules. In this study, a noninvasive imaging technique was developed to characterize the delivery as well as interstitial transport of a macromolecular agent, albumin-GdDTPA, in the MCF-7 human breast cancer model in vivo, using magnetic resonance imaging. The transport parameters derived included vascular volume, permeability surface area product, macromolecular fluid exudate volume, and drainage and pooling rates. Immunohistochemical staining for the lymphatic endothelial marker LYVE-1 was done to determine the contribution of lymphatics to the macromolecular drainage. Distinct pooling and draining regions were detected in the tumors using magnetic resonance imaging. A few lymphatic vessels positively stained for LYVE-1 were also detected although these were primarily collapsed and tenuous suggesting that lymphatic drainage played a minimal role, and that the bulk of drainage was due to convective transport through the ECM in this tumor model.

Key Words: Interstitial drainage • macromolecules • breast cancer • lymphatic vessels • MRI

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