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ß3-targeted Nanoparticle and 1.5 Tesla Magnetic Resonance Imaging1
Cardiovascular Magnetic Resonance Laboratories, Department of Medicine, Cardiovascular Division, Barnes-Jewish Hospital, Washington University School of Medicine [P. M. W., S. D. C., L. K. C., J. S. A., E. K. L., H. Z., S. A. W., G. M. L.] and Department of Biomedical Engineering [S. D. C., S. A. W., G. M. L.], Washington University, St. Louis, Missouri 63110; Philips Medical Systems, 5680 DA Best, the Netherlands [S. D. C., A. K.]; Bristol-Myers Squibb Medical Imaging, Inc., North Billerica, Massachusetts 01862 [T. D. H.]; and Analytical Chemistry Group, University of Missouri Research Reactor, Columbia, Missouri 65211 [J. D. R.]
Early noninvasive detection and characterization of solid tumors and their supporting neovasculature is a fundamental prerequisite for effective therapeutic intervention, particularly antiangiogenic treatment regimens. Emerging molecular imaging techniques now allow recognition of early biochemical, physiological, and anatomical changes before manifestation of gross pathological changes. Although new tumor, vascular, extracellular matrix, and lymphatic biomarkers continue to be discovered, the 
ß3-integrin remains an attractive biochemical epitope that is highly expressed on activated neovascular endothelial cells and essentially absent on mature quiescent cells. In this study, we report the first in vivo use of a magnetic resonance (MR) molecular imaging nanoparticle to sensitively detect and spatially characterize neovascularity induced by implantation of the rabbit Vx-2 tumor using a common clinical field strength (1.5T). New Zealand White rabbits (2 kg) 12 days after implantation of fresh Vx-2 tumors (2 x 2 x 2 mm3) were randomized into one of three treatment groups: (a) ß3-targeted, paramagnetic formulation; (b) nontargeted, paramagnetic formulation; and (c) ß3-targeted nonparamagnetic nanoparticles followed by (2 h) the ß3-targeted, paramagnetic formulation to competitively block magnetic resonance imaging (MRI) signal enhancement. After i.v. systemic injection (0.5 ml of nanoparticles/kg), dynamic T1-weighted MRI was used to spatially and temporally determine nanoparticle deposition in the tumor and adjacent tissues, including skeletal muscle. At 2-h postinjection, ß3-targeted paramagnetic nanoparticles increased MRI signal by 126% in asymmetrically distributed regions primarily in the periphery of the tumor. Similar increases in MR contrast were also observed within the walls of some vessels proximate to the tumor. Despite their relatively large size, nanoparticles penetrated into the leaky tumor neovasculature but did not appreciably migrate into the interstitium, leading to a 56% increase in MR signal at 2 h. Pretargeting of the ß3-integrin with nonparamagnetic nanoparticles competitively blocked the specific binding of ß3-targeted paramagnetic nanoparticles, decreasing the MR signal enhancement (50%) to a level attributable to local extravasation. The MR signal of adjacent hindlimb muscle or contralateral control tissues was unchanged by either the ß3-targeted or control paramagnetic agents. Immunohistochemistry of ß3-integrin corroborated the extent and asymmetric distribution of neovascularity observed by MRI. These studies demonstrate the potential of this targeted molecular imaging agent to detect and characterize (both biochemically and morphologically) early angiogenesis induced by minute solid tumors with a clinical 1.5 Tesla MRI scanner, facilitating the localization of nascent cancers or metastases, as well as providing tools to phenotypically categorize and segment patient populations for therapy and to longitudinally follow the effectiveness of antitumor treatment regimens.
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