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Sensitive Angiogenesis Imaging of Orthotopic Bladder Tumors in Mice Using a Selective Magnetic Resonance Imaging Contrast Agent Containing VEGF121/rGel

Cho, Eun-Jin MS*†; Yang, Jaemoon PhD*; Mohamedali, Khalid A. PhD; Lim, Eun-Kyung MS§; Kim, Eun-Jung MS§; Farhangfar, Carol J. PhD; Suh, Jin-Suck MD, PhD*; Haam, Seungjoo PhD§; Rosenblum, Michael G. PhD; Huh, Yong-Min MD, PhD*¶∥**

doi: 10.1097/RLI.0b013e3182174fad
Original Article
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Objectives: To investigate the efficiency of magnetic resonance imaging (MRI) contrast agents employing vascular endothelial growth factor (VEGF121)/rGel conjugated MnFe2O4 nanocrystals for imaging of neovasculature using a bladder tumor model.

Materials and Methods: VEGF121/rGel was conjugated to MnFe2O4 nanoparticles (MNPs). The targeting efficiency and detection capability of the VEGF121/rGel-MNPs were investigated in both KDR-deficient (253JB-V) and KDR-overexpressing (PAE/KDR) cells using MRI. The internalization of VEGF121/rGel-MNPs into cells was confirmed by electron microscopy. Their phosphorylation ability and cytotoxicity were compared with unconjugated VEGF121/rGel. The orthotopic tumor mice were established by implanting low KDR-expressing 253JB-V cells into the bladder dome. After tail-vein injection of VEGF121/rGel-MNPs, the MR signal enhancement of intratumoral vessels by VEGF121/rGel-MNPs was observed and inhibition test using VEGF121 was also conducted. Ex vivo MR imaging of tumor tissue, and a fluorescence immunostaining study was also performed.

Results: The water-soluble VEGF121/rGel-MNPs (44.5 ± 1.2 nm) were stably suspended in the biologic media and exhibited a high relaxivity coefficient (423 mM−1s−1). They demonstrated sufficient targeting capability against KDR-overexpressing PAE/KDR cells, as confirmed by dose-dependent MR images and VEGF121 inhibition tests. The phosphorylation activity of KDR and cytotoxicity of VEGF121/rGel-MNPs were evaluated. VEGF121/rGel-MNPs successfully targeted the tumor and provided accurate anatomic details through (i) acquisition of clear neoangiogenic vascular distributions and (ii) obvious enhancement of the MR signal in T2*-weighted images. Immunostaining and blocking studies demonstrated the specific targeting ability of VEGF121/rGel-MNPs toward intratumoral angiogenesis.

Conclusions: Synthesized VEGF121/rGel-MNPs as targeted MR imaging contrast agents can be specifically delivered to tumors and bind to KDR-expressing angiogenic tumor vessels.

From the *Department of Radiology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea; †Program for Nanomedical Science and Technology, Yonsei University, Seoul 120-749, Republic of Korea; ‡Immunopharmacology and Targeted Therapy Laboratory, Department of Experimental Therapeutics, Division of Cancer Medicine, M.D. Anderson Cancer Center, Houston, TX; §Department of Chemical and Biomolecular Engineering, Yonsei University, Seoul 120-749; Republic of Korea; ¶YUHS-KRIBB Medical Convergence Research Institute, Seoul 120-752, Republic of Korea; ∥Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 120-752, Republic of Korea; and **Severance Biomedical Science Institute (SBSI), Seoul 120-752, Republic of Korea.

Received October 21, 2010; accepted for publication (after revision) January 16, 2011.

Supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (A090728) and the Clayton Foundation.

Author contributions: E.J.C. and J.Y. contributed equally to this manuscript. Guarantors of integrity of entire study, M.G.R., Y.M.H.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, all authors; and manuscript editing, E.J.C., J.Y., K.A.M, M.G.R., S.H., Y.M.H.

Reprints: Yong-Min Huh, MD, PhD, Department of Radiology, College of Medicine, Yonsei University, Seoul 120–752, Republic of Korea. E-mail: ymhuh@yuhs.ac.

© 2011 Lippincott Williams & Wilkins, Inc.