DOI QR코드

DOI QR Code

Visualization of Tumor Angiogenesis Using MR Imaging Contrast Agent Gd-DTPA-anti-VEGF Receptor 2 Antibody Conjugate in a Mouse Tumor Model

  • Jun, Hong-Young (Institute for Radiological Imaging Science, Wonkwang University Schoolof Medicine) ;
  • Yin, Hong-Hua (Institute for Radiological Imaging Science, Wonkwang University Schoolof Medicine) ;
  • Kim, Sun-Hee (Institute for Radiological Imaging Science, Wonkwang University Schoolof Medicine) ;
  • Park, Seong-Hoon (Department of Radiology, Wonkwang University School of Medicine) ;
  • Kim, Hun-Soo (Department of Pathology, Wonkwang University School of Medicine) ;
  • Yoon, Kwon-Ha (Institute for Radiological Imaging Science, Wonkwang University Schoolof Medicine)
  • 투고 : 2009.08.25
  • 심사 : 2010.02.22
  • 발행 : 2010.08.01

초록

Objective: To visualize tumor angiogenesis using the MRI contrast agent, Gd- DTPA-anti-VEGF receptor 2 antibody conjugate, with a 4.7-Tesla MRI instrument in a mouse model. Materials and Methods: We designed a tumor angiogenesis-targeting T1 contrast agent that was prepared by the bioconjugation of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) and an anti-vascular endothelial growth factor receptor-2 (VEGFR2) antibody. The specific binding of the agent complex to cells that express VEGFR2 was examined in cultured murine endothelial cells (MS-1 cells) with a 4.7-Tesla magnetic resonance imaging scanner. Angiogenesis-specific T1 enhancement was imaged with the Gd-DTPA-anti-VEGFR2 antibody conjugate using a CT-26 adenocarcinoma tumor model in eight mice. As a control, the use of the Gd-DTPA-anti-rat immunoglobulin G (Gd-DTPA-anti-rat IgG) was imaged with a tumor model in eight mice. Statistical significance was assessed using the Mann-Whitney test. Tumor tissue was examined by immunohistochemical analysis. Results: The Gd-DTPA-anti-VEGFR2 antibody conjugate showed predominant binding to cultured endothelial cells that expressed a high level of VEGFR2. Signal enhancement was approximately three-fold for in vivo T1-weighted MR imaging with the use of the Gd-DTPA-anti-VEGFR2 antibody conjugate as compared with the Gd-DTPA-rat IgG in the mouse tumor model (p < 0.05). VEGFR2 expression in CT-26 tumor vessels was demonstrated using immunohistochemical staining. Conclusion: MR imaging using the Gd-DTPA-anti-VEGFR2 antibody conjugate as a contrast agent is useful in visualizing noninvasively tumor angiogenesis in a murine tumor model.

키워드

참고문헌

  1. Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82:4-6 https://doi.org/10.1093/jnci/82.1.4
  2. Bruns CJ, Liu W, Davis DW, Shaheen RM, McConkey DJ, Wilson MR, et al. Vascular endothelial growth factor is an in vivo survival factor for tumor endothelium in a murine model of colorectal carcinoma liver metastases. Cancer 2000;89:488-499 https://doi.org/10.1002/1097-0142(20000801)89:3<488::AID-CNCR3>3.0.CO;2-X
  3. Ferrara N. Molecular and biological properties of vascular endothelial growth factor. J Mol Med 1999;77:527-543 https://doi.org/10.1007/s001099900019
  4. Brown LF, Berse B, Jackman RW, Tognazzi K, Guidi AJ, Dvorak HF, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol 1995;26:86-91 https://doi.org/10.1016/0046-8177(95)90119-1
  5. Warren RS, Yuan H, Matli MR, Gillett NA, Ferrara N. Regulation by vascular endothelial growth factor of human colon cancer tumorigenesis in a mouse model of experimental liver metastasis. J Clin Invest 1995;95:1789-1797 https://doi.org/10.1172/JCI117857
  6. Boocock CA, Charnock-Jones DS, Sharkey AM, McLaren J, Barker PJ, Wright KA, et al. Expression of vascular endothelial growth factor and its receptors flt and KDR in ovarian carcinoma. J Natl Cancer Inst 1995;87:506-516 https://doi.org/10.1093/jnci/87.7.506
  7. Berkman RA, Merrill MJ, Reinhold WC, Monacci WT, Saxena A, Clark WC, et al. Expression of the vascular permeability factor/vascular endothelial growth factor gene in central nervous system neoplasms. J Clin Invest 1993;91:153-159 https://doi.org/10.1172/JCI116165
  8. Brasch R, Turetschek K. MRI characterization of tumors and grading angiogenesis using macromolecular contrast media: status report. Eur J Radiol 2000;34:148-155 https://doi.org/10.1016/S0720-048X(00)00195-9
  9. Zhang D, Feng XY, Henning TD, Wen L, Lu WY, Pan H, et al. MR imaging of tumor angiogenesis using sterically stabilized Gd-DTPA liposomes targeted to CD105. Eur J Radiol 2009;70:180-189 https://doi.org/10.1016/j.ejrad.2008.04.022
  10. Li KC, Bednarski MD. Vascular-targeted molecular imaging using functionalized polymerized vesicles. J Magn Reson Imaging 2002;16:388-393 https://doi.org/10.1002/jmri.10174
  11. Sipkins DA, Cheresh DA, Kazemi MR, Nevin LM, Bednarski MD, Li KC. Detection of tumor angiogenesis in vivo by alphaVbeta3-targeted magnetic resonance imaging. Nat Med 1998;4:623-626 https://doi.org/10.1038/nm0598-623
  12. Sipkins DA, Gijbels K, Tropper FD, Bednarski M, Li KC, Steinman L. ICAM-1 expression in autoimmune encephalitis visualized using magnetic resonance imaging. J Neuroimmunol 2000;104:1-9 https://doi.org/10.1016/S0165-5728(99)00248-9
  13. Poduslo JF, Curran GL, Peterson JA, McCormick DJ, Fauq AH, Khan MA, et al. Design and chemical synthesis of a magnetic resonance contrast agent with enhanced in vitro binding, high blood-brain barrier permeability, and in vivo targeting to Alzheimer's disease amyloid plaques. Biochemistry 2004;43:6064-6075 https://doi.org/10.1021/bi0359574
  14. Choi KS, Kim SH, Cai QY, Kim SY, Kim HO, Lee HJ, et al. Inflammation-specific T1 imaging using anti-intercellular adhesion molecule 1 antibody-conjugated gadolinium diethylenetriaminepentaacetic acid. Mol Imaging 2007;6:75-84
  15. Otrock ZK, Makarem JA, Shamseddine AI. Vascular endothelial growth factor family of ligands and receptors: review. Blood Cells Mol Dis 2007;38:258-268 https://doi.org/10.1016/j.bcmd.2006.12.003
  16. Luo JC, Yamaguchi S, Shinkai A, Shitara K, Shibuya M. Significant expression of vascular endothelial growth factor/vascular permeability factor in mouse ascites tumors. Cancer Res 1998;58:2652-2660
  17. Nagy JA, Masse EM, Herzberg KT, Meyers MS, Yeo KT, Yeo TK, et al. Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation. Cancer Res 1995;55:360-368
  18. Rosen LS. VEGF-targeted therapy: therapeutic potential and recent advances. Oncologist 2005;10:382-391 https://doi.org/10.1634/theoncologist.10-6-382
  19. Luo JC, Toyoda M, Shibuya M. Differential inhibition of fluid accumulation and tumor growth in two mouse ascites tumors by an antivascular endothelial growth factor/permeability factor neutralizing antibody. Cancer Res 1998;58:2594-2600
  20. Shibuya M. Differential roles of vascular endothelial growth factor receptor-1 and receptor-2 in angiogenesis. J Biochem Mol Biol 2006;39:469-478 https://doi.org/10.5483/BMBRep.2006.39.5.469
  21. Ran S, Huang X, Downes A, Thorpe PE. Evaluation of novel antimouse VEGFR2 antibodies as potential antiangiogenic or vascular targeting agents for tumor therapy. Neoplasia 2003;5:297-307 https://doi.org/10.1016/S1476-5586(03)80023-4
  22. Ferrara K, Pollard R, Borden M. Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery. Annu Rev Biomed Eng 2007;9:415-447 https://doi.org/10.1146/annurev.bioeng.8.061505.095852
  23. Bekeredjian R, Katus HA, Kuecherer HF. Therapeutic use of ultrasound targeted microbubble destruction: a review of noncardiac applications. Ultraschall Med 2006;27:134-140 https://doi.org/10.1055/s-2005-858993
  24. Lindner JR, Song J, Christiansen J, Klibanov AL, Xu F, Ley K. Ultrasound assessment of inflammation and renal tissue injury with microbubbles targeted to P-selectin. Circulation 2001;104:2107-2112 https://doi.org/10.1161/hc4201.097061
  25. Kaufmann BA, Sanders JM, Davis C, Xie A, Aldred P, Sarembock IJ, et al. Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1. Circulation 2007;116:276-284 https://doi.org/10.1161/CIRCULATIONAHA.106.684738
  26. Janssen ML, Oyen WJ, Dijkgraaf I, Massuger LF, Frielink C, Edwards DS, et al. Tumor targeting with radiolabeled alpha(v)beta(3) integrin binding peptides in a nude mouse model. Cancer Res 2002;62:6146-6151
  27. Lu E, Wagner WR, Schellenberger U, Abraham JA, Klibanov AL, Woulfe SR, et al. Targeted in vivo labeling of receptors for vascular endothelial growth factor: approach to identification of ischemic tissue. Circulation 2003;108:97-103 https://doi.org/10.1161/01.CIR.0000079100.38176.83
  28. Provenzale JM. Imaging of angiogenesis: clinical techniques and novel imaging methods. AJR Am J Roentgenol 2007;188:11-23 https://doi.org/10.2214/AJR.06.0280
  29. Lyons SK. Advances in imaging mouse tumour models in vivo. J Pathol 2005;205:194-205 https://doi.org/10.1002/path.1697
  30. Lee SI, Lee SY, Yoon KH, Choi KS, Jang KY, Yoo WH, et al. Molecular MR imaging for visualizing ICAM-1 expression in the inflamed synovium of collagen-induced arthritic mice. Korean J Radiol 2009;10:472-480 https://doi.org/10.3348/kjr.2009.10.5.472

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