Detection of vascular endothelial growth factor in colon cancer xenografts using bevacizumab based near infrared fluorophore conjugate

Journal of Biomedical Science

Keigo Endo²  Yoshito Tsushima¹  Hideyuki Tominaga¹  Dilip Shah³  Pramila Paudyal¹  Bishnuhari Paudyal¹ 

[1] Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan;Kyoto College of Medical Science, Nantan, Kyoto 6220041, Japan;Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA

关键词: Colorectal cancer;    Bevacizumab;    Optical Imaging;    VEGF;    Near infrared fluorescence;   

Others  :  817663
DOI  :  10.1186/1423-0127-21-35

 received in 2014-03-10, accepted in 2014-04-23,  发布年份 2014

【 摘 要 】

Background

The aim of this study was to develop the near infrared fluorescence (NIRF)-based imaging agent for the visualization of vascular endothelial growth factor (VEGF) in colon cancer. AlexaFluor 750 conjugating with bevacizumab, and injected intravenously into nude mice bearing VEGF over-expressing HT29 human colorectal cancer. Optical imaging was performed at 15 min, 24 h and 48 h post injection. Immunofluorescences staining of the tumor sections were performed. HT29 colorectal cancer xenografts were clearly visualized with bevacizumab-AlexaFluor 750.

Results

Ex vivo analysis showed 2.1 ± 0.4%, 37.6 ± 6.3% and 38.5 ± 6.2% injected dose/g accumulated in the tumors at 15 min, 24 h and 48 h respectively. Tumor uptake was significantly decreased in pretreated with excess of bevacizumab (p = 0.002). Immunofluorescence analysis showed strong staining of anti-CD 31 antibody around the blood vessels. Anti-VEGF-A and bevacizumab showed heterogeneous expression throughout the tumor.

Conclusions

Current study successfully detected the VEGF expression in HT29 colorectal cancer xenografts, signifying as a potential agent for non-invasive imaging of VEGF expression, which may be applied in clinical practice.

【 授权许可】

   
2014 Paudyal et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Weissleder R, Mahmood U: Molecular imaging. Radiology 2001, 219:316-333.
• [2]Herschman HR: Molecular imaging: looking at problems, seeing solutions. Science 2003, 302:605-608.
• [3]Paudyal B, Zhang K, Chen CP, Wampole ME, Mehta N, Mitchell EP, Gray BD, Mattis JA, Pak KY, Thakur ML, Wickstrom E: Determining efficacy of breast cancer therapy by PET imaging of HER2 mRNA. Nucl Med Biol 2013, 40:994-999.
• [4]Paudyal B, Oriuchi N, Paudyal P, Tsushima Y, Iida Y, Higuchi T, Hanaoka H, Miyakubo M, Takano A, Ishikita T, Endo K: Early diagnosis of recurrent hepatocellular carcinoma with 18 F-FDG PET after radiofrequency ablation therapy. Oncol Rep 2007, 18:1469-1473.
• [5]Paudyal B, Paudyal P, Oriuchi N, Tsushima Y, Nakajima T, Endo K: Clinical implication of glucose transport and metabolism evaluated by 18 F-FDG PET in hepatocellular carcinoma. Int J Oncol 2008, 33:1047-1054.
• [6]Paudyal P, Paudyal B, Hanaoka H, Oriuchi N, Iida Y, Yoshioka H, Tominaga H, Watanabe S, Ishioka NS, Endo K: Imaging and biodistribution of Her2/neu expression in non-small cell lung cancer xenografts with Cu-labeled trastuzumab PET. Cancer Sci 2010, 101:1045-1050.
• [7]Hoffman RM: The multiple uses of fluorescent proteins to visualize cancer in vivo. Nat Rev Cancer 2005, 5:796-806.
• [8]Ke S, Wen X, Gurfinkel M, Charnsangavej C, Wallace S, Sevick-Muraca EM, Li C: Near-infrared optical imaging of epidermal growth factor receptor in breast cancer xenografts. Cancer Res 2003, 63:7870-7875.
• [9]Weissleder R, Ntziachristos V: Shedding light onto live molecular targets. Nat Med 2003, 9:123-128.
• [10]Klohs J, Wunder A, Licha K: Near-infrared fluorescent probes for imaging vascular pathophysiology. Basic Res Cardiol 2008, 103:144-151.
• [11]Paudyal P, Paudyal B, Iida Y, Oriuchi N, Hanaoka H, Tominaga H, Ishikita T, Yoshioka H, Higuchi T, Endo K: Dual functional molecular imaging probe targeting CD20 with PET and optical imaging. Oncol Rep 2009, 22:115-119.
• [12]Mahmood U, Tung CH, Bogdanov A Jr, Weissleder R: Near-infrared optical imaging of protease activity for tumor detection. Radiology 1999, 213:866-870.
• [13]Chang SK, Rizvi I, Solban N, Hasan T: In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment. Clin Cancer Res 2008, 14:4146-4153.
• [14]Zhu Q, Tannenbaum S, Hegde P, Kane M, Xu C, Kurtzman SH: Noninvasive monitoring of breast cancer during neoadjuvant chemotherapy using optical tomography with ultrasound localization. Neoplasia 2008, 10:1028-1040.
• [15]Zhang Y, Hong H, Engle JW, Yang Y, Barnhart TE, Cai W: Positron Emission Tomography and Near-Infrared Fluorescence Imaging of Vascular Endothelial Growth Factor with Dual-Labeled Bevacizumab. Am J Nucl Med Mol Imaging 2012, 2:1-13.
• [16]Thakur ML, Zhang K, Paudyal B, Devakumar D, Covarrubias MY, Chen CP, Gray BD, Wickstrom E, Pak KY: Targeting apoptosis for optical imaging of infection. Mol Imaging Biol 2012, 14:163-171.
• [17]Terwisscha van Scheltinga AG, van Dam GM, Nagengast WB, Ntziachristos V, Hollema H, Herek JL, Schroder CP, Kosterink JG, Lub-de Hoog MN, de Vries EG: Intraoperative near-infrared fluorescence tumor imaging with vascular endothelial growth factor and human epidermal growth factor receptor 2 targeting antibodies. J Nucl Med 2011, 52:1778-1785.
• [18]Leevy WM, Lambert TN, Johnson JR, Morris J, Smith BD: Quantum dot probes for bacteria distinguish Escherichia coli mutants and permit in vivo imaging. Chem Commun (Camb) 2008, 20:2331-2333.
• [19]Pierce MC, Javier DJ, Richards-Kortum R: Optical contrast agents and imaging systems for detection and diagnosis of cancer. Int J Cancer 2008, 123:1979-1990.
• [20]Bremer C, Ntziachristos V, Weissleder R: Optical-based molecular imaging: contrast agents and potential medical applications. Eur Radiol 2003, 13:231-243.
• [21]Withrow KP, Newman JR, Skipper JB, Gleysteen JP, Magnuson JS, Zinn K, Rosenthal EL: Assessment of bevacizumab conjugated to Cy5.5 for detection of head and neck cancer xenografts. Technol Cancer Res Treat 2008, 7:61-66.
• [22]Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J 1999, 13:9-22.
• [23]Brown LF, Berse B, Jackman RW, Tognazzi K, Manseau EJ, Senger DR, Dvorak HF: Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 1993, 53:4727-4735.
• [24]Paudyal B, Paudyal P, Oriuchi N, Hanaoka H, Tominaga H, Endo K: Positron emission tomography imaging and biodistribution of vascular endothelial growth factor with 64Cu-labeled bevacizumab in colorectal cancer xenografts. Cancer Sci 2011, 102:117-121.
• [25]Folkman J: Tumor angiogenesis: therapeutic implications. N Engl J Med 1971, 285:1182-1186.
• [26]Ferrara N, Hillan KJ, Gerber HP, Novotny W: Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 2004, 3:391-400.
• [27]Gasparini G, Longo R, Fanelli M, Teicher BA: Combination of antiangiogenic therapy with other anticancer therapies: results, challenges, and open questions. J Clin Oncol 2005, 23:1295-1311.
• [28]Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004, 350:2335-2342.
• [29]Vermeulen PB, Gasparini G, Fox SB, Toi M, Martin L, McCulloch P, Pezzella F, Viale G, Weidner N, Harris AL, Dirix LY: Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer 1996, 32A:2474-2484.
• [30]Ferrara N, Gerber HP, LeCouter J: The biology of VEGF and its receptors. Nat Med 2003, 9:669-676.
• [31]Stollman TH, Scheer MG, Leenders WP, Verrijp KC, Soede AC, Oyen WJ, Ruers TJ, Boerman OC: Specific imaging of VEGF-A expression with radiolabeled anti-VEGF monoclonal antibody. Int J Cancer 2008, 122:2310-2314.
• [32]Nagengast WB, de Vries EG, Hospers GA, Mulder NH, de Jong JR, Hollema H, Brouwers AH, van Dongen GA, Perk LR, Lub-de Hooge MN: In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med 2007, 48:1313-1319.
• [33]Abbas Rizvi SM, Song EY, Raja C, Beretov J, Morgenstern A, Apostolidis C, Russell PJ, Kearsley JH, Abbas K, Allen BJ: Preparation and testing of bevacizumab radioimmunoconjugates with Bismuth-213 and Bismuth-205/Bismuth-206. Cancer Biol Ther 2008, 7:1547-1554.
• [34]Scheer MG, Stollman TH, Boerman OC, Verrijp K, Sweep FC, Leenders WP, Ruers TJ, Oyen WJ: Imaging liver metastases of colorectal cancer patients with radiolabelled bevacizumab: Lack of correlation with VEGF-A expression. Eur J Cancer 2008, 44:1835-1840.
• [35]Jain RK: Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng 1999, 1:241-263.
• [36]Fujimori K, Covell DG, Fletcher JE, Weinstein JN: A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier. J Nucl Med 1990, 31:1191-1198.
• [37]Adams GP, Schier R, McCall AM, Simmons HH, Horak EM, Alpaugh RK, Marks JD, Weiner LM: High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res 2001, 61:4750-4755.