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Erschienen in: Annals of Surgical Oncology 6/2014

01.06.2014 | Translational Research and Biomarkers

Molecular Imaging of Tumor-Associated Angiogenesis Using a Novel Magnetic Resonance Imaging Contrast Agent Targeting αvβ3 Integrin

verfasst von: Isabelle Debergh, MD, Nancy Van Damme, PhD, Dieter De Naeyer, PhD, Peter Smeets, MD, Pieter Demetter, MD, PhD, Philippe Robert, PhD, Sabin Carme, PhD, Piet Pattyn, MD, PhD, Wim Ceelen, MD, PhD

Erschienen in: Annals of Surgical Oncology | Ausgabe 6/2014

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Abstract

Background

The recent introduction of biological anticancer therapy has renewed the interest in functional imaging of tumor-associated angiogenesis (TAA) as a tool to monitor early therapy response. The present study evaluated imaging of TAA using P1227, a novel, small molecular magnetic resonance imaging (MRI) probe targeting αvβ3 integrin.

Methods

HT29 human colorectal cancers were grown in athymic mice. Dynamic MRI was performed using a three-dimensional VIBE sequence up to 110 min after injection of P1227 or gadolinium–tetraazacyclododecane tetraacetic acid (Gd–DOTA). Specificity was assessed by using P1227 1 h after intravenous administration of the αvβ3 inhibitor cilengitide. Regions of interest were drawn encompassing the tumor rim and normal muscle. Imaging data were compared with microvessel density and αvβ3 expression.

Results

Using P1227, specific enhancement of the angiogenic tumor rim, but not of normal muscle, was observed, whereas Gd–DOTA enhanced tumor and normal muscle. After administering cilengitide, enhancement with P1227, but not with DOTA, was significantly suppressed during the first 20 min. When using P1227, a significant correlation was observed between normalized enhancement of the tumor rim and immunohistochemical αvβ3 integrin expression.

Conclusions

Molecular MRI using a small monogadolinated tracer targeting αvβ3 integrin and moderate magnetic field strength holds promise in assessing colorectal TAA.
Literatur
1.
Zurück zum Zitat Desar IME, van Herpen CML, van Laarhoven HWM, Barentsz JO, Oyen WJG, van der Graaf WTA. Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy. Cancer Treat Rev. 2009;35:309–321.PubMedCrossRef Desar IME, van Herpen CML, van Laarhoven HWM, Barentsz JO, Oyen WJG, van der Graaf WTA. Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy. Cancer Treat Rev. 2009;35:309–321.PubMedCrossRef
2.
Zurück zum Zitat Kochhar R, Manoharan P, Leahy M, Taylor MB. Imaging in gastrointestinal stromal tumors: current status and future directions. Clin Radiol. 2010;65:584–592.PubMedCrossRef Kochhar R, Manoharan P, Leahy M, Taylor MB. Imaging in gastrointestinal stromal tumors: current status and future directions. Clin Radiol. 2010;65:584–592.PubMedCrossRef
3.
Zurück zum Zitat Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.PubMedCrossRef Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.PubMedCrossRef
4.
Zurück zum Zitat Ceelen W, Smeets P, Backes W, Van Damme N, Boterberg T, Demetter P, et al. Noninvasive monitoring of radiotherapy-induced microvascular changes using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in a colorectal tumor model. Int J Radiat Oncol Biol. 2006;64:1188–1196.CrossRef Ceelen W, Smeets P, Backes W, Van Damme N, Boterberg T, Demetter P, et al. Noninvasive monitoring of radiotherapy-induced microvascular changes using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in a colorectal tumor model. Int J Radiat Oncol Biol. 2006;64:1188–1196.CrossRef
5.
Zurück zum Zitat Ceelen W, Boterberg T, Smeets P, Van Damme N, Demetter P, Zwaenepoel O, et al. Recombinant human erythropoietin alpha modulates the effects of radiotherapy on colorectal cancer microvessels. Br J Cancer. 2007;96:692–700.PubMedCentralPubMedCrossRef Ceelen W, Boterberg T, Smeets P, Van Damme N, Demetter P, Zwaenepoel O, et al. Recombinant human erythropoietin alpha modulates the effects of radiotherapy on colorectal cancer microvessels. Br J Cancer. 2007;96:692–700.PubMedCentralPubMedCrossRef
6.
Zurück zum Zitat Meyer A, Auemheimer J, Modlinger A, Kessler H. Targeting RGD recognizing integrins: Drug development, biomaterial research, tumor imaging and targeting. Current Pharm Design. 2006;12:2723–2747.CrossRef Meyer A, Auemheimer J, Modlinger A, Kessler H. Targeting RGD recognizing integrins: Drug development, biomaterial research, tumor imaging and targeting. Current Pharm Design. 2006;12:2723–2747.CrossRef
7.
Zurück zum Zitat Beer AJ, Schwaiger M. Imaging of integrin alpha v beta 3 expression. Cancer Metastasis Rev. 2008;27:631–644.PubMedCrossRef Beer AJ, Schwaiger M. Imaging of integrin alpha v beta 3 expression. Cancer Metastasis Rev. 2008;27:631–644.PubMedCrossRef
8.
Zurück zum Zitat Brooks PC, Clark RAF, Cheresh DA. Requirement of vascular integrin alpha(V)beta(3) for angiogenesis. Science. 1994;264:569–571.PubMedCrossRef Brooks PC, Clark RAF, Cheresh DA. Requirement of vascular integrin alpha(V)beta(3) for angiogenesis. Science. 1994;264:569–571.PubMedCrossRef
9.
Zurück zum Zitat Debergh I, Van Damme N, Pattyn P, Peeters M, Ceelen WP. The low-molecular-weight heparin, nadroparin, inhibits tumor angiogenesis in a rodent dorsal skinfold chamber model. Br J Cancer. 2010;102(5):837–43.PubMedCentralPubMedCrossRef Debergh I, Van Damme N, Pattyn P, Peeters M, Ceelen WP. The low-molecular-weight heparin, nadroparin, inhibits tumor angiogenesis in a rodent dorsal skinfold chamber model. Br J Cancer. 2010;102(5):837–43.PubMedCentralPubMedCrossRef
10.
Zurück zum Zitat Schnell O, Krebs B, Wagner E, Romagna A, Beer AJ, Grau SJ, et al.. Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol. 2008; 18(3):378–86.PubMedCentralPubMedCrossRef Schnell O, Krebs B, Wagner E, Romagna A, Beer AJ, Grau SJ, et al.. Expression of integrin alphavbeta3 in gliomas correlates with tumor grade and is not restricted to tumor vasculature. Brain Pathol. 2008; 18(3):378–86.PubMedCentralPubMedCrossRef
11.
Zurück zum Zitat Kiessling F, Morgenstern B, Zhang C. Contrast agents and applications to assess tumor angiogenesis in vivo by magnetic resonance imaging. Curr Med Chem. 2007;14:77–91.PubMedCrossRef Kiessling F, Morgenstern B, Zhang C. Contrast agents and applications to assess tumor angiogenesis in vivo by magnetic resonance imaging. Curr Med Chem. 2007;14:77–91.PubMedCrossRef
13.
Zurück zum Zitat Hood J, Cheresh D. Role of integrins in cell invasion and migration. Nat Rev Cancer. 2002;2:91–100.PubMedCrossRef Hood J, Cheresh D. Role of integrins in cell invasion and migration. Nat Rev Cancer. 2002;2:91–100.PubMedCrossRef
14.
Zurück zum Zitat Dunehoo A, Anderson M, Majumdar S, Kobayashi N, Berkland C, Siahaan TJ. Cell adhesion molecules for targeting drug delivery. J Pharm Sci. 2006;95:1856–1872.PubMedCrossRef Dunehoo A, Anderson M, Majumdar S, Kobayashi N, Berkland C, Siahaan TJ. Cell adhesion molecules for targeting drug delivery. J Pharm Sci. 2006;95:1856–1872.PubMedCrossRef
15.
Zurück zum Zitat Kemperman H, Wijnands YM, Roos E. Alpha V integrins on HT-29 colon carcinoma cells: adhesion to fibronectin is mediated solely by small amounts of alpha V beta 6, and alpha V beta 5 is codistributed with actin fibers. Exp Cell Res. 1997;234:156–164.PubMedCrossRef Kemperman H, Wijnands YM, Roos E. Alpha V integrins on HT-29 colon carcinoma cells: adhesion to fibronectin is mediated solely by small amounts of alpha V beta 6, and alpha V beta 5 is codistributed with actin fibers. Exp Cell Res. 1997;234:156–164.PubMedCrossRef
16.
Zurück zum Zitat Haier J, Nasralla M, Nicolson GL. Different adhesion properties of highly and poorly metastatic HT-29 colon carcinoma cells with extracellular matrix components: role of integrin expression and cytoskeletal components. Br J Cancer. 1999;80:1867–1874.PubMedCentralPubMedCrossRef Haier J, Nasralla M, Nicolson GL. Different adhesion properties of highly and poorly metastatic HT-29 colon carcinoma cells with extracellular matrix components: role of integrin expression and cytoskeletal components. Br J Cancer. 1999;80:1867–1874.PubMedCentralPubMedCrossRef
17.
Zurück zum Zitat Liu Z, Jia B, Shi J, Jin X, Zhao H, Li F, et al. Tumor uptake of the RGD dimeric probe (99m)Tc-G(3)-2P(4)-RGD2 is correlated with integrin alpha(v)beta(3) expressed on both tumor cells and neovasculature. Bioconjug Chem. 2010;21(3):548–555.PubMedCrossRef Liu Z, Jia B, Shi J, Jin X, Zhao H, Li F, et al. Tumor uptake of the RGD dimeric probe (99m)Tc-G(3)-2P(4)-RGD2 is correlated with integrin alpha(v)beta(3) expressed on both tumor cells and neovasculature. Bioconjug Chem. 2010;21(3):548–555.PubMedCrossRef
18.
Zurück zum Zitat Zhou Y, Kim YS, Chakraborty S, Shi J, Gao H, Liu S. 99mTc-labeled cyclic RGD peptides for noninvasive monitoring of tumor integrin αVβ3 expression. Mol Imaging. 2011;10:386–397.PubMed Zhou Y, Kim YS, Chakraborty S, Shi J, Gao H, Liu S. 99mTc-labeled cyclic RGD peptides for noninvasive monitoring of tumor integrin αVβ3 expression. Mol Imaging. 2011;10:386–397.PubMed
19.
Zurück zum Zitat Winter PM, Caruthers SD, Kassner A, Harris TD, Chinen LK, Allen JS, et al. Molecular imaging of angiogenesis in nascent vx-2 rabbit tumors using a novel alpha(v)beta(3)-targeted nanoparticle and 1.5 tesla magnetic resonance imaging. Cancer Res. 2003;63:5838–5843.PubMed Winter PM, Caruthers SD, Kassner A, Harris TD, Chinen LK, Allen JS, et al. Molecular imaging of angiogenesis in nascent vx-2 rabbit tumors using a novel alpha(v)beta(3)-targeted nanoparticle and 1.5 tesla magnetic resonance imaging. Cancer Res. 2003;63:5838–5843.PubMed
20.
Zurück zum Zitat Mulder WJ, Strijkers GJ, Habets JW, Bleeker EJ, van der Schaft DW, Storm G, et al. MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle. FASEB J. 2005;19:2008–2010.PubMed Mulder WJ, Strijkers GJ, Habets JW, Bleeker EJ, van der Schaft DW, Storm G, et al. MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle. FASEB J. 2005;19:2008–2010.PubMed
21.
Zurück zum Zitat Zhang C, Jugold M, Woenne EC, Lammers T, Morgenstern B, Mueller MM, et al. Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner. Cancer Res. 2007;67:1555–1562.PubMedCrossRef Zhang C, Jugold M, Woenne EC, Lammers T, Morgenstern B, Mueller MM, et al. Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner. Cancer Res. 2007;67:1555–1562.PubMedCrossRef
22.
Zurück zum Zitat Jiang T, Zhang CF, Zheng X, Xu XF, Xie X, Liu HC, et al. Noninvasively characterizing the different alpha v beta 3 expression patterns in lung cancers with RgD-USPIO using a clinical 3.0T MR scanner. Int J Nanomed. 2009;4:241–249.CrossRef Jiang T, Zhang CF, Zheng X, Xu XF, Xie X, Liu HC, et al. Noninvasively characterizing the different alpha v beta 3 expression patterns in lung cancers with RgD-USPIO using a clinical 3.0T MR scanner. Int J Nanomed. 2009;4:241–249.CrossRef
23.
Zurück zum Zitat Kiessling F, Huppert J, Zhang C, Jayapaul J, Zwick S, Woenne EC, et al. RGD-labeled USPIO inhibits adhesion and endocytotic activity of alpha(v)beta(3)-integrin-expressing glioma cells and only accumulates in the vascular tumor compartment. Radiology. 2009;253:462–469.PubMedCrossRef Kiessling F, Huppert J, Zhang C, Jayapaul J, Zwick S, Woenne EC, et al. RGD-labeled USPIO inhibits adhesion and endocytotic activity of alpha(v)beta(3)-integrin-expressing glioma cells and only accumulates in the vascular tumor compartment. Radiology. 2009;253:462–469.PubMedCrossRef
24.
Zurück zum Zitat Wong C, Stylianopoulos T, Cui J, Martin J, Chauhan VP, Jiang W, et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc Natl Acad Sci USA. 2011;108:2426–2431.PubMedCentralPubMedCrossRef Wong C, Stylianopoulos T, Cui J, Martin J, Chauhan VP, Jiang W, et al. Multistage nanoparticle delivery system for deep penetration into tumor tissue. Proc Natl Acad Sci USA. 2011;108:2426–2431.PubMedCentralPubMedCrossRef
25.
Zurück zum Zitat Sharma R, Saini S, Ros PR, Hahn PF, Small WC, de Lange EE, et al. Safety profile of ultrasmall superparamagnetic iron oxide ferumoxtran-10: phase II clinical trial data. J Magn Reson Imaging. 1999;9:291–294.PubMedCrossRef Sharma R, Saini S, Ros PR, Hahn PF, Small WC, de Lange EE, et al. Safety profile of ultrasmall superparamagnetic iron oxide ferumoxtran-10: phase II clinical trial data. J Magn Reson Imaging. 1999;9:291–294.PubMedCrossRef
26.
Zurück zum Zitat 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.PubMedCrossRef 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.PubMedCrossRef
27.
Zurück zum Zitat Bloch S, Xu B, Ye Y, Liang K, Achilefu S. Internalization of RGD peptide conjugates of near-infrared fluorescent probes in different cell lines occurs via different integrin receptor subtypes. Proc SPIE. 2006;6097:60970H.CrossRef Bloch S, Xu B, Ye Y, Liang K, Achilefu S. Internalization of RGD peptide conjugates of near-infrared fluorescent probes in different cell lines occurs via different integrin receptor subtypes. Proc SPIE. 2006;6097:60970H.CrossRef
28.
Zurück zum Zitat 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(21):6146–51.PubMed 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(21):6146–51.PubMed
29.
Zurück zum Zitat Dijkgraaf I, Kruijtzer JA, Liu S, Soede AC, Oyen WJ, Corstens FH, et al. Improved targeting of the alpha(v)beta (3) integrin by multimerisation of RGD peptides. Eur J Nucl Med Mol Imaging. 2007;34(2):267–73.PubMedCrossRef Dijkgraaf I, Kruijtzer JA, Liu S, Soede AC, Oyen WJ, Corstens FH, et al. Improved targeting of the alpha(v)beta (3) integrin by multimerisation of RGD peptides. Eur J Nucl Med Mol Imaging. 2007;34(2):267–73.PubMedCrossRef
30.
Zurück zum Zitat Strijkers GJ, Kluza E, Van Tilborg GAF, van der Schaft DWJ, Griffioen AW, Mulder WJM, et al. Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis. Angiogenesis. 2010;13:161–173.PubMedCentralPubMedCrossRef Strijkers GJ, Kluza E, Van Tilborg GAF, van der Schaft DWJ, Griffioen AW, Mulder WJM, et al. Paramagnetic and fluorescent liposomes for target-specific imaging and therapy of tumor angiogenesis. Angiogenesis. 2010;13:161–173.PubMedCentralPubMedCrossRef
Metadaten
Titel
Molecular Imaging of Tumor-Associated Angiogenesis Using a Novel Magnetic Resonance Imaging Contrast Agent Targeting αvβ3 Integrin
verfasst von
Isabelle Debergh, MD
Nancy Van Damme, PhD
Dieter De Naeyer, PhD
Peter Smeets, MD
Pieter Demetter, MD, PhD
Philippe Robert, PhD
Sabin Carme, PhD
Piet Pattyn, MD, PhD
Wim Ceelen, MD, PhD
Publikationsdatum
01.06.2014
Verlag
Springer US
Erschienen in
Annals of Surgical Oncology / Ausgabe 6/2014
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-013-3444-1

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