Skip to main content
Top
Published in: Journal of Nuclear Cardiology 6/2015

01-12-2015 | Original Article

Feasibility of [18F]-RGD for ex vivo imaging of atherosclerosis in detection of αvβ3 integrin expression

Authors: Reza Golestani, MD, PhD, Leila Mirfeizi, PhD, Clark J. Zeebregts, MD, PhD, Johanna Westra, MD, PhD, Hans J. de Haas, BS, Andor W. J. M. Glaudemans, MD, Michel Koole, PhD, Gert Luurtsema, PhD, René A. Tio, MD, PhD, Rudi A. J. O. Dierckx, MD, PhD, Hendrikus H. Boersma, PharmD, PhD, Philip H. Elsinga, PhD, Riemer H. J. A. Slart, MD, PhD

Published in: Journal of Nuclear Cardiology | Issue 6/2015

Login to get access

Abstract

Background

Inflammation and angiogenesis play an important role in atherosclerotic plaque rupture. Therefore, molecular imaging of these processes could be used for determination of rupture-prone atherosclerotic plaques. αvβ3 integrin is involved in the process of angiogenesis. Targeted imaging of αvβ3 integrin has been shown to be possible in previous studies on tumor models, using radiolabeled arginine-glycine-aspartate (RGD). Our aim was to investigate feasibility of ex vivo detection of αvβ3 integrin in carotid endarterectomy (CEA) specimens.

Methods and Results

Nineteen CEA specimens were incubated in 5 MBq [18F]-RGD-K5 for 1 hour followed by 1 hour emission microPET scan. The results were quantified in 4 mm wide segments as percent incubation dose per gram (%Inc/g). Segmental-to-total ratio was calculated and presence of αvβ3 integrin and endothelial cells in each segment was confirmed by immunohistochemical staining for CD31 and αvβ3 integrin, respectively. [18F]-RGD-K5 uptake was heterogeneously distributed across CEA specimens and was localized within the vessel wall. Significant correlations were observed between segmental-to-total ratio with αvβ3 integrin staining score (r = 0.58, P = .038) and CD31 staining score (ρ = 0.67, P < .002).

Conclusion

This study showed the feasibility of integrin imaging by determination of αvβ3 integrin expression in human atherosclerotic plaques.
Literature
1.
go back to reference Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: A call for new definitions and risk assessment strategies: Part I. Circulation 2003;108:1664-72.CrossRefPubMed Naghavi M, Libby P, Falk E, Casscells SW, Litovsky S, Rumberger J, et al. From vulnerable plaque to vulnerable patient: A call for new definitions and risk assessment strategies: Part I. Circulation 2003;108:1664-72.CrossRefPubMed
2.
go back to reference Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: Angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:2054-61.CrossRefPubMed Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture: Angiogenesis as a source of intraplaque hemorrhage. Arterioscler Thromb Vasc Biol 2005;25:2054-61.CrossRefPubMed
3.
go back to reference Nagengast WB, de Vries EG, Hospers GA, Mulder NH, de Jong JR, Hollema H, et al. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med 2007;48:1313-9.CrossRefPubMed Nagengast WB, de Vries EG, Hospers GA, Mulder NH, de Jong JR, Hollema H, et al. In vivo VEGF imaging with radiolabeled bevacizumab in a human ovarian tumor xenograft. J Nucl Med 2007;48:1313-9.CrossRefPubMed
4.
go back to reference Cai W, Chen K, Mohamedali KA, Cao Q, Gambhir SS, Rosenblum MG, et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med 2006;47:2048-56.PubMed Cai W, Chen K, Mohamedali KA, Cao Q, Gambhir SS, Rosenblum MG, et al. PET of vascular endothelial growth factor receptor expression. J Nucl Med 2006;47:2048-56.PubMed
5.
go back to reference Lam MK, Al-Ansari S, van Dam GM, Tio RA, Breek JC, Slart RH, et al. Single-chain VEGF/Cy5.5 targeting vegf receptors to indicate atherosclerotic plaque instability. Mol Imaging Biol 2013;15:250-61.CrossRefPubMed Lam MK, Al-Ansari S, van Dam GM, Tio RA, Breek JC, Slart RH, et al. Single-chain VEGF/Cy5.5 targeting vegf receptors to indicate atherosclerotic plaque instability. Mol Imaging Biol 2013;15:250-61.CrossRefPubMed
6.
go back to reference Schnell O, Krebs B, Carlsen J, Miederer I, Goetz C, Goldbrunner RH, et al. Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] galacto-RGD positron emission tomography. Neuro Oncol 2009;11:861-70.PubMedCentralCrossRefPubMed Schnell O, Krebs B, Carlsen J, Miederer I, Goetz C, Goldbrunner RH, et al. Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] galacto-RGD positron emission tomography. Neuro Oncol 2009;11:861-70.PubMedCentralCrossRefPubMed
7.
go back to reference Hoshiga M, Alpers CE, Smith LL, Giachelli CM, Schwartz SM. Alpha-v beta-3 integrin expression in normal and atherosclerotic artery. Circ Res 1995;77:1129-35.CrossRefPubMed Hoshiga M, Alpers CE, Smith LL, Giachelli CM, Schwartz SM. Alpha-v beta-3 integrin expression in normal and atherosclerotic artery. Circ Res 1995;77:1129-35.CrossRefPubMed
8.
go back to reference Liu S. Radiolabeled multimeric cyclic RGD peptides as integrin alphavbeta3 targeted radiotracers for tumor imaging. Mol Pharm 2006;3:472-87.CrossRefPubMed Liu S. Radiolabeled multimeric cyclic RGD peptides as integrin alphavbeta3 targeted radiotracers for tumor imaging. Mol Pharm 2006;3:472-87.CrossRefPubMed
9.
go back to reference McParland BJ, Miller MP, Spinks TJ, Kenny LM, Osman S, Khela MK, et al. The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18F-AH111585 in healthy volunteers. J Nucl Med 2008;49:1664-7.CrossRefPubMed McParland BJ, Miller MP, Spinks TJ, Kenny LM, Osman S, Khela MK, et al. The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18F-AH111585 in healthy volunteers. J Nucl Med 2008;49:1664-7.CrossRefPubMed
10.
go back to reference Beer AJ, Lorenzen S, Metz S, Herrmann K, Watzlowik P, Wester HJ, et al. Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: A PET study using 18F-galacto-RGD and 18F-FDG. J Nucl Med 2008;49:22-9.CrossRefPubMed Beer AJ, Lorenzen S, Metz S, Herrmann K, Watzlowik P, Wester HJ, et al. Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: A PET study using 18F-galacto-RGD and 18F-FDG. J Nucl Med 2008;49:22-9.CrossRefPubMed
11.
go back to reference Razavian M, Marfatia R, Mongue-Din H, Tavakoli S, Sinusas AJ, Zhang J, et al. Integrin-targeted imaging of inflammation in vascular remodeling. Arterioscler Thromb Vasc Biol 2011;31:2820-6.PubMedCentralCrossRefPubMed Razavian M, Marfatia R, Mongue-Din H, Tavakoli S, Sinusas AJ, Zhang J, et al. Integrin-targeted imaging of inflammation in vascular remodeling. Arterioscler Thromb Vasc Biol 2011;31:2820-6.PubMedCentralCrossRefPubMed
12.
go back to reference Laitinen I, Saraste A, Weidl E, Poethko T, Weber AW, Nekolla SG, et al. Evaluation of alphavbeta3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice. Circ Cardiovasc Imaging 2009;2:331-8.CrossRefPubMed Laitinen I, Saraste A, Weidl E, Poethko T, Weber AW, Nekolla SG, et al. Evaluation of alphavbeta3 integrin-targeted positron emission tomography tracer 18F-galacto-RGD for imaging of vascular inflammation in atherosclerotic mice. Circ Cardiovasc Imaging 2009;2:331-8.CrossRefPubMed
13.
go back to reference Masteling MG, Zeebregts CJ, Tio RA, Breek JC, Tietge UJ, de Boer JF, et al. High-resolution imaging of human atherosclerotic carotid plaques with micro18F-FDG PET scanning exploring plaque vulnerability. J Nucl Cardiol 2011;18:1066-75.PubMedCentralCrossRefPubMed Masteling MG, Zeebregts CJ, Tio RA, Breek JC, Tietge UJ, de Boer JF, et al. High-resolution imaging of human atherosclerotic carotid plaques with micro18F-FDG PET scanning exploring plaque vulnerability. J Nucl Cardiol 2011;18:1066-75.PubMedCentralCrossRefPubMed
14.
go back to reference Golestani R, Zeebregts CJ, Terwisscha van Scheltinga AG, Lub-de Hooge MN, van Dam GM, Glaudemans AW, et al. Feasibility of vascular endothelial growth factor imaging in human atherosclerotic plaque using (89)Zr-bevacizumab positron emission tomography. Mol Imaging 2013;12:235-43.PubMed Golestani R, Zeebregts CJ, Terwisscha van Scheltinga AG, Lub-de Hooge MN, van Dam GM, Glaudemans AW, et al. Feasibility of vascular endothelial growth factor imaging in human atherosclerotic plaque using (89)Zr-bevacizumab positron emission tomography. Mol Imaging 2013;12:235-43.PubMed
15.
go back to reference Gaertner FC, Kessler H, Wester HJ, Schwaiger M, Beer AJ. Radiolabelled RGD peptides for imaging and therapy. Eur J Nucl Med Mol Imaging 2012;39:S126-38.CrossRefPubMed Gaertner FC, Kessler H, Wester HJ, Schwaiger M, Beer AJ. Radiolabelled RGD peptides for imaging and therapy. Eur J Nucl Med Mol Imaging 2012;39:S126-38.CrossRefPubMed
16.
go back to reference Narula J, Nakano M, Virmani R, Kolodgie FD, Petersen R, Newcomb R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol 2013;61:1041-51.PubMedCentralCrossRefPubMed Narula J, Nakano M, Virmani R, Kolodgie FD, Petersen R, Newcomb R, et al. Histopathologic characteristics of atherosclerotic coronary disease and implications of the findings for the invasive and noninvasive detection of vulnerable plaques. J Am Coll Cardiol 2013;61:1041-51.PubMedCentralCrossRefPubMed
17.
go back to reference Ribatti D, Levi-Schaffer F, Kovanen PT. Inflammatory angiogenesis in atherogenesis—A double-edged sword. Ann Med 2008;40:606-21.CrossRefPubMed Ribatti D, Levi-Schaffer F, Kovanen PT. Inflammatory angiogenesis in atherogenesis—A double-edged sword. Ann Med 2008;40:606-21.CrossRefPubMed
18.
go back to reference Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 2008;49:879-86.CrossRefPubMed Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med 2008;49:879-86.CrossRefPubMed
19.
go back to reference Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]galacto-RGD. PLoS Med 2005;2:e70.PubMedCentralCrossRefPubMed Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]galacto-RGD. PLoS Med 2005;2:e70.PubMedCentralCrossRefPubMed
20.
go back to reference Doss M, Kolb HC, Zhang JJ, Belanger MJ, Stubbs JB, Stabin MG, et al. Biodistribution and radiation dosimetry of the integrin marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. J Nucl Med 2012;53:787-95.CrossRefPubMed Doss M, Kolb HC, Zhang JJ, Belanger MJ, Stubbs JB, Stabin MG, et al. Biodistribution and radiation dosimetry of the integrin marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. J Nucl Med 2012;53:787-95.CrossRefPubMed
21.
go back to reference Verjans J, Wolters S, Laufer W, Schellings M, Lax M, Lovhaug D, et al. Early molecular imaging of interstitial changes in patients after myocardial infarction: Comparison with delayed contrast-enhanced magnetic resonance imaging. J Nucl Cardiol 2010;17:1065-72.PubMedCentralCrossRefPubMed Verjans J, Wolters S, Laufer W, Schellings M, Lax M, Lovhaug D, et al. Early molecular imaging of interstitial changes in patients after myocardial infarction: Comparison with delayed contrast-enhanced magnetic resonance imaging. J Nucl Cardiol 2010;17:1065-72.PubMedCentralCrossRefPubMed
22.
go back to reference Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, et al. Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 2001;61:1781-5.PubMed Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, et al. Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 2001;61:1781-5.PubMed
23.
go back to reference Meerwaldt R, Slart RH, van Dam GM, Luijckx GJ, Tio RA, Zeebregts CJ. PET/SPECT imaging: From carotid vulnerability to brain viability. Eur J Radiol 2010;74:104-9.CrossRefPubMed Meerwaldt R, Slart RH, van Dam GM, Luijckx GJ, Tio RA, Zeebregts CJ. PET/SPECT imaging: From carotid vulnerability to brain viability. Eur J Radiol 2010;74:104-9.CrossRefPubMed
24.
go back to reference West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 2010;467:972-6.PubMedCentralCrossRefPubMed West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 2010;467:972-6.PubMedCentralCrossRefPubMed
25.
go back to reference Holm PW, Slart RH, Zeebregts CJ, Hillebrands JL, Tio RA. Atherosclerotic plaque development and instability: A dual role for VEGF. Ann Med 2009;41:257-64.CrossRefPubMed Holm PW, Slart RH, Zeebregts CJ, Hillebrands JL, Tio RA. Atherosclerotic plaque development and instability: A dual role for VEGF. Ann Med 2009;41:257-64.CrossRefPubMed
26.
go back to reference Chen W, Bural GG, Torigian DA, Rader DJ, Alavi A. Emerging role of FDG-PET/CT in assessing atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging 2009;36:144-51.CrossRefPubMed Chen W, Bural GG, Torigian DA, Rader DJ, Alavi A. Emerging role of FDG-PET/CT in assessing atherosclerosis in large arteries. Eur J Nucl Med Mol Imaging 2009;36:144-51.CrossRefPubMed
27.
go back to reference Razavian M, Tavakoli S, Zhang J, Nie L, Dobrucki LW, Sinusas AJ, et al. Atherosclerosis plaque heterogeneity and response to therapy detected by in vivo molecular imaging of matrix metalloproteinase activation. J Nucl Med 2011;52:1795-802.PubMedCentralCrossRefPubMed Razavian M, Tavakoli S, Zhang J, Nie L, Dobrucki LW, Sinusas AJ, et al. Atherosclerosis plaque heterogeneity and response to therapy detected by in vivo molecular imaging of matrix metalloproteinase activation. J Nucl Med 2011;52:1795-802.PubMedCentralCrossRefPubMed
28.
go back to reference Razansky D, Harlaar NJ, Hillebrands JL, Taruttis A, Herzog E, Zeebregts CJ, et al. Multispectral optoacoustic tomography of matrix metalloproteinase activity in vulnerable human carotid plaques. Mol Imaging Biol 2012;14:277-85.PubMedCentralCrossRefPubMed Razansky D, Harlaar NJ, Hillebrands JL, Taruttis A, Herzog E, Zeebregts CJ, et al. Multispectral optoacoustic tomography of matrix metalloproteinase activity in vulnerable human carotid plaques. Mol Imaging Biol 2012;14:277-85.PubMedCentralCrossRefPubMed
Metadata
Title
Feasibility of [18F]-RGD for ex vivo imaging of atherosclerosis in detection of αvβ3 integrin expression
Authors
Reza Golestani, MD, PhD
Leila Mirfeizi, PhD
Clark J. Zeebregts, MD, PhD
Johanna Westra, MD, PhD
Hans J. de Haas, BS
Andor W. J. M. Glaudemans, MD
Michel Koole, PhD
Gert Luurtsema, PhD
René A. Tio, MD, PhD
Rudi A. J. O. Dierckx, MD, PhD
Hendrikus H. Boersma, PharmD, PhD
Philip H. Elsinga, PhD
Riemer H. J. A. Slart, MD, PhD
Publication date
01-12-2015
Publisher
Springer US
Published in
Journal of Nuclear Cardiology / Issue 6/2015
Print ISSN: 1071-3581
Electronic ISSN: 1532-6551
DOI
https://doi.org/10.1007/s12350-014-0061-8

Other articles of this Issue 6/2015

Journal of Nuclear Cardiology 6/2015 Go to the issue