Dual-targeting of α(v)β(3) and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo

E. Kluza, I. Jacobs, S.J.C.G. Hectors, K.H. Mayo, A.W. Griffioen, G.J. Strijkers, K. Nicolay

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Abstract

Molecular imaging of angiogenesis requires a highly specific and efficient contrast agent for targeting activated endothelium. We have previously demonstrated that paramagnetic and fluorescent liposomes functionalized with two angiogenesis-specific ligands, the galectin-1-specific anginex (Anx) and the a vß 3integrin-specific RGD, produce synergistic targeting effect in vitro. In the current study, we applied Anx and RGD dual-conjugated liposomes (Anx/RGD-L) for angiogenesis-specific MRI in vivo, focusing on the specificity and efficacy of liposome association with tumor endothelium. The targeting properties, clearance kinetics and biodistribution of Anx/RGD-L were investigated in B16F10 melanoma-bearing mice, and compared to liposomes functionalized with either Anx (Anx-L) or RGD (RGD-L). The contrast enhancement produced by dual- and single-targeted nanoparticles in the tumor was measured using in vivo T 1-weighted MRI, complemented by ex vivo immunohistochemical evaluation of tumor tissues. Blood clearance kinetics of Anx/RGD-L was three-fold more rapid than for RGD-L, but comparable to Anx-L. Both dual- and single-targeted liposomes produced similar changes in MRI contrast parameters in tumors with high inter-tumor variability (¿R 1 = 0.04 ± 0.03 s -1, 24 h post-contrast). Importantly, however, the specificity of Anx/RGD-L association with tumor endothelium of 53 ± 6%, assessed by fluorescence microscopy, was significantly higher compared to 43 ± 9% (P = 0.043) and 28 ± 8% (P = 0.0001) of Anx-L and RGD-L, respectively. In contrast, long-circulating RGD-L were on average 16% more efficient in targeting tumor endothelium compared to Anx/RGD-L. Significant differences were also found in the biodistribution of investigated contrast agents. In conclusion, synergistic targeting of a vß 3 and galectin-1 improved the specificity of the association of the liposomal contrast agent to tumor endothelium in vivo, providing therefore a more reliable MRI readout of the angiogenic activity. © 2011 Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)207-214
JournalJournal of Controlled Release
Volume158
Issue number2
DOIs
Publication statusPublished - 2012

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Galectin 1
Liposomes
Endothelium
Neoplasms
Contrast Media
Molecular Imaging
Fluorescence Microscopy
Nanoparticles
Melanoma
Ligands

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@article{190907979b2b42039f0060ceace6bfc1,
title = "Dual-targeting of α(v)β(3) and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo",
abstract = "Molecular imaging of angiogenesis requires a highly specific and efficient contrast agent for targeting activated endothelium. We have previously demonstrated that paramagnetic and fluorescent liposomes functionalized with two angiogenesis-specific ligands, the galectin-1-specific anginex (Anx) and the a v{\ss} 3integrin-specific RGD, produce synergistic targeting effect in vitro. In the current study, we applied Anx and RGD dual-conjugated liposomes (Anx/RGD-L) for angiogenesis-specific MRI in vivo, focusing on the specificity and efficacy of liposome association with tumor endothelium. The targeting properties, clearance kinetics and biodistribution of Anx/RGD-L were investigated in B16F10 melanoma-bearing mice, and compared to liposomes functionalized with either Anx (Anx-L) or RGD (RGD-L). The contrast enhancement produced by dual- and single-targeted nanoparticles in the tumor was measured using in vivo T 1-weighted MRI, complemented by ex vivo immunohistochemical evaluation of tumor tissues. Blood clearance kinetics of Anx/RGD-L was three-fold more rapid than for RGD-L, but comparable to Anx-L. Both dual- and single-targeted liposomes produced similar changes in MRI contrast parameters in tumors with high inter-tumor variability (¿R 1 = 0.04 ± 0.03 s -1, 24 h post-contrast). Importantly, however, the specificity of Anx/RGD-L association with tumor endothelium of 53 ± 6{\%}, assessed by fluorescence microscopy, was significantly higher compared to 43 ± 9{\%} (P = 0.043) and 28 ± 8{\%} (P = 0.0001) of Anx-L and RGD-L, respectively. In contrast, long-circulating RGD-L were on average 16{\%} more efficient in targeting tumor endothelium compared to Anx/RGD-L. Significant differences were also found in the biodistribution of investigated contrast agents. In conclusion, synergistic targeting of a v{\ss} 3 and galectin-1 improved the specificity of the association of the liposomal contrast agent to tumor endothelium in vivo, providing therefore a more reliable MRI readout of the angiogenic activity. {\circledC} 2011 Elsevier B.V. All rights reserved.",
author = "E. Kluza and I. Jacobs and S.J.C.G. Hectors and K.H. Mayo and A.W. Griffioen and G.J. Strijkers and K. Nicolay",
year = "2012",
doi = "10.1016/j.jconrel.2011.10.032",
language = "English",
volume = "158",
pages = "207--214",
journal = "Journal of Controlled Release",
issn = "0168-3659",
publisher = "Elsevier",
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Dual-targeting of α(v)β(3) and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo. / Kluza, E.; Jacobs, I.; Hectors, S.J.C.G.; Mayo, K.H.; Griffioen, A.W.; Strijkers, G.J.; Nicolay, K.

In: Journal of Controlled Release, Vol. 158, No. 2, 2012, p. 207-214.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Dual-targeting of α(v)β(3) and galectin-1 improves the specificity of paramagnetic/fluorescent liposomes to tumor endothelium in vivo

AU - Kluza, E.

AU - Jacobs, I.

AU - Hectors, S.J.C.G.

AU - Mayo, K.H.

AU - Griffioen, A.W.

AU - Strijkers, G.J.

AU - Nicolay, K.

PY - 2012

Y1 - 2012

N2 - Molecular imaging of angiogenesis requires a highly specific and efficient contrast agent for targeting activated endothelium. We have previously demonstrated that paramagnetic and fluorescent liposomes functionalized with two angiogenesis-specific ligands, the galectin-1-specific anginex (Anx) and the a vß 3integrin-specific RGD, produce synergistic targeting effect in vitro. In the current study, we applied Anx and RGD dual-conjugated liposomes (Anx/RGD-L) for angiogenesis-specific MRI in vivo, focusing on the specificity and efficacy of liposome association with tumor endothelium. The targeting properties, clearance kinetics and biodistribution of Anx/RGD-L were investigated in B16F10 melanoma-bearing mice, and compared to liposomes functionalized with either Anx (Anx-L) or RGD (RGD-L). The contrast enhancement produced by dual- and single-targeted nanoparticles in the tumor was measured using in vivo T 1-weighted MRI, complemented by ex vivo immunohistochemical evaluation of tumor tissues. Blood clearance kinetics of Anx/RGD-L was three-fold more rapid than for RGD-L, but comparable to Anx-L. Both dual- and single-targeted liposomes produced similar changes in MRI contrast parameters in tumors with high inter-tumor variability (¿R 1 = 0.04 ± 0.03 s -1, 24 h post-contrast). Importantly, however, the specificity of Anx/RGD-L association with tumor endothelium of 53 ± 6%, assessed by fluorescence microscopy, was significantly higher compared to 43 ± 9% (P = 0.043) and 28 ± 8% (P = 0.0001) of Anx-L and RGD-L, respectively. In contrast, long-circulating RGD-L were on average 16% more efficient in targeting tumor endothelium compared to Anx/RGD-L. Significant differences were also found in the biodistribution of investigated contrast agents. In conclusion, synergistic targeting of a vß 3 and galectin-1 improved the specificity of the association of the liposomal contrast agent to tumor endothelium in vivo, providing therefore a more reliable MRI readout of the angiogenic activity. © 2011 Elsevier B.V. All rights reserved.

AB - Molecular imaging of angiogenesis requires a highly specific and efficient contrast agent for targeting activated endothelium. We have previously demonstrated that paramagnetic and fluorescent liposomes functionalized with two angiogenesis-specific ligands, the galectin-1-specific anginex (Anx) and the a vß 3integrin-specific RGD, produce synergistic targeting effect in vitro. In the current study, we applied Anx and RGD dual-conjugated liposomes (Anx/RGD-L) for angiogenesis-specific MRI in vivo, focusing on the specificity and efficacy of liposome association with tumor endothelium. The targeting properties, clearance kinetics and biodistribution of Anx/RGD-L were investigated in B16F10 melanoma-bearing mice, and compared to liposomes functionalized with either Anx (Anx-L) or RGD (RGD-L). The contrast enhancement produced by dual- and single-targeted nanoparticles in the tumor was measured using in vivo T 1-weighted MRI, complemented by ex vivo immunohistochemical evaluation of tumor tissues. Blood clearance kinetics of Anx/RGD-L was three-fold more rapid than for RGD-L, but comparable to Anx-L. Both dual- and single-targeted liposomes produced similar changes in MRI contrast parameters in tumors with high inter-tumor variability (¿R 1 = 0.04 ± 0.03 s -1, 24 h post-contrast). Importantly, however, the specificity of Anx/RGD-L association with tumor endothelium of 53 ± 6%, assessed by fluorescence microscopy, was significantly higher compared to 43 ± 9% (P = 0.043) and 28 ± 8% (P = 0.0001) of Anx-L and RGD-L, respectively. In contrast, long-circulating RGD-L were on average 16% more efficient in targeting tumor endothelium compared to Anx/RGD-L. Significant differences were also found in the biodistribution of investigated contrast agents. In conclusion, synergistic targeting of a vß 3 and galectin-1 improved the specificity of the association of the liposomal contrast agent to tumor endothelium in vivo, providing therefore a more reliable MRI readout of the angiogenic activity. © 2011 Elsevier B.V. All rights reserved.

U2 - 10.1016/j.jconrel.2011.10.032

DO - 10.1016/j.jconrel.2011.10.032

M3 - Article

C2 - 22079810

VL - 158

SP - 207

EP - 214

JO - Journal of Controlled Release

JF - Journal of Controlled Release

SN - 0168-3659

IS - 2

ER -