Dual-targeting of αvβ3 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 α(v)β(3) integrin-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 (ΔR(1)=0.04±0.03s(-1), 24h 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 α(v)β(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.

• Authors: Ewelina Kluza, Igor Jacobs, Stefanie J C G Hectors, Kevin H Mayo, Arjan W Griffioen, Gustav J Strijkers, Klaas Nicolay
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 158 Issue 2 Pg. 207-14 (Mar 10 2012) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 22079810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Contrast Media
• Galectin 1
• Integrin alphaVbeta3
• Liposomes
• Oligopeptides
• Peptides
• anginex peptide
• arginyl-glycyl-aspartic acid

Topics

• Animals
• Cell Line, Tumor
• Contrast Media (administration & dosage, pharmacokinetics)
• Endothelium, Vascular (metabolism)
• Galectin 1 (metabolism)
• Integrin alphaVbeta3 (metabolism)
• Liposomes
• Magnetics
• Melanoma, Experimental (metabolism)
• Mice
• Mice, Inbred C57BL
• Microscopy, Fluorescence
• Oligopeptides (administration & dosage, pharmacokinetics)
• Peptides (administration & dosage, pharmacokinetics)