title: MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle.
abstract: In oncological research, there is a great need for imaging techniques that specifically identify angiogenic blood vessels in tumors on the basis of differences in the expression level of biomolecular markers. In the angiogenic cascade, different cell surface receptors, including the alphavbeta3-integrin, are strongly expressed on activated endothelial cells. In the present study, we aimed to image angiogenesis by detecting the expression of alphavbeta3 in tumor bearing mice with a combination of magnetic resonance imaging (MRI) and fluorescence microscopy. To that end, we prepared MR-detectable and fluorescent liposomes, which carry approximately 700 alphavbeta3-specific RGD peptides per liposome. RGD competition experiments and RAD-conjugated liposomes were used as controls for specificity. In vivo, both RAD liposomes and RGD liposomes gave rise to signal increase on T1-weighted MR images. It was established by the use of ex vivo fluorescence microscopy that RGD liposomes and RAD liposomes accumulated in the tumor by different mechanisms. RGD liposomes were specifically associated with activated tumor endothelium, while RAD liposomes were located in the extravascular compartment. This study demonstrates that MR molecular imaging of angiogenesis is feasible by using a targeted contrast agent specific for the alphavbeta3-integrin, and that the multimodality imaging approach gave insight into the exact mechanism of accumulation in the tumor.
authors.affiliation: Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, MB Eindhoven, The Netherlands. w.j.m.mulder@tue.nl
authors.forename: Willem J M
authors.initials: WJ
authors.lastname: Mulder
authors.forename: Gustav J
authors.initials: GJ
authors.lastname: Strijkers
authors.forename: Jo W
authors.initials: JW
authors.lastname: Habets
authors.forename: Egbert J W
authors.initials: EJ
authors.lastname: Bleeker
authors.forename: Daisy W J
authors.initials: DW
authors.lastname: van der Schaft
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.forename: Klaas
authors.initials: K
authors.lastname: Nicolay
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence / Q000379:methods*; D008954:Models, Biological; D049329:Nanostructures; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000737:chemistry; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D014471:Umbilical Veins / Q000166:cytology
chemical_list: D039302:Integrin alphaVbeta3; D008055:Lipids; D008081:Liposomes; D009842:Oligopeptides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C047981:arginyl-glycyl-aspartic acid