title: Molecular profiling of angiogenesis with targeted ultrasound imaging: early assessment of antiangiogenic therapy effects.
abstract: Molecular ultrasound is capable of elucidating the expression of angiogenic markers in vivo. However, the capability of the method for volumetric "multitarget quantification" and for the assessment of antiangiogenic therapy response has rather been investigated. Therefore, we generated cyanoacrylate microbubbles linked to vascular endothelial growth factor receptor 2 (VEGFR2) and alphavbeta3 integrin binding ligands and quantified their accumulation in squamous cell carcinoma xenografts (HaCaT-ras-A-5RT3) in mice with the quantitative volumetric ultrasound scanning technique, sensitive particle acoustic quantification. Specificity of VEGFR2 and alphavbeta3 integrin binding microbubbles was shown, and changes in marker expression during matrix metalloproteinase inhibitor treatment were investigated. In tumors, accumulation of targeted microbubbles was significantly higher compared with nonspecific ones and could be inhibited competitively by addition of the free ligand in excess. Also, multimarker imaging could successfully be done during the same imaging session. Molecular ultrasound further indicated a significant increase of VEGFR2 and alphavbeta3 integrin expression during tumor growth and a considerable decrease in both marker densities after matrix metalloproteinase inhibitor treatment. Histologic data suggested that the increasing VEGFR2 and alphavbeta3 integrin concentrations in tumors during growth are related to an up-regulation of its expression by the endothelial cells, whereas its decrease under therapy is more related to the decreasing relative vessel density. In conclusion, targeted ultrasound appears feasible for the longitudinal molecular profiling of tumor angiogenesis and for the sensitive assessment of therapy effects in vivo.
authors.affiliation: Department of Diagnostic Radiology, Ruprecht-Karls University, Heidelberg, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Palmowski
authors.forename: Jochen
authors.initials: J
authors.lastname: Huppert
authors.forename: Gesa
authors.initials: G
authors.lastname: Ladewig
authors.forename: Peter
authors.initials: P
authors.lastname: Hauff
authors.forename: Michael
authors.initials: M
authors.lastname: Reinhardt
authors.forename: Margareta M
authors.initials: MM
authors.lastname: Mueller
authors.forename: Eva C
authors.initials: EC
authors.lastname: Woenne
authors.forename: Juergen W
authors.initials: JW
authors.lastname: Jenne
authors.forename: Mathias
authors.initials: M
authors.lastname: Maurer
authors.forename: Guenter W
authors.initials: GW
authors.lastname: Kauffmann
authors.forename: Wolfhard
authors.initials: W
authors.lastname: Semmler
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D014463:Ultrasonography; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D061965:Matrix Metalloproteinase Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2; D020782:Matrix Metalloproteinases