title: Molecular and functional ultrasound imaging in differently aggressive breast cancer xenografts using two novel ultrasound contrast agents (BR55 and BR38).
abstract: OBJECTIVE
  To characterise clinically translatable long-circulating (BR38) and VEGFR2-targeted (BR55) microbubbles (MB) and to assess their ability to discriminate breast cancer models with different aggressiveness.
  
  
  METHODS
  The circulation characteristics of BR38 and BR55 were investigated in healthy mice. The relative blood volume (rBV) of MDA-MB-231 (n = 5) or MCF-7 (n = 6) tumours was determined using BR38. In the same tumours in-vivo binding specificity of BR55 was tested and VEGFR2 expression assessed. Data validation included quantitative immunohistological analysis.
  
  
  RESULTS
  BR38 had a longer blood half-life than BR55 (>600 s vs. 218 s). BR38-enhanced ultrasound showed greater vascularisation in MDA-MB-231 tumours (p = 0.022), which was in line with immunohistology (p = 0.033). In-vivo competitive binding experiments proved the specificity of BR55 to VEGFR2 (p = 0.027). Binding of BR55 was significantly higher in MDA-MB-231 than in MCF-7 tumours (p = 0.049), which corresponded with the VEGFR2 levels found histologically (p = 0.015). However, differences became smaller when normalising the levels of BR55 to the rBV.
  
  
  CONCLUSIONS
  BR38 and BR55 are well suited to characterising and distinguishing breast cancers with different angiogenesis and aggressiveness. Long-circulating BR38 MB allow extensive 3-dimensional examinations of larger or several organs. BR55 accumulation faithfully reflects the VEGFR2 status in tumours and depicts even small differences in angiogenesis.
authors.affiliation: Institute for Experimental Molecular Imaging, RWTH-Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Bzyl
authors.forename: Wiltrud
authors.initials: W
authors.lastname: Lederle
authors.forename: Anne
authors.initials: A
authors.lastname: Rix
authors.forename: Christoph
authors.initials: C
authors.lastname: Grouls
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tardy
authors.forename: Sibylle
authors.initials: S
authors.lastname: Pochon
authors.forename: Monica
authors.initials: M
authors.lastname: Siepmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Penzkofer
authors.forename: Michel
authors.initials: M
authors.lastname: Schneider
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.forename: Moritz
authors.initials: M
authors.lastname: Palmowski
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D003287:Contrast Media / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005466:Fluorocarbons / Q000493:pharmacokinetics; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D045423:Microbubbles; D008967:Molecular Biology; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009584:Nitrogen / Q000493:pharmacokinetics; D011897:Random Allocation; D012016:Reference Values; D012680:Sensitivity and Specificity; D014183:Transplantation, Heterologous; D018608:Ultrasonography, Doppler / Q000379:methods*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D003287:Contrast Media; D005466:Fluorocarbons; D040301:Vascular Endothelial Growth Factor Receptor-2; D009584:Nitrogen; C108042:perfluorobutane