title: Tumor vascular permeability to a nanoprobe correlates to tumor-specific expression levels of angiogenic markers.
abstract: BACKGROUND
  Vascular endothelial growth factor (VEGF) receptor-2 is the major mediator of the mitogenic, angiogenic, and vascular hyperpermeability effects of VEGF on breast tumors. Overexpression of VEGF and VEGF receptor-2 is associated with the degree of pathomorphosis of the tumor tissue and unfavorable prognosis. In this study, we demonstrate that non-invasive quantification of the degree of tumor vascular permeability to a nanoprobe correlates with the VEGF and its receptor levels and tumor growth.
  
  
  RESULTS
  We designed an imaging nanoprobe and a methodology to detect the intratumoral deposition of a 100 nm-scale nanoprobe using mammography allowing measurement of the tumor vascular permeability in a rat MAT B III breast tumor model. The tumor vascular permeability varied widely among the animals. Notably, the VEGF and VEGF receptor-2 gene expression of the tumors as measured by qRT-PCR displayed a strong correlation to the imaging-based measurements of vascular permeability to the 100 nm-scale nanoprobe. This is in good agreement with the fact that tumors with high angiogenic activity are expected to have more permeable blood vessels resulting in high intratumoral deposition of a nanoscale agent. In addition, we show that higher intratumoral deposition of the nanoprobe as imaged with mammography correlated to a faster tumor growth rate. This data suggest that vascular permeability scales to the tumor growth and that tumor vascular permeability can be a measure of underlying VEGF and VEGF receptor-2 expression in individual tumors.
  
  
  CONCLUSIONS
  This is the first demonstration, to our knowledge, that quantitative imaging of tumor vascular permeability to a nanoprobe represents a form of a surrogate, functional biomarker of underlying molecular markers of angiogenesis.
authors.affiliation: Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, Atlanta, Georgia, USA.
authors.forename: Efstathios
authors.initials: E
authors.lastname: Karathanasis
authors.forename: Leslie
authors.initials: L
authors.lastname: Chan
authors.forename: Lohitash
authors.initials: L
authors.lastname: Karumbaiah
authors.forename: Kathleen
authors.initials: K
authors.lastname: McNeeley
authors.forename: Carl J
authors.initials: CJ
authors.lastname: D'Orsi
authors.forename: Ananth V
authors.initials: AV
authors.lastname: Annapragada
authors.forename: Ioannis
authors.initials: I
authors.lastname: Sechopoulos
authors.forename: Ravi V
authors.initials: RV
authors.lastname: Bellamkonda
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D004578:Electron Spin Resonance Spectroscopy; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology; D036103:Nanotechnology / Q000379:methods; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology; D009389:Neovascularization, Pathologic; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D014965:X-Rays
chemical_list: D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2