Tumor vascular permeability to a nanoprobe correlates to tumor-specific expression levels of angiogenic markers.
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.
Karathanasis
Efstathios
E
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University, Atlanta, Georgia, USA.
Chan
Leslie
L
Karumbaiah
Lohitash
L
McNeeley
Kathleen
K
D'Orsi
Carl J
CJ
Annapragada
Ananth V
AV
Sechopoulos
Ioannis
I
Bellamkonda
Ravi V
RV
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
D015415:Biomarkers; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2