The goal of this project is to improve transvascular transport in solid tumors. This will involve quantification of various physiological, morphological and molecular pathways in vascular transport. We plan to measure permeability and permeability related factors, hydraulic conductivity and microvascular pressures, and endothelial pore-sizes, involved in these transport mechanisms. These goals will be accomplished by using various different but complementary techniques: i) a highly specialized in vivo technique that allows quantification of transport parameters in individual tumor microvessels, i.e. permeability (P) and hydraulic conductivity (Lp), ii) macromolecules of increasing size to quantify pore-sizes, iii) immunohistology to localize Vascular Permeability Factor, also known as Vascular Endothelial Growth Factor (VPF/VEGF) and its receptors flt-1 and flk (or kdr), iv) in situ hybridization to quantify mRNA expression of VPF and its cognate receptors in vascular endothelial cells and v) northern blotting to quantify the total amount of VPF present in tumors. Combination of the results of these techniques will greatly enhance our understanding of transvascular transport in individual tumor vessels and allow us to improve the delivery of therapeutic molecules in solid tumors. The proposed project represents the first detailed and comprehensive investigation of molecular transport at the level of individual vessels in tumors.
| Lichtenbeld, H C; Ferarra, N; Jain, R K et al. (1999) Effect of local anti-VEGF antibody treatment on tumor microvessel permeability. Microvasc Res 57:357-62 |
