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Augmentation of Transvascular Transport of Macromolecules and Nanoparticles in Tumors Using Vascular Endothelial Growth Factor¹

Edwin L. Steele Laboratory [W. L. M., D. F., T. G., F. Y., R. K. J.], Department of Radiation Oncology [M. A.], Center for Imaging and Pharmaceutical Research [V. P. T.], Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114; Department of Radiobiological Sciences, Beth Israel-Deaconess Medical Center, Boston, Massachusetts 02114 [W. L. M.]; and Department of Gene Regulation and Differentiation, National Research Center for Biotechnology, Branschweig, Germany [H. A. W.]

The goal of this investigation was to measure changes in vascular permeability, pore cutoff size, and number of transvascular transport pathways as a function of time and in response to vascular endothelial growth factor (VEGF), placenta growth factor (PlGF-1 and PlGF-2), or basic fibroblast growth factor (bFGF). Two human and two murine tumors were implanted in the dorsal skin chamber or cranial window. Vascular permeability to BSA (7 nm in diameter) and extravasation of polyethylene glycol-stabilized long-circulating liposomes (100–400 nm) and latex microspheres (800 nm) were determined by intravital microscopy. Vascular permeability was found to be temporally heterogeneous. VEGF superfusion (100 ng/ml) significantly increased vascular permeability to albumin in normal s.c. vessels, whereas a 30-fold higher dose of VEGF (3000 ng/ml) was required to increase permeability in pial vessels, suggesting that different tissues exhibit different dose thresholds for VEGF activity. Furthermore, VEGF superfusion (1000 ng/ml) increased vascular permeability to albumin in a hypopermeable human glioma xenograft in cranial window, whereas VEGF superfusion (10–1000 ng/ml) failed to increase permeability in a variety of hyperpermeable tumors grown in dorsal skin chamber. Interestingly, low-dose VEGF treatment (10 ng/ml) doubled the maximum pore size (from 400 to 800 nm) and significantly increased the frequency of large (400 nm) pores in human colon carcinoma xenografts. PlGF-1, PlGF-2, or bFGF did not show any significant effect on permeability or pore size in tumors. These findings suggest that exogenous VEGF may be useful for augmenting the transvascular delivery of larger antineoplastic agents such as gene targeting vectors and encapsulated drug carriers (typical range, 100–300 nm) into tumors.

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