Augmentation of transvascular transport of macromolecules and nanoparticles in tumors using vascular endothelial growth factor

The goal of this investigation was to measure changes in vascular permeabil ity, pore cutoff size, and number of transvascular transport pathways as a function of time and in response to vascular endothelial growth factor (VEG F), placenta growth factor (PIGF-1 and PIGF-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 (approximate to 7 nm in diameter) and extravasation of polyethylene glycol-stabilized lo ng-circulating liposomes (100-400 nm) and latex microspheres (approximate t o 800 mm) were determined by intravital microscopy. Vascular permeability w as found to be temporally heterogeneous. VEGF superfusion (100 ng/ml) signi ficantly increased vascular permeability to albumin in normal s.c. vessels, whereas a 30-fold higher dose of VEGF (3000 ng/ml) was required to increas e permeability in pial vessels, suggesting that different tissues exhibit d ifferent dose thresholds for VEGF activity. Furthermore, VEGF superfusion ( 1000 ng/ml) increased vascular permeability to albumin in a hypopermeable h uman glioma xenograft in cranial window, whereas VEGF superfusion (10-1000 ng/ml) failed to increase permeability in a variety of hyperpermeable tumor s 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 x enografts. PIGF-1, PIGF-2, or bFGF did not show any significant effect on p ermeability or pore size in tumors. These findings suggest that exogenous V EGF may be useful for augmenting the transvascular delivery of larger antin eoplastic agents such as gene targeting vectors and encapsulated drug carri ers (typical range, 100-300 nm) into tumors.