Effect of increasing vascular hydraulic conductivity on delivery of macromolecular drugs to tumor cells.

PURPOSE: To examine the assumption that increasing the hydraulic conductivity Lp of microvessels (by such strategies as radiation, hyperthermia, or inducing inflammation) improves the transport of macromolecular drugs to tumors. METHODS AND MATERIALS: A theoretical model is used to investigate the effect of varying Lp on macromolecular transport in spherical tumor nodules. The model is generalized to nonspherical tumors. The equations governing fluid flow in the tumors are solved numerically to obtain the pressure in the interior, and macromolecule fluxes are deduced using Starling's equation.
RESULTS: Because of the interaction of two opposing effects, the filtration rate at the tumor center is maximized at an "optimum" value of Lp, which depends strongly on tumor size. Only for tumor nodules smaller than about 0.2 cm across is this value lower than the actual estimated value. By considering spheroidal tumor nodules, it is found that dependence on shape is much weaker than dependence on size, except for extremely elongated or flattened shapes.
CONCLUSIONS: While total fluid filtration for the entire tumor region always increases with increasing Lp, the local filtration rate at points inside the tumor decreases if the tumor is larger than about 0.2 cm, leading to a less uniform distribution of the drug, and therapeutic disadvantage. Increased vessel leakiness is an unlikely explanation for reported experimental findings that hyperthermia and inflammation result in more uniform distributions of monoclonal antibodies throughout tumors much larger than 0.2 cm.