Transport of fluid and macromolecules in tumors. I. Role of interstitial pressure and convection.

A general theoretical framework for transvascular exchange and extravascular transport of fluid and macromolecules in tumors is developed. The resulting equations are applied to the most simple case of a homogeneous, alymphatic tumor, with no extravascular binding. Numerical simulations show that in a uniformly perfused tumor the elevated interstitial pressure is a major cause for heterogeneous distribution of nonbinding macromolecules, because it (i) reduces the driving force for extravasation of fluid and macromolecules in tumors, (ii) results in nonuniform filtration of fluid and macromolecules from blood vessels, and (iii) leads to experimentally verifiable, radially outward convection which opposes the inward diffusion. The models are used to predict the interstitial pressure, interstitial fluid velocity, and concentration profiles as a function of radial position and tumor size. The model predictions agree with the following experimental data: (i) the interstitial pressure in a tumor is lowest at the periphery of the tumor and increases towards the center; (ii) the radially outward fluid velocity predicted by the fluid transport model is of the same order of magnitude as that measured in tissue-isolated tumors; and (iii) the concentration of macromolecules is higher in the periphery than in the center of tumors at short times postinjection; however, at later times the peripheral concentration is less than the concentration in the center. This work shows that in addition to the heterogeneous distribution of blood supply, hindered interstitial transport, and rapid extravascular binding of macromolecules (e.g., monoclonal antibodies), the elevated interstitial pressure plays an important role in determining the penetration of macromolecules into tumors. If the genetically engineered macromolecules are to fulfill their clinical promise, methods must be developed to overcome these physiological barriers in tumors.