Transport of fluid and macromolecules in tumors. II. Role of heterogeneous perfusion and lymphatics.

We have recently developed a general theoretical framework for transvascular exchange and extravascular transport of fluid and macromolecules in tumors. The model was applied to a homogeneous, alymphatic tumor with no extravascular binding. For this simplified system, the interstitial pressure was found to be a major contributing factor to the heterogeneous distribution of macromolecules within solid tumors. A steep pressure gradient was predicted at the periphery of the tumor. Our recent experiments have verified these predicted profiles. The purpose of this investigation was to apply this theoretical framework to the more realistic case of a nonuniformly perfused tumor. The role of lymphatics for macromolecular transport was also studied using the model. The uptake and distribution of IgG and its fragment, Fab, were simulated. The novel result from this work is that necrosis does not reduce the central interstitial pressure in a tumor. Other results showed that (i) macromolecules do not penetrate a necrotic core at early times after injection; (ii) at longer time periods after a bolus injection (days for Fab, months for IgG in a tumor of radius approximately 1cm) a "reservoir" of material may be formed in the necrotic core; (iii) continuous infusion or repeated injections should maintain a higher interstitial concentration of macromolecules; and (iv) lymphatics, if present in a tumor, would rapidly remove material and result in much lower concentration levels. The model is also used to explain some previous experimental data in the literature on antibody distribution.