TIME-DEPENDENT BEHAVIOR OF INTERSTITIAL FLUID PRESSURE IN SOLID TUMORS - IMPLICATIONS FOR DRUG-DELIVERY

Elevated interstitial fluid pressure (IFP) may constitute a significan t physiological barrier to drug delivery in solid tumors. Strategies f or overcoming this barrier have not been developed to date, To identif y and characterize various mechanisms regulating IFP and to develop st rategies for overcoming the IFP barrier, we modeled the tumor as a por oelastic solid, We used this model to simulate the effect of changes i n microvascular pressure and tumor blood now (TBF) on IFP, To test mod el predictions, the effects of changes in arterial pressure and TBF on IFP were measured using a tissue-isolated tumor preparation. IFP in t he center of an isolated tumor was predicted to follow variation of th e arterial pressure with a time delay of the order of magnitude of 10 s, and this delay was found to be 11 +/- 6 s experimentally, Following a cessation of TBP, the time constant of the drop in IFP was predicte d to be of the order of 1000 s and was found to be 1500 +/- 900 s expe rimentally, The former time scale is characteristic of transcapillary fluid exchange, and the latter of percolation of fluid through the int erstitial matrix, Relying on the good agreement between theoretical pr edictions and experimental data, we estimated the effect of blood pres sure modulation on macromolecular uptake in solid tumors, Our results show that no appreciable increase of macromolecular uptake should occu r either by an acute or by a chronic increase of blood pressure. On th e other hand, higher uptake would result from periodic modulation of b lood pressure, Therefore, the effectiveness of a vasoconstrictor such as angiotensin II to increase macromolecular delivery should be signif icantly enhanced by periodic rather than bolus or continuous administr ation of the vasoactive agent.