Drugs are transferred to tissues according to concentration gradients and pressure gradients. Solid tumors often develop high interstitial fluid pressure due to increased water leakage from the capillaries and impaired lymphatic drainage, which leads to water accumulation, as well as due to increased collagen production and interaction with the fibroblasts surrounding the tumors' cells, which posses pressure on the tissue. The high interstitial fluid pressure modulates the physiological positive pressure gradients from the capillaries outwards and forms a barrier to drug delivery. We have developed a novel, non invasive method based on MRI, which maps throughout the entire tumor the transfer rates determined by pressure gradients and concentration gradients, and hence enables to predict barriers to drug delivery. This method was applied in order to monitor the results of treatment with collagenase, an enzyme that degradates the collagen fibers and reduces interstitial hypertension. The method and its application to monitor collagenase effects were tested in H460 ectopic human non-small-cell lung cancer xenografts in immunodeficient mice. Sequential images were recorded during slow infusion of a Gd-based contrast agent and were analyzed using an extended mathematical model of tumor perfusion. The final output provided physiological parameters such as concentration dependent and pressure dependent transfer constants, intravascular and extracellular volume fractions. The tumors exhibited positive pressure dependent transfer constants at the boundaries and negative pressure dependent transfer constants in internal region. These negative transfer constants reflected increased interstitial fluid pressure as was confirmed by using the wick in needle method. After treatment with collagenase the tumors' central regions demonstrated a significant increase in the pressure dependent transfer constant, from negative to positive values, while the concentration gradients dependent transfer rates, as well as the other physiological parameters did not change significantly. It is therefore possible to map non invasively, for the first time, the in vivo physiological parameters which could be used to evaluate the barriers to successful drug delivery to tumors, and provide a quantitative measure for testing new drugs that eliminate these barriers.
- American Association for Cancer Research