Drug distribution in tumors: mechanisms, role in drug resistance, and methods for modification.

Distribution of antineoplastic agents within tumors remains one of the major challenges in cancer chemotherapy because distribution is hampered by several factors related to the drug (its physicochemical characteristics) and to the neoplastic tissue (blood and lymphatic vasculature, cell density, extracellular matrix composition, and interstitium). The inhomogeneous distribution and structure of tumor vasculature lead to large avascular and hypoxic areas with low pH and high interstitial oncotic pressure. In these critical conditions, the gradient of drug concentrations from the vessels to the inner parts of the tumor is not sufficient to promote diffusion of pharmacologic agents. Again, cellular sequestration and binding to extracellular matrix represent further factors that limit drug distribution and reduce tumor sensitivity to chemotherapy. Several strategies have been investigated to circumvent drug resistance. The evaluation of liposomal and nanoparticle formulations and the characterization of newer bioreductive agents and drugs that should normalize tumor vasculature are in progress.