Determinants of drug delivery and transport to solid tumors

This presentation addresses the barriers and determinants and the importanc e of drug-induced apoptosis, in drug transport and delivery to organs and s olid tumors. In particular, we examined the roles of interstitial space, dr ug removal by capillaries, tissue structure and tissue composition on drug distribution. Drug transport in bladder tissues is described by the distrib uted model which combined monodimensional Fickian diffusion and first order removal of drug by the per-fusing blood. Microscopic evaluation of the spa tial drug distribution in bladder, prostate and tongue indicates heterogene ous drug distribution with large and erratic concentration gradient. In gen eral, drug distribution favors interstitial space and vasculature. with lit tle penetration in muscles. Drug penetration into 3-dimensional solid tumor s is typically 5- to 10-fold slower than in monolayer cultures. The transpo rt of highly protein-bound drugs such as paclitaxel and doxorubicin in a so lid tumor is retarded by a high tumor cell density and enhanced by drug-ind uced apoptosis. Accordingly, the delivery of a highly protein-bound drug to cells in a solid tumor is affected by its apoptotic effects and is therefo re determined by the drug concentration and the treatment duration, Le, tre atment schedule, Under in vitro and in vivo conditions, the delivery of hig hly protein-bound drugs to tumor can be enhanced by using a pretreatment th at induces apoptosis and reduction in cell density, and by using treatment schedules designed to take advantage of these drug-induced changes in tumor tissue composition. In conclusion, in addition to the usual processes invo lved in drug transport such as distribution through vascular space, transpo rt across microvessel walls, and diffusion through interstitial space in tu mor tissue, other factors including tissue structure and composition and al teration by drug-induced apoptosis are important determinants of drug distr ibution in organs and solid tumors. (C) 2001 Elsevier Science B.V. All righ ts reserved.