Clinical aspects of drug delivery to tumors

• Published in: Journal of controlled release Vol. 78; no. 1; pp. 81 - 95
• Main Authors: Au, Jessie L.-S, Jang, Seong H, Wientjes, M.Guill
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Amsterdam Elsevier B.V 17.01.2002; Elsevier
• Subjects: Administration, Intravesical; Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Apoptosis; Biological and medical sciences; Bladder; Chemotherapy; Clinical Trials as Topic; Drug delivery; Drug Delivery Systems; Drug transport; Humans; Medical sciences; Mitomycin - administration & dosage; Neoplasms - drug therapy; Organ; Pharmacology. Drug treatments; Research Design; Urinary Bladder Neoplasms - drug therapy; Drug transport; w 1/2, half-width or the thickness of tissue over which the drug concentration declines by 50; V res, volume of residual urine at the time of instillation; Bladder; Drug delivery; k 0, urine production rate constant; C b, average free drug concentration in perfusing blood; C× T, area under the concentration–time curve; V u, urine volume at time t; C depth, concentration at a tissue depth; k d, apparent degradation rate constant; V 0, volume of the dosing solution; C 200, concentration at the interface between the urothelium and the deep tissues; C× T-depth profiles, profiles of cumulative tissue concentration over time as a function of tissue depth; k a, apparent absorption rate constant; C u, urine concentration at time t during treatment; Organ; Apoptosis; MMC, mitomycin C; Antineoplastic agent; Pharmacokinetic pharmacodynamic relationship; Solid tumor; Biological transport; Cytotoxicity; Review; Doxorubicin; Taxane derivatives; Paclitaxel; Human; Urine; Urinary system disease; Mitomycin; Controlled therapeutic trial; Urinary tract disease; Malignant tumor; In vitro; In vivo; Chemotherapy; Treatment; Animal; Anthracyclins; Bladder disease; Intravesical administration; Pharmacokinetics
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/S0168-3659(01)00488-6

This report describes our experience on enhancement of drug delivery to solid tumors. Results of our preclinical and clinical studies including a randomized prospective phase III trial have validated the concept that enhanced drug delivery can significantly improve the treatment efficacy of intravesical mitomycin C therapy of superficial bladder cancer. The report further describes the roles of interstitial space, drug removal by capillaries, tissue structure and tissue composition on drug distribution. In general, drug distribution favors interstitial space and vasculature, with little penetration in muscles. The transport of highly protein-bound drugs such as paclitaxel and doxorubicin in a solid tumor is retarded by a high tumor cell density and enhanced by drug-induced apoptosis. Results of in vitro studies using solid tumor histocultures and in vivo studies using tumor-bearing animals demonstrate that the delivery of highly protein-bound drugs to tumor can be enhanced using a pretreatment that induces apoptosis and reduces cell density, and by using treatment schedules designed to take advantage of these drug-induced changes in tumor tissue composition.