DOXORUBICIN ENCAPSULATED IN STERICALLY STABILIZED LIPOSOMES FOR THE TREATMENT OF A BRAIN-TUMOR MODEL - BIODISTRIBUTION AND THERAPEUTIC EFFICACY

Anthracyclines entrapped in small-sized, sterically stabilized liposom es have the advantage of long circulation time, reduced systemic toxic ity, increased uptake into systemic tumors, and gradual release of the ir payload. To date, there is no information on the behavior of these liposomes in brain tumors. The objective of this study was to compare the biodistribution and clinical efficacy of free doxorubicin (F-DOX) and stealth liposome-encapsulated DOX (SL-DOX) in a secondary brain tu mor model. Nine days after tumor inoculation Fischer rats with a right parietal malignant sarcoma received an intravenous dose of 6 mg/kg of either F-DOX or SL-DOX for evaluation of drug biodistribution. For th erapeutic trials a single dose of 8 mg/kg was given 6 or 11 days after tumor induction, or alternatively, weekly doses (5 mg/kg) were given on Days 6, 13, and 20. Liposome-encapsulated DOX was slowly cleared fr om plasma with a t(1/2) of 35 hours. Free-DOX maximum tumor drug level s reached a mean value of 0.8 mu g/g and were identical in the adjacen t brain and contralateral hemisphere. In contrast, SL-DOX tumor levels were 14-fold higher at their peak levels at 48 hours, declining to ni nefold increased levels at 120 hours. A gradual increase in drug level s in the brain adjacent to tumor was noted between 72 and 120 hours (u p to 4 mu g/g). High-performance liquid chromatography analysis identi fied a small amount of aglycone metabolites within the tumor mass from 96 hours and beyond, after SL-DOX injection. Cerebrospinal fluid leve ls were barely detectable in tumor-bearing rats treated with F-DOX up to 120 hours after drug injection (less than or equal to 0.05 mu g/ml) , whereas the levels found after SL-DOX were 10- to 30-fold higher. An F-DOX single-dose treatment given 6 days after tumor inoculation incr eased the rats' life span (ELS) by 135% over controls (p < 0.05) but w as not effective if given on Day 11. In contrast, SL-DOX treatment res ulted in an]LS of 168% (p < 0.0003) with no difference when given afte r 6 or 11 days. Treatment with three weekly doses of SL-DOX produced a n ILS of 189% compared to 126% by F-DOX (p < 0.0002). The authors conc lude that the use of long-circulating liposomes as cytotoxic drug carr iers in brain tumor results in enhanced drug exposure and improved the rapeutic activity, with equal effectiveness against early small- and l arge-sized brain tumors.