Enhancement of anticancer drug delivery to the brain by microwave induced hyperthermia

Methotrexate (MTX) is a widely prescribed antifolate in cancer chemotherapy far a variety of neoplasms. Like many useful, hydrophilic antitumor drugs, MTX is excluded from the brain after systemic administration due to its inability to cross the blood-brain barrier (BBB). The blood-brain barrier functions as a differential filter which permits the selective passage of substance from blood to extracellular brain spaces. It maintains the physical and chemical environments of the brain within certain narrow limits. We have studied enhanced uptake of MTX in brains of male rats (10-week old Wistar, 500 g, three per group) subjected to selective microwave hyperthermia of the left hemisphere. The rat was anesthetized using 40 mg/kg of sodium pentobarbital, IP and was placed in a stereotaxic head holder. Microwave energy (2450 MHz, 2.6 W/cm(2), 208 W/kg, CW) was applied for 20 min. The body temperature was kept at 37.8 +/- 0.4 degrees C. The brain temperature recorded in a similar group of rats using a carbon filament probe (Vitek) was 42.7 +/- 0.4 degrees C. Three different MTX dosages, 50, 100, and 200 mg/kg, were injected intravenously immediately following microwave irradiation into the rat in 1.5, 3 and 6 min, respectively. The drug was allowed to circulate for 5 min before brains were removed for analysis. Standard HPLC assays were applied to samples from the anterior and posterior left hemisphere of the cerebrum, and the cerebellum. Samples from the right hemisphere were used for controls. The average uptake at the posterior left hemisphere was found to be 2.25 +/- 0.43, 10.40 +/- 2.59, and 17.23 +/- 1.13 mu g of MTX per g of brain tissue for 50, 100, and 200 mg/kg doses, respectively. In another series of experiments, MTX bolus was not injected until 15 or 45 min after cessation of microwave irradiation. Brains of rats injected 45 min after irradiation were free of MTX. Animals euthanized 15 min post-irradiation had an average midbrain MTX concentration of 2.5 +/- 0.46 mu g/g of tissue. These results indicate that MTX uptake is significantly increased in rat brains subjected to noninvasive microwave hyperthermia treatment. Furthermore, the increase is reversible within 45 min post-irradiation. (C) 1998 Elsevier Science S.A. All rights reserved.