Effects of lazaroid U-74389G liposomes in a glioblastoma mouse model.

Abstract

2098 Background: Lazaroid U-74389G (LAZ) is a 21-aminosteroid that has radioprotective effects against radiation-induced lipid peroxidation. Also in vitro antiproliferative effects have been reported against glioblastoma cell lines. The aim of this study was to use a liposomal formulation to evaluate LAZ radioprotective and antiproliferative effects in a glioblastoma mouse model. Methods: LAZ PEGylated liposomes (Lipo G) were developed at the University of Houston, College of Pharmacy. Glioblastoma cell line U87-expressing firefly luciferase reporter gene (100,000 cells in 2 μL) was injected intracranially in each male SCID hairless outbred mouse. There were 4 treatment groups (n=8-9, each): brain model (M) without treatment (control), radiation 2Gy weekly (M+R), Lipo G at 5 mg/kg dose IP twice per week (M+L) and radiation with Lipo G (M+R+L). Treatment lasted three weeks. Tumor size was monitored using non-invasive bioluminescence imaging (BLI), in each mouse. Mice were sacrificed after 3 weeks. Brain was harvested for immunohistochemistry examinations. Lipid peroxidation of brain tissues was quantified by measuring malondialdehyde (MDA) as a surrogate biomarker. Survival was evaluated using Kaplan Meier analysis at P= 0.05. Results: The relative BLI intensity was 4002.03±1737.67, 2034±737.72, 1387.36±684.53 and 2498.89±2521.32 % for M, M+R, M+L and M+R+L, respectively. The tumor size of the M+L group was reduced by 65% compared to control . For the radiation treated groups (M+R and M+R+L), there was no significant difference in tumor size compared to control group. MDA brain concentration in M+L and M+R+L groups was significantly less than in M+R group (8.27±0.78 and 10.37±3.30 µM/gm vs. 23.09± 3.79 µM/gm). The survival mean was 22.67, 25.33, 25.22 and 27.13 days for M, M+R, M+R+L and M+L groups, respectively. Mean survival of LAZ treated groups (M+L and M+R+L) was significantly longer than that of the control group Conclusions: LAZ liposomal formulations administered at 5 mg/kg dose reduced tumor growth by 65%. LAZ also protected brain tissue from radiation-induced lipid peroxidation by reducing MDA concentration by 50%. These provocative data warrant further investigation of LAZ as a radiation protectant and chemotherapeutic agent.