Abstract 4402: Lazaroid formulations for brain delivery in treatment of glioblastoma multiforme
Authors: Gadgil Prajakta , Chow Diana S-L. , New Pamela , Shah Jaymin 
Published: August 2015

Lazaroid U-74389G (LAZ) has potential radio-protective and anti-proliferative activities in treatment of glioblastoma, but it exhibits poor brain penetration and high hepatic clearance. To increase the brain exposure of LAZ, we formulated LAZ in co-solvent system and as nanostructured lipid carriers (NLC). The rationale behind this approach is that LAZ formulations due to their high drug payload for administration at higher doses and prolonged circulation results in greater systemic exposure compared to unformulated LAZ solution. The purpose of this study was to comparatively evaluate the brain exposures of unformulated LAZ solution in citrate buffer (pH 3), LAZ co-solvent formulation in mixture of propylene glycol and citrate buffer (pH 3), and LAZ NLC, prepared using ultra-sonication and optimized using Central Composite Design (CCD). Statistical analysis was carried out using Student's t-test. Male Sprague Dawley rats were randomized into 3 groups and were administered unformulated LAZ solution at 5 mg/kg dose and LAZ co-solvent and LAZ NLC at 15 mg/kg dose, intravenously through jugular vein cannula. The brain tissues were homogenized in normal saline and LAZ in the brain tissue was quantified using Absciex Qtrap 5500 LC/MS/MS with linear range of 1 (LLOQ) - 250 ng/mL.

The concentrations of unformulated LAZ solution and the LAZ co-solvent solution were 2 mg/mL and 8.5 mg/mL, respectively. The optimized LAZ NLC had particle size of 150 ± 2.86 nm, zeta potential of (-6.79) ± 0.39 mV, encapsulation efficiency of 81.34 ± 6.06%. The LAZ NLC preparation is monodisperse with polydispersity index of 0.158 ± 0.01 (N = 3). The amount of LAZ in brain tissues after 4 hours is significantly higher in formulation groups (LAZ co-solvent 37.48 ± 7.06 ng/gm and LAZ NLC 27.49 ng/gm) than the unformulated groups (LAZ solution 6.84 ± 1.87 ng/gm). Upon dose normalization there was a significant increase in amount of LAZ in brain tissues (N = 3 each) after 4 hours in LAZ co-solvent group (2.72 ± 0.53 ng/gm/mg) in comparison to unformulated LAZ solution group (1.37 ± 0.37 ng/gm/mg), at p&lt;0.05.

Developing LAZ formulations will offer potential merits of enabling administrations at higher doses, facilitating LAZ delivery to the brain at therapeutic levels and decreasing its systemic clearance. LAZ formulations are capable of incorporating LAZ at higher drug payload than unformulated solution. Upon dose normalization, the amount of LAZ in brain tissue at 4 hours is significantly higher (1.5-2 times) in LAZ formulations in comparison to LAZ unformulated group. This study helps to build a strong foundational background for use of LAZ as an alternative agent in treatment of glioblastoma utilizing its dual properties of lipid peroxidation inhibition and anti-proliferation.

Citation Format: Prajakta Gadgil, Diana S-L. Chow, Pamela New, Jaymin Shah. Lazaroid formulations for brain delivery in treatment of glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4402. doi:10.1158/1538-7445.AM2015-4402