Enhancement of brain distribution of anticancer agents using Δ G, the 12 kDa active fragment of ZOT

Abstract

Objective The objective of this study was to evaluate the ability of Δ G, the 12 kDa active fragment of ZOT, to increase the brain distribution of MTX and paclitaxel, two commonly used anticancer agents with poor distribution into the brain. Methods As part of dose estimation of Δ G, [ 14C]-sucrose (40 μCi/kg), a hydrophilic paracellular marker, was co-administered with Δ G (0, 400 and 800 μg/kg) with and without protease inhibitors to male Sprague–Dawley rats ( n = 3 per group) via an intracarotid cannula. MTX (50 mg/kg) and [ 3H]-paclitaxel (120 μCi/kg) were co-administered with the effective doses of Δ G determined from the above study via the intracarotid cannula. Animals were euthanized by carbon dioxide asphyxiation at the specified time periods and brain and plasma samples were analyzed for the respective drug. Results The brain distribution of [ 14C]-sucrose was significantly enhanced at both doses of Δ G. A fold enhancement in the B/ P ratios of 1.88 and 2.68 was observed at the 400 and 800 μg/kg doses respectively, when the protein was protected from metabolic degradation with PIs. Δ G significantly increased the brain distribution of MTX at each of the doses administered, with over a seven-fold increase at the 600 μg/kg dose. [ 3H]-paclitaxel brain AUC 0–60 min was significantly higher in the presence of Δ G (800 μg/kg with PIs) with a 2.5-fold enhancement in brain exposure. Conclusions Δ G significantly enhances the brain distribution of MTX (hydrophilic) and paclitaxel (lipophilic) and has the potential to be further developed as adjunct therapy to increase delivery of poorly permeable chemotherapeutic and other CNS targeted compounds.