Enhancement of brain distribution of anticancer agents using DeltaG, the 12 kDa active fragment of ZOT.
OBJECTIVE
The objective of this study was to evaluate the ability of DeltaG, 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 DeltaG, [14C]-sucrose (40 microCi/kg), a hydrophilic paracellular marker, was co-administered with DeltaG (0, 400 and 800 microg/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 microCi/kg) were co-administered with the effective doses of DeltaG 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 DeltaG. A fold enhancement in the B/P ratios of 1.88 and 2.68 was observed at the 400 and 800 microg/kg doses respectively, when the protein was protected from metabolic degradation with PIs. DeltaG significantly increased the brain distribution of MTX at each of the doses administered, with over a seven-fold increase at the 600 microg/kg dose. [3H]-paclitaxel brain AUC(0-60 min) was significantly higher in the presence of DeltaG (800 microg/kg with PIs) with a 2.5-fold enhancement in brain exposure.


CONCLUSIONS
DeltaG 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.
Menon
Divya
D
Pharmacokinetics Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 Penn Street, HSF II 543, Baltimore, MD 21201-6808, USA.
Karyekar
Chetan S
CS
Fasano
Alessio
A
Lu
Ruliang
R
Eddington
Natalie D
ND
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism*; D002772:Cholera Toxin / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D004339:Drug Compounding; D004731:Endotoxins; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D004337:Drug Carriers; D004731:Endotoxins; C077728:zonula occludens toxin, Vibrio cholerae; D002772:Cholera Toxin; D017239:Paclitaxel; D008727:Methotrexate