Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model

Abstract

Purpose Mebendazole (MBZ), first used as an antiparasitic drug, shows preclinical efficacy in models of glioblastoma and medulloblastoma. Three different MBZ polymorphs (A, B and C) exist and a detailed assessment of the brain penetration, pharmacokinetics and anti-tumor properties of each individual MBZ polymorph is necessary to improve mebendazole-based brain cancer therapy. Experimental Design and Results In this study, various marketed and custom-formulated MBZ tablets were analyzed for their polymorph content by IR spectroscopy and subsequently tested in orthotopic GL261 mouse glioma model for efficacy and tolerability. The pharmacokinetics and brain concentration of MBZ polymorphs and two main metabolites were analyzed by LC-MS. We found that polymorph B and C both increased survival in a GL261 glioma model, as B exhibited greater toxicity. Polymorph A showed no benefit. Both, polymorph B and C, reached concentrations in the brain that exceeded the IC50 in GL261 cells 29-fold. In addition, polymorph C demonstrated an AUC0-24h brain-to-plasma (B/P) ratio of 0.82, whereas B showed higher plasma AUC and lower B/P ratio. In contrast, polymorph A presented markedly lower levels in the plasma and brain. Furthermore, the combination with elacridar was able to significantly improve the efficacy of polymorph C in GL261 glioma and D425 medulloblastoma models in mice. Conclusion Among MBZ polymorphs, C reaches therapeutically effective concentrations in the brain tissue and tumor with less side effects and is the better choice for brain cancer therapy. Its efficacy can be further enhanced by combination with elacridar.

Repurposing Mebendazole as a Replacement for Vincristine for the Treatment of Brain Tumors

“…However, once dissolved, the respective polymorphs have identical properties. As has been shown recently, polymorphs B and C display similar therapeutic efficacy in the GL261-C57BL/6 model, with polymorph C being slightly more effective than polymorph B, and polymorph A totally lacking in efficacy (12). In this study, therefore, for all in vivo experiments, we used polymorph C.…”

“…With regard to therapeutic efficacy, it is important to note that, depending on crystallization conditions, mebendazole can form three different polymorphs, termed A, B and C, which display significant differences in solubility and bioavailability (11,12). As a result, the distinct polymorphs, when administered orally, also have different toxicity and therapeutic effects, as both anthelmintic and anticancer agents (11,12).…”

“…As a result, the distinct polymorphs, when administered orally, also have different toxicity and therapeutic effects, as both anthelmintic and anticancer agents (11,12). However, once dissolved, the respective polymorphs have identical properties.…”

“…Most likely, this lack of efficacy is due to vincristine's poor BBB permeability (4,5), in contrast to the good BBB permeability of mebendazole (12).…”

“…However, once dissolved, the respective polymorphs have identical properties. Both polymorphs B and C have good bioavailability and BBB penetration and display similar therapeutic efficacy in the GL261-C57BL/6 glioblastoma model, whereas polymorph A totally lacks in efficacy (12).…”