Cyclodextrin-formulated ferrocifen penetrates the brain and significantly improves survival in an orthotopic mouse model of glioblastoma.

Abstract

OBJECTIVES: Despite intensive chemotherapeutic and radiotherapeutic approaches for its treatment, glioblastoma (GBM) remains incurable, in part due to the difficulty of active molecules in crossing the blood-brain-barrier (BBB). Developing a suitable formulation for molecules with promising in vitro anticancer activity thus represents an essential step toward their in vivo translation. METHODS: We report here the formulation of the lipophilic compound P15, a ferrocenyl analog of hydroxytamoxifen with broad antiproliferative activity, in randomly methylated β-cyclodextrin (RAMEB), together with the extensive characterization of the inclusion complex, pharmacokinetic (PK) studies, and an in vivo efficacy study in an orthotopic model of human glioblastoma in mice. RESULTS: Inclusion of P15 as its citrate salt is significantly more efficient, with a 5 mM solution of RAMEB being able to solubilize 12 times more P15-cit than P15. The inclusion complex P15-cit@RAMEB exhibits a favorable stability constant on the order of 104 M-1, as determined from the phase solubility diagram. The inclusion complex is characterized by a 2:1 host:guest ratio, with that the ferrocenyl moiety inserted into one of the cyclodextrins while the other incorporates an aromatic ring. PK analyses suggest a marked biodistribution of P15 in the mouse brain following IV administration of P15-cit@RAMEB at 20 mg/kg. Crucially, the survival of orthotopic GBM-bearing mice is significantly improved, resulting in 17-33% long-term survivors. RNA sequencing analysis of treated mouse brains compared with controls reveals that the treatment is associated with the inhibition of pathways related to angiogenesis, metal ion homeostasis and calcium signaling. CONCLUSIONS: Formulation of the citrate form of P15 in RAMEB represents a promising strategy for developing a more effective therapy for GBM patients.

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