Protracted Intraventricular Infusion of Gemcitabine to Circumvent the Blood Brain Barrier

Poor prognosis of brain tumors is partly related to the blood brain barrier (BBB) to hydrophilic anticancer drugs. Early studies demonstrated that intracranial injection of vital dyes bypassed BBB in cats. We investigated if intraventricular infusion of gemcitabine can circumvent the blood-brain barrier and achieve therapeutically relevant drug concentrations within the brain and cerebrospinal fluid.

Brain diffusion of the vital hydrophilic Bleu Patente dye was studied after intracranial or intravenous injection in guinea pig, or after a 24 h protracted intraventricular infusion in sheep. Gemcitabine, a hydrophilic anticancer drug, was quantified by high-performance liquid chromatography. Viability of human glioblastoma cells was studied in vitro. Cells were maintained in drug-free fresh culture medium for 72 h after drug exposure before an assay with Crystal Violet. Tolerance of a single 24 h intraventricular infusion of gemcitabine was evaluated in sheep.

Bleu Patente diffused into brain of guinea pigs after an intracranial injection, whereas brain remained unstained after an intravenous administration. After a 24 h intraventricular infusion, dye penetrated deeply into the cerebral cortex of sheep. Brain concentration of gemcitabine was higher following intracranial injection than after intravenous administration in guinea pigs. At the end of a 24 h intraventricular infusion of 20 mg gemcitabine in sheep, mean concentrations reached 1,415 microg/l in cerebrospinal fluid and 850 microg/kg in brain. These concentrations exceeded the IC₉₀ values of gemcitabine for A172, U87-MG, and U118-MG human glioblastoma cell lines. Tolerance of a single 24 h intraventricular infusion of 20 mg gemcitabine was good in sheep.

We hypothesize that intraventricular injections allow the hydrophilic drugs to circumvent BBB by using the glymphatic system. Given high concentrations in the cerebrospinal fluid and brain, and given its good tolerability, we propose to study protracted intraventricular infusion of gemcitabine in patients with refractory primary, secondary brain tumors, and meningeal metastasis.