Efficacy of local convection enhanced delivery of chemotherapy using an intracerebral osmotic pump in a rat model of glioblastoma

Background Modern protocols for the treatment of glioblastoma multiforme (GBM) involve resection surgery, followed by chemotherapy and radiation therapy and subsequently adjuvant chemotherapy. While modestly successful in prolonging overall survival, peripherally administered chemotherapy drugs have limited ability to cross the blood brain barrier (BBB), limiting their bioavailability, and thus efficacy, at the tumor site. One way of circumventing the BBB is direct delivery of chemotherapy to the tumor site. Direct application of chemotherapy into the resection cavity during surgery in the form of carmustine/bis-chloroethylnitrosourea (BCNU) wafers has had limited success, in part due to the need for wafer solubilization, which restricts drug distribution and efficacy. The primary limitation, however, is that the drug is only distributed over short distances, for a short time. Methods In this study, we evaluated the efficacy of drug perfusion into the tumor resection cavity in a rat glioma model through convection enhanced delivery (CED), using an implanted microfluidic osmotic pump. We compared the effects of two alkylating agents, BCNU and temozolomide (TMZ), on tumor recurrence and survival. Results Using pumps containing a high concentration of ferumoxytol — a superparamagnetic iron oxide nanoparticle (SPION) — tissue perfusion was demonstrated in vivo by MRI and by post-mortem histology, confirming the effectiveness of the microfluidic pump as a drug delivery device. When delivered by implanted pumps, BCNU (4mg/ml) showed significantly greater efficacy against tumor recurrence than either TMZ; 2-4mg/ml or control (a low concentration of SPION). Conclusion BCNU may be an effective choice for CED-driven, locally delivered chemotherapy in GBM.