ET-37EFFICACY OF INTRACRANIAL DELIVERY OF DICHLOROACETATE AND CARBOPLATIN VIA AN LCP POLYMER MICROCAPSULE DEVICE IN AN EXPERIMENTAL GLIOMA MODEL

摘要

BACKGROUND: Multi-targeted therapy is a promising strategy for patients with glioblastoma and controlled delivery of these chemotherapeutics is crucial for effective intracranial chemotherapy. Studies combining platinum pharmacophores with apoptosis inducers, such as Dichloroacetae (DCA), suggest that DCA enhances the sensitivity of cancer cells to platinum compounds. We assessed the efficacy of DCA in combination with Carboplatin (CB) delivered from a biocompatible liquid crystal polymer (LCP) microcapsule in an experimental glioma model in rats. METHODS: In vitro studies were performed to assess the cytotoxicity of DCA and CB on F98 rodent glioma cells. Efficacy was assessed in vivo in rats with intracranially implanted F98 with intracranial implantation of 50% DCA and 5% CB wafers, in monotherapy and in combination. A second study assessed the efficacy of DCA and CB released from an LCP microcapsule as a multi-drug delivery device. RESULTS: The IC50 values for DCA and CB at 24 hours were 70mM and 39mM(R² =0.989 and 0.948, respectively). The initial efficacy study showed no difference in median survival between the control group and either DCA or CB monotherapy treatments. However, the animals that received CB wafer in combination with DCA wafer had significantly increased survival as compared to the control group (p = 0.016). The microcapsule efficacy study showed that animals given intracranial LCP microcapsule loaded with 5% CB/pCPP:SA and 50% DCA/pCPP:SA had significant improvement in survival (p= 0.0042 vs. control). CONCLUSION: We show that the intracranial delivery of Dichloroacetate and Carboplatin significantly increases survival in an experimental glioma model, when delivered via polymeric wafer as well as when delivered from LCP microcapsule. The LCP microcapsule is a safe and effective method for intracranial dual-drug delivery and may be a novel strategy for obtaining controlled release of multiple drugs with drug-specific kinetics and independent release times.