TARGETING MEDULLOBLASTOMA WITH BENZODIAZAPINES DELIVERED USING TUNABLE BIODEGRADABLE HYDROGELS

Medulloblastoma (MB) is a common pediatric malignant primary brain tumor originating in the posterior fossa. MB is generally classified into one of four molecular subgroups: Wnt, Shh, Group 3, and Group 4. Subgroup 3 is the most clinically aggressive of the four and exhibits a molecular signature that includes over expression of the GABRA5 receptor. Previously, we reported on use of a novel microdevice to screen a broad range of benzodiazepine compounds that functioned as GABRA5 agonists (Jonas et al., 2016). This study identified a new benzodiazepine compound (KRM-II-08) that was particularly efficacious and thus an attractive candidate as a therapeutic against Group 3 medulloblastoma. The Cook laboratory have now synthesized a new series of benzodiazepine derived allosteric modulators. These compounds will initially be tested in tissue culture, those that are efficacious will be tested in the nude mouse tumor xenograft model. While the microdevice used previously provided a superb platform to screen a number of compounds in the same tumor, it is not a satisfactory system to bring forward into the clinic for brain tumor treatment. We are therefore exploring use of biodegradable hydrogels where the compounds are chemically “clicked” onto a modified chondroitan sulfate or hyaluronic acid (HA). Importantly, the hydrogels being employed have mechanical properties and covalent modifications to allow for the tunable release of the benzodiazepines in targeting medulloblastoma tumors. We will report on the progress in characterizing the new benzodiazepine compounds under study and the design of and observations regarding use of hydrogel formulations employed. Reference: Jonas O., Calligaris D., Muthuku K.R. et al. (2016) J. Biomed. Nanotech. 12: 1-6.