1335 Intracranial Nanogel Pellets Carrying Temozolomide and Paclitaxel for Adjuvant Glioblastoma Therapy

INTRODUCTION: The local delivery of chemotherapeutic agents to glioblastoma using implantable biodegradable polymers emerged as an appealing mechanism to overcome the BBB. Additionally, the use of synergistic drug combinations is a plausible method to prevent treatment resistance. METHODS: We prepared a nanogel pellet with a PLGA-PEG-PLGA triblock backbone and loaded it with a combination of TMZ and PTX. We characterized the thermosensitive transition of this formulation and studied its drug release kinetics in artificial cerebrospinal fluid using high-performance liquid chromatography. Finally, we tested the safety and efficacy of the drug-loaded nanogel pellet in an orthotopic 9L rat gliosarcoma model and an orthotopic CT2A mouse glioma model. RESULTS: The nanogel pellet remained as a solid at room temperature and formed a viscous gel at temperatures higher than 32ºC. Drug release from nanogels followed first-order release kinetics showing gradual release in over time. In vivo, the PTX/TMZ-loaded nanogel pellets significantly increased the overall survival of rats implanted with 9L tumors when added to resection as compared to resection alone (log-rank test p-value = 0.003). Additionally, in mice implanted with firefly luciferase-tagged CT2A cells and confirmed to have established tumors via bioluminescence-based imaging, the PTX/TMZ nanogel pellet group had a significantly enhanced overall survival (log-rank test, p-value= 0.037) and prolonged median survival of 17 days (95% confidence interval (CI): 14.6-19.4) as compared to the control group (12 days [95% CI: 11.3-12.7]). CONCLUSIONS: We report the synthesis and characterization of a TMZ/PTX-loaded biodegradable nanogel pellet that undergoes gelation at physiological temperatures, achieves gradual sustained drug release, and significantly enhances survival in two robust in vivo models of glioblastoma.