Overall survival in an orthotopic GBM model is significantly prolonged by neurosurgical delivery of PLGA/PEG interstitial chemotherapy

INTRODUCTION: The blood brain barrier is a critical limiting step to achieving therapeutic CNS drug concentrations. We have developed a poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG)-based platform technology to interstitially deliver multiple chemotherapy agents from a single thermo-setting biodegradable paste, achieving high local but low systemic concentrations and sustained delivery of cytotoxic drugs directly to the CNS. Here we evaluate mouldable PLGA/PEG paste for combined temozolomide (TMZ) and etoposide (ETOP) delivery in an orthotopic high grade glioma animal model. METHODS: Drug release and preserved stability of the active TMZ molecule (AIC) was evaluated by fluoroscopic and LC-mass spectrometer based methods. In vitro cytotoxicity of released TMZ/ETOP was evaluated against high grade glioma cell lines and patient-derived primary cultures using metabolic assays. In vivo efficacy and overall survival were evaluated in the syngeneic orthotopic 9L glioma rat model of intra cavity chemotherapy. RESULTS: TMZ and ETOP were released from PLGA/PEG alone or in dual combinations over 2 weeks in vitro. Cytotoxicity of released drugs in vitro is comparable to directly applied agents, demonstrating the retained molecular integrity of TMZ/ETOP upon loading and releasing from PLGA/PEG. Both high (20% w/w TMZ / 50% w/w ETOP) and low (10% w/w TMZ / 25% w/w ETOP) doses were well tolerated in vivo, with no observable weight loss nor neurological deficits. Significant positive survival benefits from PLGA/PEG/TMZ/ETOP therapy were observed in vivo compared to surgery alone, surgery with blank paste (49 vs. 14 days; p < 0.001) or surgery plus oral TMZ (49 vs. 33 days; p < 0.004). CONCLUSIONS: This study demonstrates that localised dual release of TMZ/ETOP achieves a significant extension to overall survival in vivo. As such, PLGA/PEG paste applied to the post-surgical resection cavity offers a realistic opportunity for localised control of residual malignant glioma cells.