OP22: SIMULTANEOUS INTRA-CAVITY DELIVERY OF MULTIPLE CHEMOTHERAPEUTICS FROM A MOULDABLE NEUROSURGICALLY-APPLIED POLYMER PASTE

INTRODUCTION: A thermo-setting biomaterial containing a depot of clinically relevant chemotherapeutics applied to the post-surgical resection cavity offers an opportunity for localised control of residual malignant glioma. Here we evaluate mouldable polymer matrices of poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) microparticles for tailored combination drug release. METHOD: Clinically-approved or experimental chemotherapeutics, alone and in combination, were loaded onto PLGA/PEG microparticle matrices, or encapsulated inside PLGA microspheres. Mono- and dual-therapy release rates were measured by liquid chromatography and stability verified by mass spectrometry. Cytotoxicity of released drugs was assessed using patient-derived invasive margin cells and flank mouse xenografts. RESULTS: Temozolomide (TMZ), etoposide (ETO) and methotrexate were released from PLGA/PEG alone or in dual combinations over 2 weeks in vitro, whilst irinotecan, cilengitide and imatinib released over a similar period as monotherapies. Cytotoxicity was not impaired by polymer interaction. Drug encapsulation in PLGA microspheres dampens the rapid burst release. PLGA/PEG overcomes TMZ instability, resulting in a 10-day release where the AIC active component was measured. In vivo ETO release markedly reduced glioma bioluminescence with longer-term survivors relative to resection-only controls. CONCLUSION: We have developed a PLGA-based platform technology to deliver multiple clinically relevant chemotherapy agents, including TMZ, from a single matrix. Prolonged release kinetics can be achieved by drug encapsulating drugs, potentially filling the 3 week therapy gap that currently exists between surgery and radiotherapy commencement.