@article { , title = {Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste}, abstract = {Purpose: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood brain barrier. We evaluate the unique intra-cavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. Experimental Design: To prolong stability of temozolomide pro-drug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytical methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized pre-clinically to develop GliadelĀ®. Results: Combined etoposide and temozolomide in vitro release (22 and 7 days respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in post-surgery 9L orthotopic gliosarcomas treated with intra-cavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histological confirmation of disease-free brain. Conclusions: The significant survival benefit of intra-cavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds.}, doi = {10.1158/1078-0432.ccr-18-3850}, eissn = {1557-3265}, issn = {1078-0432}, issue = {16}, journal = {Clinical Cancer Research}, note = {For OA. Article not yet published in issue will need to add volume, pagination and doi. Only AAM online. When final version published change OA type to gold, replace AAM with published version and add REF exception. KJB 03.06.2019}, pages = {5094-5106}, publicationstatus = {Published}, publisher = {American Association for Cancer Research}, url = {https://nottingham-repository.worktribe.com/output/2129930}, volume = {25}, keyword = {Drug delivery, Efficacy, Etoposide, Glioma, PLGA/PEG, Temozolomide}, year = {2019}, author = {Smith, Stuart J. and Tyler, Betty and Gould, Toby W.A. and Veal, Gareth J. and Gorelick, Noah L. and Rowlinson, Jonathan and Serra, Riccardo and Ritchie, Alison A. and Berry, Philip and Otto, Annette and Choi, John and Skuli, Nicolas and Estevez-Cebrero, Maria Angeles and Shakesheff, Kevin M. and Brem, Henry and Grundy, Richard G. and Rahman, Ruman} }