Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste

Smith, Stuart J.; Tyler, Betty; Gould, Toby W.A.; Veal, Gareth J.; Gorelick, Noah L.; Rowlinson, Jonathan; Serra, Riccardo; Ritchie, Alison A.; Berry, Philip; Otto, Annette; Choi, John; Skuli, Nicolas; Estevez-Cebrero, Maria Angeles; Shakesheff, Kevin M.; Brem, Henry; Grundy, Richard G.; Rahman, Ruman

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 Gliadel®. 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.

Citation

Smith, S. J., Tyler, B., Gould, T. W., Veal, G. J., Gorelick, N. L., Rowlinson, J., Serra, R., Ritchie, A. A., Berry, P., Otto, A., Choi, J., Skuli, N., Estevez-Cebrero, M. A., Shakesheff, K. M., Brem, H., Grundy, R. G., & Rahman, R. (2019). Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste. Clinical Cancer Research, 25(16), 5094-5106. https://doi.org/10.1158/1078-0432.ccr-18-3850

• Journal Article Type: Article
• Acceptance Date: May 17, 2019
• Online Publication Date: May 21, 2019
• Publication Date: 2019-08
• Deposit Date: Jun 3, 2019
• Publicly Available Date: May 22, 2020
• Journal: Clinical Cancer Research
• Print ISSN: 1078-0432
• Electronic ISSN: 1557-3265
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 16
• Pages: 5094-5106
• DOI: https://doi.org/10.1158/1078-0432.ccr-18-3850
• Keywords: Drug delivery, Efficacy, Etoposide, Glioma, PLGA/PEG, Temozolomide
• Public URL: https://nottingham-repository.worktribe.com/output/2129930
• Publisher URL: http://clincancerres.aacrjournals.org/content/early/2019/05/21/1078-0432.CCR-18-3850.article-info
• Contract Date: Jun 3, 2019