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

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

Research output: Contribution to journalArticle

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 intracavity 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 prodrug, combined in vitro drug release was quantitatively assessed from low pH–based PLGA/PEG using advanced analytic 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 preclinically 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 postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. Conclusions: The significant survival benefit of intracavity 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.

Original languageEnglish (US)
Pages (from-to)5094-5106
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number16
DOIs
StatePublished - Aug 15 2019

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temozolomide
Etoposide
Ointments
Glioma
Survival
Gliosarcoma
Adjuvant Radiotherapy
glycolic acid
Prodrugs
Ethylene Glycol
Brain Diseases
Pharmaceutical Preparations
Allografts
polyethylene glycol-poly(lactide-co-glycolide)
Milk
Research Design
Survival Rate

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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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 Mae; Gould, Toby; Veal, Gareth J.; Gorelick, Noah; Rowlinson, Jonathan; Serra, Riccardo; Ritchie, Alison; Berry, Phillip; Otto, Annette; Choi, John; Skuli, Nicolas; Estevez-Cebrero, Maria; Shakesheff, Kevin M.; Brem, Henry; Grundy, Richard G.; Rahman, Ruman.

In: Clinical Cancer Research, Vol. 25, No. 16, 15.08.2019, p. 5094-5106.

Research output: Contribution to journalArticle

Smith, SJ, Tyler, BM, Gould, T, Veal, GJ, Gorelick, N, Rowlinson, J, Serra, R, Ritchie, A, Berry, P, Otto, A, Choi, J, Skuli, N, Estevez-Cebrero, M, Shakesheff, KM, Brem, H, Grundy, RG & 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, vol. 25, no. 16, pp. 5094-5106. https://doi.org/10.1158/1078-0432.CCR-18-3850
Smith, Stuart J. ; Tyler, Betty Mae ; Gould, Toby ; Veal, Gareth J. ; Gorelick, Noah ; Rowlinson, Jonathan ; Serra, Riccardo ; Ritchie, Alison ; Berry, Phillip ; Otto, Annette ; Choi, John ; Skuli, Nicolas ; Estevez-Cebrero, Maria ; Shakesheff, Kevin M. ; Brem, Henry ; Grundy, Richard G. ; Rahman, Ruman. / Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 16. pp. 5094-5106.
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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 intracavity 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 prodrug, combined in vitro drug release was quantitatively assessed from low pH–based PLGA/PEG using advanced analytic 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 preclinically 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 postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. Conclusions: The significant survival benefit of intracavity 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.",
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T1 - Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste

AU - Smith, Stuart J.

AU - Tyler, Betty Mae

AU - Gould, Toby

AU - Veal, Gareth J.

AU - Gorelick, Noah

AU - Rowlinson, Jonathan

AU - Serra, Riccardo

AU - Ritchie, Alison

AU - Berry, Phillip

AU - Otto, Annette

AU - Choi, John

AU - Skuli, Nicolas

AU - Estevez-Cebrero, Maria

AU - Shakesheff, Kevin M.

AU - Brem, Henry

AU - Grundy, Richard G.

AU - Rahman, Ruman

PY - 2019/8/15

Y1 - 2019/8/15

N2 - 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 intracavity 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 prodrug, combined in vitro drug release was quantitatively assessed from low pH–based PLGA/PEG using advanced analytic 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 preclinically 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 postsurgery 9L orthotopic gliosarcomas, treated with intracavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histologic confirmation of disease-free brain. Conclusions: The significant survival benefit of intracavity 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.

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