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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
- Source :
- Clinical Cancer Research. 25:5094-5106
- Publication Year :
- 2019
- Publisher :
- American Association for Cancer Research (AACR), 2019.
-
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.
- Subjects :
- 0301 basic medicine
Cancer Research
Polyesters
medicine.medical_treatment
macromolecular substances
Polyethylene Glycols
03 medical and health sciences
chemistry.chemical_compound
Drug Delivery Systems
0302 clinical medicine
Cell Line, Tumor
Glioma
Antineoplastic Combined Chemotherapy Protocols
PEG ratio
Temozolomide
medicine
Animals
Humans
Etoposide
Drug Carriers
Chemotherapy
Drug delivery, Efficacy, Etoposide, Glioma, PLGA/PEG, Temozolomide
technology, industry, and agriculture
medicine.disease
Delivery mode
Xenograft Model Antitumor Assays
Disease Models, Animal
Drug Liberation
PLGA
Treatment Outcome
030104 developmental biology
Oncology
chemistry
030220 oncology & carcinogenesis
Cancer research
Nanoparticles
Drug carrier
medicine.drug
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....ccd6aba360d17f745de484600c7a41fa