Abstract
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. 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. 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. 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.
Highlights
WHO (World Health Organization) IV high-grade gliomas (HGG) represent the most aggressive and genetically heterogeneous group of primary brain tumors
poly(DL-lactic-co-glycolic acid) (PLGA)/poly(ethylene glycol) (PEG) paste offers a future platform for combination delivery of molecular targeted compounds
PLGA/PEG microparticles mixed with 500-mg temozolomide and 0.05% organic acid-based saline carrier (1.0:0.8 polymer:carrier), retained the ability to sinter at 37C to form matrices (Fig. 1A)
Summary
WHO (World Health Organization) IV high-grade gliomas (HGG) represent the most aggressive and genetically heterogeneous group of primary brain tumors. The median survival for patients diagnosed with GBM remains dismal at 14.6 months and has not improved in recent years [2, 3], despite advances in neuroimaging, surgery, radiotherapy, and chemotherapy [4]. The slight improvement in terms of patient survival for high-grade gliomas, does not match the general trend in cancer survival over the past 2 decades [5]. Techniques such as the use of 5-aminolevulinic (5ALA)-based fluorescence-guided neurosurgery (Gliolan) have improved rates of gross total resection and increased progression-free survival [6, 7], but infiltrative disease remains within adjacent brain parenchyma and is responsible for tumor regrowth
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