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 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.

Ion Channels as Therapeutic Targets in High Grade Gliomas

“…Studies looking into coupling ion channel inhibitors with nano particles [ 104 ] and utilising cavity depot delivery [ 105 ] stand at the forefront of overcoming this issue. A disease-based approach would be beneficial in this circumstance as we have a thorough understanding of the pathology of glioma.…”

Therapeutic Potential of Mesenchymal Stem Cells for Cancer Therapy

“…The use of Gliadel in patients receiving surgical removal of brain tumors is associated with moderated survival benefits (Bregy et al, 2013). Latest investigations have discovered a thermo-responsive biodegradable paste that allows delivering of multiple anti-cancer agents with improved results in glioma patients survival (Smith et al, 2019). Once optimized the composition and design of biomaterials, it may be possible to use them in combination with stem cells to release anti-cancer agents in a cooperative manner.…”

<p>Local Delivery of Minocycline and Vorinostat Targets the Tumor Microenvironment to Inhibit the Recurrence of Glioma</p>

“…14,15 Unfortunately, the bloodbrain barrier (BBB) restricts the concentrations of minocycline delivered within the tumor microenvironment (TME). 16 Higher doses of minocycline are not prescribed due to severe liver and kidney toxicity. 17 The immune response may be suppressed by polarization of macrophages within TME into M2 macrophages, which hamper immune responses by releasing anti-inflammatory cytokines and angiogenic factors.…”