DDRugging glioblastoma through the development of surgically-deliverable biomaterials

Introduction: Glioblastoma is the most common and aggressive primary brain cancer. Despite surgery followed by chemoradiotherapy, survival rates are low, with reoccurrence close to the surgical resection cavity. The blood-brain barrier (BBB) and upregulated DNA damage response (DDR) pathways in glioblastoma stem cells (GSC) are key contributors to the ineffectiveness of treatments. DDR inhibitors (DDRi) offer the potential of sensitising GSCs to chemoradiation but must overcome the BBB. Surgically-delivered therapies allow localised drug delivery, avoiding the BBB. We have modified pegylated PGS to develop a novel long-term drug delivery system with the aim of eradicating post-surgical/residual GSC niches that cause tumour recurrence. Such polymers are designed around FDA-approved biomaterials that could be potentially applied following tumour resection surgery.

Methods: Drug release profiles from pegylated PGS were determined by UV-Vis spectroscopy. Clonogenic survival, western blot and immunofluorescence assays were used to assess drug release/efficacy on glioblastoma cells.

Results: Pegylated PGS form a soft, gel-like material that is suitable for loading with chemotherapeutics and/or DDRi. Release from pegylated PGS has demonstrated biologically effective payloads are still released up to 4 months post loading.

Conclusions: These results reveal that pegylated PGS can deliver gradual release of drugs, including chemotherapeutics and/or DDRi, at concentrations which have been indicated to kill glioblastoma cells within our studies. Our DDRi clonogenic survival data provides a rationale for loading these targeted therapies into pegylated PGS to increase cell death whilst bypassing the BBB. The drug release properties highlight the emerging potential of pegylated PGS to enhance longer-term disease control at the tumour resection cavity, aiming towards improving outcomes for future patients.