Design of a Drug Delivery System for the Localized Treatment of Resected Glioblastoma

Design of a Drug Delivery System for the Localized Treatment of Resected Glioblastoma Glioblastoma (GBM), a grade 4 glioma, is the most common primary malignant brain tumor in adults.. The standard of care (SOC) for GBM has remained almost unchanged since 2005 ("Stupp protocol"), comprising surgical resection, radiation, and oral chemotherapy (temozolomide,) combined with corticosteroids after an interval of three to four weeks. Overall this treatment supports a median survival of 14–16 months. Treatment remains challenging due to the inherent complexity, heterogeneity, and proliferative nature of GBM. Moreover, the blood-brain barrier (BBB) precludes the passage of systemically administered chemotherapeutic agents to the brain. Among the strategies investigated to find effective therapies for the treatment of GBM, the local delivery of active agents within the tumor resection cavity has emerged as promising. This approach bypasses the BBB, and increases the local concentration at the tumor site; in parallel it reduces systemic side effects, opening the doors for many more molecules to be used to fight this devastating disease. In this project, we developed a novel intra-cavity drug delivery system, consisting of a non-covalently conjugated gum-like polymer made from polyvinyl alcohol (PVA) and tannic acid (TA); both structures are rich in hydroxyl groups prone to forming hydrogen bonds. To the PVA we conjugated irinotecan, DNA topoisomerase I inhibitor and immunogenic cell death agonist, which will be slowly released in tumor resection cavity targeting residual cancer cells and boosting an immuno-response. Moreover, TA is widely recognized for its anti-oxidant capacity; this property can be harnessed to reduce the local inflammation that origins after surgery and promotes the re-growth of GBM. Also, studies support the capacity of anti-inflammatory to boost ICD capacity of anticancer drugs. The therapeutic potential of this novel biomaterial warrants further investigation, particularly with other chemo-immunotherapeutics or cancer vaccines as a promising combinatorial therapeutic approach in the context of GBM.