Localized Delivery of Hyaluronic Acid-Doxorubicin from a Surgical Paste for Post-operative Glioblastoma Treatment

Glioblastoma stem cells (GSCs) and residual tumor cells - which resist conventional therapies, drive disease recurrence, and contribute to the formation of an immunosuppressive tumor-immune microenvironment (TIME) - represent a crucial barrier to the effective treatment of post-operative glioblastoma, the most aggressive and lethal primary brain tumor in adults. The cavity left after tumor resection represents a valuable opportunity to deliver therapeutics locally via the placement of conformable scaffolds for the immediate chemotherapeutic targeting of GSCs and residual glioblastoma cells. We hypothesized that Surgiflo™, a moldable, FDA-approved gelatin-based hemostatic paste, could serve as a dual-purpose platform that minimizes postoperative bleeding and functions as a conformable, local, and sustained drug-delivery system. We incorporated a pH-sensitive designed hyaluronic acid-doxorubicin polymer-drug conjugate (HA-DOX) into the Surgiflo™ matrix, exploiting HA's selective affinity for CD44 (highly expressed by both GBM and GSCs) and promoting the depletion of GBM and GSCs via immunogenic cell death (ICD)-inducing properties of DOX. In vitro studies of HA-DOX-containing paste confirmed enhanced HA-DOX uptake in GSC-enriched models, improved ICD induction in GBM cells, favorable biocompatibility, and sustained drug release. In vivo evaluations revealed that intracavitary implantation of the HA-DOX-containing paste significantly prolonged the median survival of treated mice compared to the untreated group (37 days vs 25 days, respectively) and modulated the glioblastoma-associated TIME, resulting in a 44% reduction in GSC levels and a significant increase in CD8+ T cell levels (*p<0.5), compared to resected mice. Embedding HA-DOX within Surgiflo™ offers a promising strategy for localized, sustained delivery of chemotherapeutics to the resected cavity, with the potential to improve therapeutic outcomes and minimize systemic toxicity in postoperative glioblastoma treatment.