Localized glioblastoma therapy using a tenascin-C inhibitor peptide-modified hyaluronic acid hydrogel

Glioblastoma (GB) is the most aggressive and lethal primary brain tumor, with currently no cure. Thus, effective and safe treatments are urgently needed. This study focused on developing an injectable hydrogel composed of high molecular weight hyaluronic acid, functionalized with a tenascin C (TN-C) inhibitor peptide to be immediately administered in the resection cavity after the initial therapeutic intervention. Homogenous liposomes encapsulating docosahexaenoic acid and doxorubicin were incorporated in the hydrogel for targeted therapy. The hydrogel matrix also included 2-deoxy-d-glucose as a chemotactic agent to actively recruit GB cells, inhibiting their migration and invasion into the healthy brain. The TN-C inhibitor peptide-functionalized HA hydrogel demonstrated rheological properties like those of the brain tissue and led to decreased GB cell proliferation in comparison with the non-functionalized hydrogel. In vitro assays demonstrated the efficiency of the hydrogel containing the chemotactic agent and liposomes encapsulating drugs to efficiently damage GB cells. Also, this formulation did not show cytotoxicity for astrocytes, proving its safety. The final formulation also shown to be effective in damaging GB cells in a biofabricated 3D tumor model that replicates the in vivo scenario after surgical resection. Thus, the formulation has potential to be a new therapeutic hope for GB patients.