Local delivery of doxorubicin prodrug via lipid nanocapsule–based hydrogel for the treatment of glioblastoma

Glioblastoma (GBM) recurrences appear in most cases around the resection cavity borders and arise from residual GBM cells that cannot be removed by surgery. Here, we propose a novel treatment that combines the advantages of nanomedicine and local drug delivery to target these infiltrating GBM cells. We developed an injectable lipid nanocapsule (LNC)–based formulation loaded with lauroyl-doxorubicin prodrug (DOXC 12 ). Firstly, we demonstrated the efficacy of intratumoral administration of DOXC 12 in GL261 GBM-bearing mice, which extended mouse survival. Then, we formulated an injectable hydrogel by mixing the appropriate amount of prodrug with the lipophilic components of LNC. We optimized the hydrogel by incorporating cytidine-C 16 (CytC 16 ) to achieve a mechanical stiffness adapted for an application in the brain post-surgery (DOXC 12 -LNC CL ). DOXC 12 -LNC CL exhibited high DOXC 12 encapsulation efficiency (95%) and a size of approximately 60 nm with sustained drug release for over 1 month in vitro. DOXC 12 -LNC CL exhibited enhanced cytotoxicity compared to free DOXC 12 (IC 50 of 349 and 86 nM, respectively) on GL261 GBM cells and prevented the growth of GL261 spheroids cultured on organotypic brain slices. In vivo, post-surgical treatment with DOXC 12 -LNC CL significantly improved the survival of GL261-bearing mice. The combination of this local treatment with the systemic administration of anti-inflammatory drug ibuprofen further delayed the onset of recurrences. In conclusion, our study presents a promising therapeutic approach for the treatment of GBM. By targeting residual GBM cells and reducing the inflammation post-surgery, we present a new strategy to delay the onset of recurrences in the gap period between surgery and standard of care therapy. Graphical Abstract