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

Abstract

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 (DOXC12). Firstly, we demonstrated the efficacy of intratumoral administration of DOXC12 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-C16 (CytC16) to achieve a mechanical stiffness adapted for an application in the brain post-surgery (DOXC12-LNCCL). DOXC12-LNCCL exhibited high DOXC12 encapsulation efficiency (95%) and a size of approximately 60 nm with sustained drug release for over 1 month in vitro. DOXC12-LNCCL exhibited enhanced cytotoxicity compared to free DOXC12 (IC50 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 DOXC12-LNCCL 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

Systemic and local immune responses to glioblastoma surgery help tailoring combinatory regimens

“…These recurrences arise in 90% of cases along the post-surgical cavity borders and no resolutive treatment succeeds in inhibiting their onset and proliferation 7,8 . We have previously demonstrated that delivering hydrogels loaded with nanomedicines in the post-surgical cavity of GBM is a safe and promising therapeutic approach to kill residual tumor cells in the gap period between surgery and chemoradiation [9][10][11][12][13][14] . For example, the Lauroyl-gemcitabine lipid nanocapsules (GemC 12 -LNC) hydrogel is injectable, well tolerated, has adequate properties for an application in the brain 9 .…”

“…The co-loading of GemC 12 -LNC with other drugs acting on tumor cells or tumor stem cells, such as paclitaxel 12 and salinomycin 15 respectively, provided a synergistic effect in vitro but did not improve the survival of animals (unpublished data) suggesting that killing tumor cells only is not enough. On the contrary, when we combined the local administration of a similar hydrogel (lauroyl-doxorubicin-LNC hydrogel) with the systemic injection of the anti-in ammatory drug ibuprofen the survival of animals was extended 14 suggesting that acting both on tumor cells and on the post-surgical in ammation could lead to a delay in the onset of recurrences. Indeed, the brain response following GBM surgery is characterized by physiological regenerative responses bene cial for the healing process, but also by distinctive timedependent peritumoral immune responses exerting glioma-supportive effects 5,16,17 .…”