Multimodal nanoparticles co-delivering bevacizumab and dichloroacetate for dual targeting of neoangiogenesis and hyperglycolysis in glioblastoma treatment

Abstract

Glioblastoma (GBM) is a virtually incurable primary brain tumor, characterized by aggressive proliferation and sustained angiogenesis. The current anti-angiogenic treatment with systemically administered bevacizumab fails to increase patient survival. Encapsulation of bevacizumab into polymeric nanoparticles has shown promise in improving drug brain bioavailability after intranasal administration. Nevertheless, therapeutic efficacy remains limited by tumor cells adopting a hyperglycolytic metabolism. Here, we optimized BDNP, a multidrug formulation for GBM treatment, by co-entrapment of the anti-angiogenic bevacizumab and the glycolysis inhibitor dichloroacetate into poly(lactic-co-glycolic) acid nanoparticles. We then confirmed BDNP therapeutic potential through a series of in vitro and in vivo assays. BDNP preserved bevacizumab functionality, effectively inhibiting chorioallantoic membrane vascularization and endothelial cell angiogenesis fueled by GBM cell lines or patient-derived neurospheres. Moreover, BDNP successfully prevented the ∼3-fold increase in lactate production triggered by bevacizumab. Surface decoration with a CD147-targeting peptide increased BDNP retention in tumor cells in vitro by ∼10-fold, though it did not significantly improve brain accumulation in a U-251MG GBM mouse model. Regardless of decoration, nanoparticles reached and accumulated in animals' brains after intranasal administration. Intranasal administration of BDNP significantly improved a GBM mouse model survival, with no evidence of toxicity. A similar trend was observed in mice bearing patient-derived neurospheres. These findings highlight BDNP as a promising strategy for GBM therapy and establish valuable protocols for developing and validating novel multidrug nanoparticles, especially for antibodies and small molecule cocktails.