Abstract
Current chemotherapeutics for glioma are not sufficiently effective due to their low tolerance and poor blood–brain barrier (BBB) permeability. Energy restriction based on co-delivery of albendazole (Abz) and nano-silver has been proven to suppress tumor growth without adverse effects. Accordingly, menthol was conjugated to BSA (MeB) to overcome the BBB-permeability issue. In this study, Abz-loaded MeB-silver nanoparticles (MBS-Abz) were developed by self-assembly of MeB, albendazole and nano silver for glioma targeting therapy. The nanoparticle entered the brain across the BBB and specifically accumulated in the glioma region. MeB delivered the nanoparticles across the brain capillary endothelial cell monolayer by promoting internalization and BBB disruption. MBS-Abz hindered ATP generation via the inhibition of glycolytic and mitochondrial pathways both in vitro and in vivo. The anti-glioma mechanisms of energy restriction were related to the cytotoxicity, proliferation inhibition, cell cycle arrest, and apoptosis induced by ATP exhaustion, and the effects of MBS-Abz were significantly better than those induced by monotherapy nanoparticles or unmodified nanoparticles. These results demonstrated that by combining the energy restriction effect of albendazole and nano silver, as well as the BBB penetration ability of menthol, MBS-Abz achieves superior anti-glioma efficacy and can be an effective strategy for glioma therapy.
Highlights
Cancer has replaced cardiovascular disease as the leading cause of death in the United States[1]
We developed a novel antitumor strategy based on energy restriction by utilizing albendazole (Abz) and silver nanoparticles (SNP) as glycolysis inhibitors and mitochondrial inhibitors, respectively[16]
We developed menthol-modified albumin as a carrier to simultaneously deliver Abz and SNP to the glioma region across the blood–brain barrier (BBB) (Scheme 1), as the subsequent inhibition of energy metabolism achieved by the combination of Abz and SNP would drastically deplete cellular Adenosine triphosphate (ATP) via glycolytic and mitochondrial pathways, causing proliferation inhibition, cell cycle arrest and apoptosis of tumor cells
Summary
Cancer has replaced cardiovascular disease as the leading cause of death in the United States[1]. Many antitumor drugs have been developed, the global burden of cancer is still high. Brain cancers account for approximately 3% of the global cancer cases[2], among which, gliomas are associated with high morbidity and mortality. Chemotherapy is a major therapeutic modality for glioma. Cytotoxic agents, such as Adenosine triphosphate (ATP) is the most direct source of energy, and compared with normal cells, glioma cells are more sensitive to ATP levels[10]. Energy restriction was confirmed to effectively inhibit glioma growth[11,12]. Energy metabolism inhibition may be an effective approach for glioma therapy. Glioma cells mainly generate ATP via the glycolytic pathway rather than oxidative
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