The failure of a long-lasting curative therapeutic benefit of currently applied chemotherapies against malignant cancers is suggested to be caused by the ineffectiveness of such interventions on cancer stem cells (CSCs). CD133/AC133 is a cell surface protein previously shown to have potential to identify CSCs in various tumors, including brain tumors. Moreover, an increase in the rate of cellular metabolism of glutamine and glucose are contributors to the fast cellular proliferation of some high-grade malignancies. Inhibition of glutaminolysis by utilizing pharmacological inhibitors of the enzyme glutaminase 1 (GLS1) can be an effective anti-CSC strategy. In this study, the clinical-stage GLS1 inhibitor Telaglenastat (CB-839) was loaded into PEGylated gold nanoparticles equipped with the covalently conjugated CD133 aptamer (Au-PEG-CD133-CB-839) and exposed to a collection of CD133-positive brain tumor models in vitro. Our results show that Au-PEG-CD133-CB-839 significantly decreased the viability of CD133-postive cancer cells in a dose-dependent manner, which was higher as compared to the effects of treatment of the cells with the individual components of the assembled nanodrug. Interestingly, the treatment effect was observed in glioblastoma stem cells modeling different transcriptomic subtypes of the disease. The presented platform is the fundament for subsequent target specificity characterization and in vivo application.

Zinc finger E-box binding homeobox 1 (ZEB1) is a master modulator of the epithelial–mesenchymal transition (EMT), a process whereby epithelial cells undergo a series of molecular changes and express certain characteristics of mesenchymal cells. ZEB1, in association with other EMT transcription factors, promotes neuroinflammation through changes in the production of inflammatory mediators, the morphology and function of immune cells, and multiple signaling pathways that mediate the inflammatory response. The ZEB1–neuroinflammation axis plays a pivotal role in the pathogenesis of different CNS disorders, such as brain tumors, multiple sclerosis, cerebrovascular diseases, and neuropathic pain, by promoting tumor cell proliferation and invasiveness, formation of the hostile inflammatory micromilieu surrounding neuronal tissues, dysfunction of microglia and astrocytes, impairment of angiogenesis, and dysfunction of the blood–brain barrier. Future studies are needed to elucidate whether the ZEB1–neuroinflammation axis could serve as a diagnostic, prognostic, and/or therapeutic target for CNS disorders.

Despite advances in glioblastoma (GBM) treatments, current approaches have failed to improve the overall survival of patients. The oncogene BMI-1, a core member of the polycomb group proteins, is a potential novel therapeutic target for GBM. To enhance the efficacy and reduce the toxicity, PTC209, a BMI-1 inhibitor, was loaded into a PLGA–PEG nanoparticle conjugated with CD133 antibody (Nano-PTC209) and its effect on the behavior of human GBM stem-like cells (GSCs) and the human glioblastoma cell line (U87MG) was assessed. Nano-PTC209 has a diameter of ~ 75 nm with efficient drug loading and controlled release. The IC50 values of Nano-PTC209 for GSCs and U87MG cells were considerably lower than PTC209. Nano-PTC209 significantly decreased the viability of both GSCs and U87MG cells in a dose-dependent manner and caused a significant enhancement of apoptosis and p53 levels as well as inhibition of AKT and JNK signaling pathways. Furthermore, Nano-PTC209 significantly inhibited the migration ability, decreased the activity of metalloproteinase-2 and -9, and increased the generation of reactive oxygen species in both GSCs and U87MG cells. Our data indicate that PLGA–PEG nanoparticle conjugated with CD133 antibody could be an ideal nanocarrier to deliver PTC209 and effectively target BMI-1 for potential approaches in the treatment of GBM.