CD133-Functionalized Gold Nanoparticles as a Carrier Platform for Telaglenastat (CB-839) against Tumor Stem Cells

Abstract

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.

Nanoparticles for Drug and Gene Delivery in Pediatric Brain Tumors’ Cancer Stem Cells: Current Knowledge and Future Perspectives

“…Recently, a 15-nucleotide base-pair aptamer targeting CD133 was loaded on Au-PEG NPs to deliver the drug Telaglenastat (CB-839). Au-PEG-CD133-CB-839 particles exerted a strong decrease in the GBM cell lines’ survival compared to controls [ 87 ]. Affinito et al described an RNA aptamer that selectively targets the Ephrin A-2 on the cell surface of GCSs, inhibiting tumor stemness and migration [ 86 ].…”

The role of the ZEB1–neuroinflammation axis in CNS disorders

“…ZEB1 as a key element of EMT promotion has been extensively studied in different brain tumors, particularly GBM. GBM is the most aggressive malignant primary brain tumor in which a variety of therapeutic strategies have failed to demonstrate efficacy [ 155 ]. Several investigations have reported that the ZEB1 pathway contributes to GBM initiation and progression, invasion, radioresistance, and chemoresistance.…”

Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells

“…Further investigation of the mechanism was performed by another study, which showed that the sensitivity to CB-839 in GSCs was not due to the contribution of glutaminolysis to the TCA cycle; rather, the sensitivity was brought on by reduced intracellular glutamate, which led to the amino acid deprivation response (AADR) [ 149 ]. Continuing this line of research, a modification of the CB-839 delivery route was developed by loading the drug into PEGylated gold nanoparticles with conjugated CD133 aptamers (Au-PEG-CD133-CB-839) [ 150 ]. The conjugation of CD133, a surface marker recognized on CSCs, was intended to improve the targeting of this drug to CSCs.…”

“…Making use of the small size and high biocompatibility of gold nanoparticles, this design contributes to improved permeability of the BBB and penetration of the tumor. A preliminary in vitro study demonstrated that Au-PEG-CD133-CB-839 significantly decreased the viability of CD133-positive cancer cells in comparison with treatment with CB-839, in which a dose-dependent effect was seen [ 150 ]. This highlighted a feasible strategy for the targeting of CSCs, while further studies in cells that are not restricted to CD133-positive populations are warranted to validate its effect.…”