Graphene Oxide Nanoscale Platform Enhances the Anti‐Cancer Properties of Bortezomib in Glioblastoma Models

Abstract

Graphene-based 2D nanomaterials possess unique physicochemical characteristics which can be utilized in various biomedical applications, including the transport and presentation of chemotherapeutic agents. In glioblastoma multiforme (GBM), intratumorally administered thin graphene oxide (GO) nanosheets demonstrate a widespread distribution throughout the tumor volume without impact on tumor growth, nor spread into normal brain tissue. Such intratumoral localization and distribution can offer multiple opportunities for treatment and modulation of the GBM microenvironment. Here, the kinetics of GO nanosheet distribution in orthotopic GBM mouse models is described and a novel nano-chemotherapeutic approach utilizing thin GO sheets as platforms to non-covalently complex a proteasome inhibitor, bortezomib (BTZ), is rationally designed. Through the characterization of the GO:BTZ complexes, a high loading capacity of the small molecule on the GO surface with sustained BTZ biological activity in vitro is demonstrated. In vivo, a single low-volume intratumoral administration of GO:BTZ complex shows an enhanced cytotoxic effect compared to free drug in two orthotopic GBM mouse models. This study provides evidence of the potential that thin and small GO sheets hold as flat nanoscale platforms for GBM treatment by increasing the bioavailable drug concentration locally, leading to an enhanced therapeutic effect.

Engineering the glioblastoma microenvironment using TLR7/8 agonist-complexed graphene oxide nanosheets

“…Previously, we have demonstrated that GO nanosheets diffuse spontaneously throughout the tumour area of GBM without traversing its borders into the brain after a single intratumoral injection. In addition, we have illustrated that GO is taken up primarily by IBA1+ macrophages and microglia cells 40,41 . Others have previously used cationic polymer (PEI)-modified GO to form complexes with R848 and nucleic acids 42,43 to demonstrate vaccine adjuvant activity in dendritic cells and macrophages in vitro.…”

“…Here, we used small, thin GO nanosheets to transport and selectively present an immunomodulatory small molecule TLR agonist into TAMMs within the GBM tumour microenvironment. Previous studies have demonstrated that GO can be used either systemically or locally as a biocompatible delivery platform for chemotherapeutic drugs or as a vaccine adjuvant system 41, 42 . However, the application of GO for localized immunomodulation of the tumour microenvironment has not been widely investigated.…”

“…However, the application of GO for localized immunomodulation of the tumour microenvironment has not been widely investigated. A single low volume administration of GO in mouse glioma models has been evidenced to translocate throughout and persist in the TME primarily within TAMMs 40, 41 . Here we exploited this advantageous biodistribution profile to passively target a small molecule TLR7/8 agonist (R848) into these tumour myeloid cells for the purpose of immunomodulation.…”

“…Sections were stained with H&E staining to observe the histological characteristics of the tumour sections and determine the tumour volume. Cryo-sections were left for 10 min at RT to dry and staining was performed as mentioned before 41 . The whole staining process was performed automatically by Leicia autostainier (Leica Biosystems, Germany).…”

Nanoparticles Mediated the Diagnosis and Therapy of Glioblastoma: Bypass or Cross the Blood–Brain Barrier

“…[96] In the chicken embryo model, researchers have confirmed that GO and rGO effectively treated glioblastoma. [97] A recent study by Sharp et al [98] validated that graphene nanosheets complexed with bortezomib could increase the bioavailable drug concentration locally and enhance the therapeutic effect of glioblastoma. Notwithstanding, current status and advances in this field are novel and satisfying, but only seldom, as graphene nanomaterials have proceeded in animal models thus far, with none having been evaluated in human clinical trials yet.…”