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

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.P.S., M.S., A.M.G., A.D., and K.K. would like to acknowledge the United Kingdom Research and Innovation (UKRI) Engineering and Physical Sciences Research Council (EPSRC) 2D-Health Programme Grant (EP/P00119X/1) for financial support. T.K. and K.K. would also like to acknowledge the UKRI (EPSRC) for an International Centre-to-Centre grant (EP/S030719/1). The European Union Horizon 2020 Research and Innovation Programme under Grant Agreement no. 881603 (Graphene Flagship Core 3) also funded this work. The ICN2 is funded by the CERCA programme, Generalitat de Catalunya, and is supported by the Severo Ochoa Centres of Excellence programme by the Spanish Research Agency (AEI, grant no. SEV-2017-0706).Peer reviewe