Abstract
Glioblastoma is the most aggressive and lethal brain cancer. Current treatments involve surgical resection, radiotherapy and chemotherapy. However, the life expectancy of patients with this disease remains short and chemotherapy leads to severe adverse effects. Furthermore, the presence of the blood–brain barrier (BBB) makes it difficult for drugs to effectively reach the brain. A promising strategy lies in the use of graphene quantum dots (GQDs), which are light-responsive graphene nanoparticles that have shown the capability of crossing the BBB. Here we investigate the effect of GQDs on U87 human glioblastoma cells and primary cortical neurons. Non-functionalized GQDs (NF-GQDs) demonstrated high biocompatibility, while dimethylformamide-functionalized GQDs (DMF-GQDs) showed a toxic effect on both cell lines. The combination of GQDs and the chemotherapeutic agent doxorubicin (Dox) was tested. GQDs exerted a synergistic increase in the efficacy of chemotherapy treatment, specifically on U87 cells. The mechanism underlying this synergy was investigated, and it was found that GQDs can alter membrane permeability in a manner dependent on the surface chemistry, facilitating the uptake of Dox inside U87 cells, but not on cortical neurons. Therefore, experimental evidence indicates that GQDs could be used in a combined therapy against brain cancer, strongly increasing the efficacy of chemotherapy and, at the same time, reducing its dose requirement along with its side effects, thereby improving the life quality of patients.
Highlights
Glioblastoma multiforme (GBM) is the most aggressive and lethal human brain cancer, with poor prognosis [1]
graphene quantum dots (GQDs) are two-dimensional materials based on graphene; they are structured as a single-atom-thick sheet of honeycomb-arranged, sp2-bonded carbon atoms and they have great electronic properties [19,20,21]
We report on the effect of GQDs functionalized with dimethylformamide (DMF-GQDs), bearing an intrinsic toxicity, and of biocompatible non-functionalized GQDs (NF-GQDs), on two neural lineages: U87 GBM cells and primary mouse cortical neurons
Summary
Glioblastoma multiforme (GBM) is the most aggressive and lethal human brain cancer, with poor prognosis [1]. Numerous reasons contribute to the ineffectiveness of current therapies against GBM It is multiform, it displays high intratumoral heterogeneity [3,4], which has great relevance in estimating the survival function related to diverse tumor cell subtypes [5]. The BBB is the anatomical border that separates the brain from the bloodstream This sophisticated cellular complex controls the BBB permeability of circulating molecules, including drugs [6]. Dox is not currently employed in clinical translation due to its poor targeting ability in vivo. This could lead to adverse, toxic effects on healthy tissues. Most of the studies employing GQDs and Dox focused on the synthesis of nano-complexes by conjugating the two molecules with cancer-targeting ligands. The mechanism of action behind this observation is discussed in this work by using confocal microscopy, cell viability measurements and by analyzing cellular uptake of the chemotherapeutic drug
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