Graphene-based phenformin carriers for cancer cell treatment: a comparative study between oxidized and pegylated pristine graphene in human cells and zebrafish.

Graphene is an attractive choice for the development of an effective drug carrier in cancer treatment due to its high adsorption area and pH-responsive drug affinity. In combination with the highly potent metabolic drug phenformin, increased doses could be efficiently delivered to cancer cells. This study compares the use of graphene oxide (GO) and polyethylene glycol stabilized (PEGylated) pristine graphene nanosheets (PGNSs) for drug delivery applications with phenformin. The cytotoxicity and mitotoxicity of the graphene-based systems were assessed in human cells and zebrafish larvae. Targeted drug release from GO and PGNSs was evaluated at different pH levels known to arise in proliferating tumor microenvironments. PGNSs were less cytotoxic and mitotoxic than GO, and showed an increased release of phenformin at lower pH in cells, compared to GO. In addition, the systemic phenformin effect was mitigated in zebrafish larvae when bound to GO and PGNSs compared to free phenformin, as measured by flavin metabolic lifetime imaging. These results pave the way for improved phenformin-based cancer therapy using graphene nano-sheets, where PGNSs were superior to GO.

Improved pH-Responsive Release of Phenformin from Low-Defect Graphene Compared to Graphene Oxide.

Graphene-based drug carriers provide a promising addition to current cancer drug delivery options. Increased accessibility of high-quality graphene made by plasma-enhanced chemical vapor deposition (PE-CVD) makes it an attractive material to revisit in comparison to the widely studied graphene oxide (GO) in drug delivery. Here, we show the potential of repurposing the metabolic drug phenformin for cancer treatment in terms of stability, binding, and pH-responsive release. Using covalent attachment of poly(ethylene glycol) (PEG) onto pristine (PE-CVD) graphene, we show that PEG stabilized graphene nanosheets (PGNS) are stable in aqueous solutions and exhibit higher binding affinity toward phenformin than GO. Moreover, we experimentally demonstrate an improved drug release from PGNS than GO at pH levels lower than physiological conditions, yet comparable to that found in tumor microenvironments.

Metformin treatment response is dependent on glucose growth conditions and metabolic phenotype in colorectal cancer cells.

Cancer cells exhibit altered metabolism, a phenomenon described a century ago by Otto Warburg. However, metabolic drug targeting is considered an underutilized and poorly understood area of cancer therapy. Metformin, a metabolic drug commonly used to treat type 2 diabetes, has been associated with lower cancer incidence, although studies are inconclusive concerning effectiveness of the drug in treatment or cancer prevention. The aim of this study was to determine how glucose concentration influences cancer cells' response to metformin, highlighting why metformin studies are inconsistent. We used two colorectal cancer cell lines with different growth rates and clinically achievable metformin concentrations. We found that fast growing SW948 are more glycolytic in terms of metabolism, while the slower growing SW1116 are reliant on mitochondrial respiration. Both cell lines show inhibitory growth after metformin treatment under physiological glucose conditions, but not in high glucose conditions. Furthermore, SW1116 converges with SW948 at a more glycolytic phenotype after metformin treatment. This metabolic shift is supported by changed GLUT1 expression. Thus, cells having different metabolic phenotypes, show a clear differential response to metformin treatment based on glucose concentration. This demonstrates the importance of growth conditions for experiments or clinical studies involving metabolic drugs such as metformin.