## 3 Results and Discussion
### Clinical Relevance  
The development of drug nanocarriers still faces large challenges in moving from bench to bedside, including issues related to efficacy, toxicity, biocompatibility, biodegradability, and clearance/excretion pathways. Some of the main issues are related to large-scale production and quality assurance. Large-scale production of graphene requires the reproduction of materials with the same size, polydispersity, morphology, charge, surface modifications, and stability, all whilst maintaining and adhering to regulatory standards. This is extremely difficult to achieve and requires extensive infrastructure, expertise, technology, and money [97].  
More specifically for drug delivery devices, one of the major translational barriers of in vitro and in vivo studies to clinical use is understanding the accumulation amount of the drug at the target site and whether in vitro studies are representative of drug concentrations that would be relevant in clinical applications. The advised clinical dosage of DOX in chemotherapy is 60-75 mg/m\({}^{2}\) over a course of 3 to 10 min every 21 days. This is dependent on the dosage regimen, type of cancer, stage of cancer, and any previous treatment or combined treatments that the patient has undergone [98,99]. The analysed publications do not address the overall delivery efficiency of DOX to the target site or the absolute accumulation of DOX within the cell; this is mainly due to the fact that the majority are limited to proof-of-concept in vitro studies.  
The GO-TD-Fe\({}_{3}\)O\({}_{4}\)@PEG composite, records a high DLE of DOX at 92.6% and a high cumulative release of 97.3% at pH 5.0 after 72 h, suggesting high delivery efficiency [67]. Whereas GO-PEG-FA/GNPs/DOX has a high loading efficiency of 84%, only \(\sim\)43% of that loaded drug is released at pH 4.0 after 295 h [76]. Finally, NGO-PEG-DA/DOX has a reasonably low loading efficiency of 50% and only releases 31.4% of that loaded drug after 24 h [65], which theoretically means that if 1 mg of DOX was loaded onto the nanohybrid, only 0.157 mg would reach the intended target. These data suggest that the amount of DOX reaching the target site can be extremely varied and often may require a higher initial dosage to account for the loss. Future research should focus on using clinically relevant concentrations of DOX in pre-clinical experiments and accurately report on the delivery efficiency of the drug to evaluate the efficacy of nanocarriers.  
In addition, the timeframe of action of the drug-loaded nanocarrier is important to understand in order to translate to clinical use. The timeframe through which the maximum cumulative release of DOX was measured varied drastically through the publications. Four of the analysed studies recorded the drug release profile over a period of more than six days, with one publication recording results up to thirteen days after initial release. It is questionable why the drug release was recorded for this long and whether this is clinically relevant or translatable to chemotherapy within this timeframe as the drug-loaded nanocarrier may be cleared from the body under physiological conditions. The terminal half-life for free DOX, for instance, is only 20-30 h [100]. Research should be undertaken to understand the optimum time frame for drug release to the specific target for maximum efficacy and to evaluate the retention time of graphene nanocarriers within the target site.