## 3 Graphene and Graphene-Related Materials for Biological Applications
### Graphene and Related Materials as Drug Delivery Platforms
This system was tailored with folic acid and chitosan through dicyclohexylcarbodiimide coupling using ethyleneglycol dimethacrylate as the cross-linker and potassium peroxdisulphate as an initiator to generate carboxylates able to react with chitosan. The authors loaded the drug by \(\pi\)-\(\pi\) stacking interactions, reporting a loading capacity of up to 95% and a high release rate at pH 5.3. This was particularly attractive for cancerous cell lines with an acidic microenvironment such as L929, HeLa, and MCF7. In vitro tests showed promising results in decrementing their proliferation. Similarly, [PERSON] et al. [104] developed an innovative pH-sensitive, injectable hydrogel composed by combining chitosan, GO, and cellulose nanow whiskers for the co-delivery of doxorubicin and curcumin that was also studied by [PERSON] et al. [105]. Figure 2: Biodegradation of cisplatin-loaded graphene foams as reported by [PERSON] et al. [96]. Authors combined GO with hyperbranched polyglycerol and grafted it with chlorine-based and hydrazine pendants. In this study, doxorubicin was loaded onto the graphene-based carrier by covalent bonding with the hydrazine pendant group, and curcumin was loaded through \(\pi\)-\(\pi\) stacking with GO sheets. The authors claimed a superior biocompatibility together with an improvement of drug internalization. [PERSON] et al. (2016) described an interesting material based on ZnO/ dopamine-tailored GO for the enhanced delivery of doxorubicin. The authors evaluated the cytotoxicity of the graphene-based nanohybrid against T47D and MCF10A cellular lines showing a good efficacy together with an antimicrobial activity against Gram-positive and -negative bacteria. [PERSON] et al. (2017) extended the graphene co-delivery systems' application by the conjugation of GO with cyclodextrins and chitosan fibres for the production of a multidrug loading system. The authors loaded gallic acid and curcumin showing anti-cancer, antimicrobial, antioxidant, and anti-inflammatory activities, which was quite challenging in the absence of graphene-like materials, requiring sophisticated encapsuling procedures ([PERSON] et al., 2017). As an alternative to co-delivering, the modification of graphene materials could be a solid choice to enhance the anticancer activity. [PERSON] et al. (2019) produced a highly fluorinated graphene by treating a graphene precursor in an acidic ionic liquid showing a 20% improvement of curcumin loading without compromising the release efficiency. Similarly, [PERSON] et al. (2019) synthesized fluorinated GO nanosheets able to deliver linoleic-curcurcuni conjugate and useful for T\({}_{2}\)-weighted magnetic resonance imaging. The authors showed that accumulation in the MCF-7 cell line was strictly dependent on pH, and the effectiveness increased moving on to MCF-10A line. Additionally, the authors estimated the relaxation rate as 67.12 (smM)\({}^{-1}\) and with the very attracting ability to reduce signal intensity in the presence of MCF10A and MCF-7 cells. In vivo studies showed a tumour cell suppression using 4T1 cell line. [PERSON] et al. (2019) functionalized GO with dopamine altering the surface properties of GO and improving the drug-ability of cytarabine. This tailoring process was modelled by using the DFT approach showing the relevance of orbital interaction during the overall drug loading and release process. Injectable formulations of graphene-related materials are not the only approach to drug delivery. [PERSON] et al. (2019) produced a membrane based on GO and Pluronic(r) F127 for the transdermal delivery of ondansetron. The authors produced a hydrogel with good mechanical properties for topical application, suggesting that the drug flux proportionally decreased with the increase in the level of GO in the hydrogel due to \(\pi\)-\(\pi\) stacking interaction decrement. This meant that the drug release rate can be tuned by tuning the amount of GO as clearly showed by bioavailability tests run on rat models. A GO membrane was also used by [PERSON] et al. (2019) for delivering tegafur.