# Recent Advances in the Synthesis of Graphene-Based Nanomaterials for Controlled Drug Delivery
## 3 Drug Delivery with Graphene-Based Nanomaterials
### Graphene-Small Molecule Nanohybrids  
In the past five years, graphene and its derivatives have attracted considerable attention because of their excellent heat and electrical conductivity, biocompatibility, high specific surface area, and various surface oxygen-containing groups, and also shown considerable potential in drug delivery. For example, GO has been employed to deliver aromatic drug molecules into cells via \(\pi\)-\(\pi\) stacking interactions [43; 44; 77]. Functional graphene quantum dots (GQDs) not only delivered the antitumor drug doxorubicin (DOX) into target cells, but can also monitor the cellular uptake and drug release process in real-time without the need of external dyes [45; 53; 78]. In the earlier work, related graphene-based carrier drugs were directly conjugated to graphene materials via \(\pi\)-\(\pi\) stacking interactions. The advantage of this method is that the preparation process is simple and has high drug loading capacity, but the stability and biocompatibility of the final graphene-drug nanohybrids are hard to control. After that, some functional small molecules were employed to improve the stability and biocompatibility of nanocarriers. For instance, [PERSON] and co-workers discovered that the activity of Hypocrellin A (a photosensitive anticancer drug) could be enhanced significantly when 7-ethyl-10-hydroxycampotthecin and Hypocrellin A were co-loaded onto the surface of GO when compared with the modification of Hypocrellin A alone [77]. In vitro experimental results also showed that the photodynamic therapy effect has been greatly improved. In another study, [PERSON] et al., conjugated the reduced graphene oxide (rGO) with folic acid (FA)through noncovalent functionalization [43]. The as-prepared rGO/FA conjugate showed high dispersion stability in physiological media and enabled the accumulation of hydrophobic DOX. The in vitro results indicated that rGO/FA loaded DOX could specific target to MDA-MB 231 cells (human breast cancer cells), with an excellent drug-release efficiency (>90%). [PERSON] and co-workers prepared starch-functionalized graphene nanosheets (starch-GNS) via reducing exfoliated GO with soluble starch [44]. The as-prepared starch-GNS showed good biocompatibility and a high drug loading capacity. The experimental data indicated that 150 \(\upmu\)g of starch-GNS can load 12 \(\upmu\)g of hydroxyemptothecine by physisorption. Small molecule-modified GQDs could also be utilized for simultaneous drug delivery cellular imaging. For example, [PERSON] et al. [45] and [PERSON] et al. [78] modified GQDs with arginine-glycine-aspartic acid (RGD) and FA, respectively (Figure 2a,b). The DOX loaded RGD- or FA-modified GQDs could not only deliver drugs to target cells effectively, but also monitor the process of cellular uptake the drug in real-time without employing external dyes, as shown in Figure 2c,d. In another case, [PERSON] and co-workers developed multifunctional paramagnetic GQDs (folate-GdGQDs) for simultaneous dual-modality bioimaging and tutor targeted drug delivery [53]. The synthetic folate-GdGQDs exhibited a strong therapeutic activity by loading DOX though \(\pi\)-\(\pi\) stacking and hydrophobic interactions, and the fabricated nanocarriers could release about 80% of DOX at pH 5.0 after 48 h. Moreover, the folate-GdGQDs also showed an excellent biocompatibility and good targeting ability for noninvasive cancer diagnosis with \(T_{1}\)-weighted magnetic resonance (MR) and fluorescence imaging. Figure 2: Small molecule-modified graphene for drug delivery. (**a**) Schematic illustration of the geometry of multifunctional graphene quantum dots (GQD) for targeted delivery of drug doxorubicin (DOX) and their interactions with cancer cells; (**b**) Schematic of the fabricated DOX- folic acid (FA)-GQD nanoassembly for DOX delivery into target cells; (**c**) DU-145 cells incubated with DOX-arginine-glycine-aspartic acid (RGD)-GQD; and, (**d**) Confocal laser scanning microscope images of HeLa cells incubated with DOX-FA-GQD.