# Recent Advances in the Synthesis of Graphene-Based Nanomaterials for Controlled Drug Delivery
## 3 Drug Delivery with Graphene-Based Nanomaterials
### Graphene-Polymer Nanohybrids  
A lot of polymers could be utilized to modify graphene for drug delivery applications. Ten years ago, [PERSON] et al., first discovered that polyethylene glycol (PEG)-functionalized GO can be used as a novel drug nanocarrier to load anti-cancer drugs via non-covalent physisorption with in vitro cellular uptake capacity [17]. After that, graphene-polymer nanocomposites have been widely explored as drug carriers in recent years. For instance, [PERSON] and co-workers developed a photothermally triggered drug delivery system by modifying rGO with branched polyethylenimine (BPEI) and PEG [61]. The as-prepared PEG-BPEI-rGO nanocomposite exhibited high water stability and dramatically enhanced DOX loading efficiency. [PERSON] et al., developed one-pot green reduction and PEGylation of GO to construct a high-efficiency drug loading and photothermally triggered drug delivery system [41]. The as-prepared PEG-GO nanohybrids showed better water stability, high near infrared irradiation absorbance, and \(\sim\)2-fold increment in resveratrol loading efficiency over the unreduced ones. [PERSON] and coworkers modified GO with biocompatible PEGylated alginate brushes (PEG-ALG-GO) via the disulfide bridge bond [57]. The obtained nanoscale 3D biocompatible, reduction-responsive PEG-ALG-GO nanohybrids showed efficiently loading (97.0 \(\pm\) 3%) and releasing (30.6%) of DOX. Other biocompatible polymers, like polyethylenimine (PEI) and hyaluronic acid (HA), also showed high potentials to modify graphene for drug delivery. For example, [PERSON] et al., used PEI-GO as a nanocarrier, the as-prepared PEI-GO nanohybrids showed high stability in both water and physiological solutions, and combined the functionalities of the nanocrystals and PEI-GO, such as luminescence, superparamagnetism, and drug delivery capacity (with a superior loading capacity of 100 wt. % for DOX) [81]. In another study, [PERSON] et al., prepared HA-GO nanohybrids (Figure 5) by conjugating GO nanosheets with 38% hexamethylenediamine (HMDA)-modified HA for targeting specific delivery of epirubicin via HA receptor mediated endocytosis [49]. The loading amount of epirubicin on HA-GO increased significantly with an increasing of the pH of epirubicin solutions, which is beneficial for the release of drug in the acidic environment of tumor (Figure 6). In other cases, HA-GO nanohybrids have been utilized for the pH-responsive delivery of DOX for tumor therapy [50; 82]. (PNIPAM), [PERSON] et al., synthesized PNIPAM-poly(ethylene oxide)-based polymer nanoparticles (PNPs) by free radical polymerization reaction and then assembled PNPs onto the 1-pyrenebutyric acid \(N\)-hydroxysuccinimide ester functionalized GO nanosheets [35], as shown in Figure 7. The obtained thermo-sensitive PNPs-GO nanohybrid had \(\sim\)87% of loading efficiency and 13-22% of release efficiency for adriamycin (ADR). This new nanohybrid showed great potential in in vivo applications, for instance to kill target cancer cells via modification with specific antibodies. In another case, [PERSON] and coworkers explored an electrically stimulated drug delivery nanocomposite composed of GO that was deposited inside a conducting polymer scaffold [42]. The amount of drug release of the nanocomposite was linear with the dosage of electrical stimulation, and in vitro results also showed that the released drug retains its bioactivity and no toxic byproducts leach from the film during electrical stimulation. [PERSON] et al., developed an innovative multifunctional pH-responsive drug delivery system for hepatocellular carcinoma-targeted therapy and imaging by coating DOX-GO with cyclic RGD-modified chitosan [51]. The obtained nanohybrids exhibited higher loading capacity for DOX (1.0 mg mg\({}^{-1}\)), pH-responsive behavior, and potential application in hepatocellular carcinoma therapy. Block co-polymers have exhibited potential to modify graphene for controlled and high performance drug delivery.