Unveiling the drug delivery mechanism of graphene oxide dots at the atomic scale.

Graphene oxide (GO) is an amphiphilic and versatile graphene-based nanomaterial that is extremely promising for targeted drug delivery, which aims to administer drugs in a spatially and temporally controlled manner. A typical GO nanocarrier features a polyethylene glycol coating and conjugation to an active targeting ligand. However, it is challenging to accurately model GO dots, because of their intrinsically complex and not unique structure. Here, realistic atomistic GO models are designed as homogeneously/inhomogeneously oxidized flakes and then coated with stealth polymeric chains conjugated to an active targeting ligand (PEG-cRGD). Doxorubicin (DOX) adsorption is investigated by metadynamics simulations for accelerated loading/release events. The presence of PEG and cRGD are found not to affect the DOX adsorption, whereas the homogeneity of oxidation plays a crucial role. We also proved that a change in pH towards acidic conditions causes a reduction in the GO/DOX affinity in line with a pH-triggered release mechanism. Based on this study, the ideal graphene-based DOX carrier is identified as a homogeneously highly oxidized GO where graphitic regions with strong DOX π-π stacking are limited. Such interactions excessively stabilize DOX and are not weakened by a pH-change. On the contrary, DOX interactions with surface oxidized groups are H-bonding and electrostatic, which can effectively be modified by a pH reduction. Our findings are useful to the experimental community to further develop successful drug delivery systems.