(176ar) Loading and Dynamics of Doxorubicin on Pegylated Graphene Oxide Nanocarriers By Molecular Dynamics Simulation

In recent years, graphene oxide (GO) and poly(ethylene glycol) (PEG) decorated GO (PEGGO) nanocarriers have attracted much attention in the drug delivery research community because of their tunable drug loading, targeting, circulation time, and release characteristics in blood plasma. Though experimental efforts have led to the design of efficient graphene-based drug delivery systems, much about the actual mechanisms of drug loading, release, as well as triggering of release have remained unexplored. Given the fundamental role of drug-nanocarrier interactions in the performance of a drug delivery system, computational methods, especially at the molecular level, offer a means to investigate these interactions, as well as the energetics, dynamics, and structures of drug-nanocarrier complexes to further reveal the mechanisms that would be exploited to achieve desired performance criteria. In this work, we performed molecular dynamics (MD) simulations to fundamentally investigate the loading and dynamics of doxorubicin (DOX) anticancer drug on GO and PEGGO nanocarriers in an aqueous environment at human body temperature (310 K) and physiological pH level of 7.4. Our goal was to elucidate the mechanisms of DOX adsorption on PEGGO as a function of PEG chain length. We observed that, while the total DOX-nanocarrier interaction energy was the same for the DOX/GO (control), DOX/Sh-PEGGO (short PEG chains consisting of 15 monomers), and DOX/L-PEGGO (long PEG chains consisting of 30 monomers) within the margin of error, the PEG-DOX interactions increased with an increase in the PEG chain length. At the same time, the PEG-DOX contact area almost doubled going from the short to long PEG chains. PEGylation of the GO effectively causes an increase in the average water density around the nanocarrier, which can act as a barrier, leading to the DOX migration to the solvated PEG-free part of the GO surface. This effect is more pronounced for shorter PEG chains. The DOX-DOX contact area is smaller in the DOX/GO system, which means the drug molecules are less aggregated in this system. However, the level of DOX aggregation is slightly higher for the PEGGO systems. The computational results in this work shed light on the fact that increasing the PEG chain length benefits DOX loading on the nanocarrier, revealing an observation that is difficult to ascertain through experiments. Moreover, a detailed picture is provided for the DOX adsorption and retention in PEGGO drug delivery systems, which would enable the researchers to improve the drug’s circulation time, as well as its delivery and targeting efficiency.