Development and evaluation of a pH-responsive and water-soluble drug delivery system based on smart polymer coating of graphene nanosheets: an in silico study

Abstract

The objective of this study is to develop a controlled and water-soluble delivery system for doxorubicin (DOX) based on the coating of graphene (G) with a smart polymer. A combination of polyethyleneimine (PEI) and G-DOX is investigated by performing density functional theory (DFT) calculations and molecular dynamics (MD) simulations. Several parameters have been employed to evaluate the effect of PEI on the adsorption and release mechanisms of DOX. The obtained results indicated that the binding energy of the drug molecule on G in the presence of PEI is enhanced by about 20% under neutral conditions, whereas the drug absorption becomes weaker in an acidic environment so that DOX could be separated from the carrier surface using near-infrared radiation (NIR). Based on the atom in molecule (AIM) theory, two hydrogen bonds with strengths of about -12.59 and -39.99 kJ mol^-1 have been established. Furthermore, evaluating the dynamic behavior of the designed systems in water solution shows that the polymer in physiological pH rapidly adsorbed on the drug-carrier complex. However, at acidic pH, it is quickly desorbed from the carrier surface and the G-DOX complex can be exposed to cancer cells. The obtained results of the present research may be used in future experimental work to design smart DDSs.

Fig. 1. The optimized structure of (A) G–DOX, (B) G–pDOX, (C) G–DOX@PEI, and (D) G–pDOX@pPEI complexes with intermolecular distances (in angstrom).

Fig. 2. Schematic representation of four simulation systems.

Fig. 3. Color-filled RDG iso-surfaces depicting noncovalent interaction (NCI) regions for (A) G–DOX, (B) G–pDOX, (C) G–DOX@PEI, and (D) G–pDOX@pPEI complexes.

Fig. 4. The final snapshot from the (A) G–DOX and (B) G–pDOX systems. The water and ions molecules are not shown for clarity.

Fig. 5. The final snapshot from the (A) G–DOX@PEI and (B) G–pDOX@pPEI systems. Top and bottom panels show top and side views of the systems. Color code gray: graphene, blue: PEI and red: DOX. The water and ions molecules are not shown for clarity.

Fig. 6. The time evolution of the distance between nitrogen atom of drug and graphene surface in G–DOX and G–pDOX systems.

Fig. 7. (A) The RDF plot between the polymer and graphene and (B) density profile of the polymer around of graphene in G–DOX@PEI and G–pDOX@pPEI systems.

Fig. 8. The time evolution of the distance between polymer and graphene surface in G–DOX@PEI and G–pDOX@pPEI systems.