Steric stabilization of β-cyclodextrin functionalized graphene oxide by host-guest chemistry: A versatile supramolecule for dual-stimuli responsive cellular delivery of doxorubicin

Abstract

Host-guest interaction is an approach for the synthesis of supramolecular three-dimensional graphene-based nanocarriers. Herein, graphene oxide (GO) was first functionalized with β-cyclodextrin (β-CD) using cystamine (Cys) as a disulfide bearing linker and then was PEGylated through the host-guest interactions of β-CD with adamantane end-capped polyethylene glycol (PEG-Ad). GO-Cys-CD-PEG was able to load anticancer drug, doxorubicin (DOX), with high loading efficiency of 94.58%. The cone shaped cavity of β-CD can act as a host for the steric stabilization of GO and DOX loading through inclusion complex formation. In-vitro release experiment showed that the platform could not only prevent the leakage of the loaded DOX under physiological conditions, but also exhibited higher extent of DOX release in acidic milieu of cancer cells and in response to glutathione (GSH) simulating intracellular redox environment. The results suggest that GO-Cys-CD-PEG is a promising dual-responsive system with potential application in drug delivery. In addition, GO-Cys-CD-PEG showed comparably superior stability against physiologic salt solution. General cytotoxicity of the nanocarrier was examined by trypan blue dye exclusion, showing that the GO-Cys-CD-PEG had significant cytocompatibility. GO-Cys-CD-PEG/DOX also exhibited a significantly higher cytotoxicity than free DOX in HepG2 cells, which can be attributed to the PEG stabilizing action and enhanced dispersibility of GO-Cys-CD-PEG/DOX in the culture medium as a prerequisite for successful drug delivery. Moreover, GO-Cys-CD-PEG can be served as a nuclear shuttle for DOX as confirmed by fluorescence microscopy and flow cytometry experiments.