Self-assembly of a disulfide-containing core/shell nanocomplex with intracellular environment-sensitive facilitated endo-lysosomal escape for enhanced antitumor efficacy

A receptor-mediated, active-targeting and glutathione (GSH) turn-on charge-reversal core/shell nanocomplex HA-MEA-s-s-TGA/PAMAM@DOX was constructed to achieve increased stability, improved cellular uptake, facilitated endo-lysosomal escape and enhanced antitumor efficacy. This nanocomplex was composed of anionic hyaluronic acid (HA)-graft GSH-sensitive HA-MEA-s-s-TGA as the outer shell and the cationic PAMAM@DOX core with encapsulated doxorubicin (DOX) into the hydrophobic cavities of polyamidoamine (PAMAM) dendrimers. We hypothesized that the anionic outer layer could promote cellular uptake of HA-MEA-s-s-TGA/PAMAM@DOX by HA receptor-mediated endocytosis. After internalization into tumor cells, the outer shell of the internalized nanocomplex was disassembled in endo-lysosomes via the destruction of disulfide linkages to re-expose PAMAM drug core. This action induced release of the encapsulated DOX and facilitated endo-lysosomal escape through the synergistic action of the proton sponge effect and cationic–anionic interaction between protonated PAMAM and endo-lysosome membranes. In vitro release profiles demonstrated the intracellular environment-responsive release behavior of DOX from this nanocomplex, with a cumulative release of 80% within 4 days in a simulated tumor intracellular microenvironment, whereas the surface charge changed from − 18.82 mV to + 10.95 mV. The MTT assay revealed the good biocompatibility of the negatively charged nanocomplex and efficient toxicity against HeLa cells. The designed pH/GSH dual-responsive nanocomplex could be an efficacious and safe delivery platform for cancer therapy. Graphical abstract