Long circulation in the blood, efficient cellular internalization, and intracellular drug release in the tumor cells are major challenges in the development of ideal anticancer drug delivery systems. In this paper, hydrophilicity/hydrophobicity reversable and redox-sensitive poly(oligo(ethylene glycol) methacrylates-ss-acrylic acid) (P(OEGMAs-ss-AA)) nanogels were constructed as drug carriers for cancer therapy. The nanogels underwent a pH-dependent hydrophilic/hydrophobic change. The nanogels were hydrophilic under physiological conditions (pH 7.4, 37 °C), resulting in fewer opsonization of proteins and less phagocytosis by macrophage RAW264.7 cells, while they were hydrophobic in the tumor tissues (pH 6.5, 37 °C), resulting in strong internalization by Bel7402 cells. The doxorubicin (DOX) release from DOX-loaded nanogels was increased in intracellular reductive and lysosome acidic environments. DOX-loaded nanogels exhibited higher cellular proliferation inhibition to GSH-OEt-pretreated Bel7402 cells at pH 6.5 than to unpretreated cells at pH 7.4. Further studies showed that the loaded DOX and nanogels were internalized into the cells together via both lipid raft/caveolae- and clathrin-mediated endocytic pathways. After internalization, the DOX-loaded nanogels were transported via the specific route in endo/lysosomal system. The loaded DOX was released from the nanogels with the introduction of intracellular GSH and entered the nucleus. This study indicated that the hydrophilicity/hydrophobicity reversable and redox-sensitive nanogels might be used as potential carriers for anticancer drugs, which provided a foundation for designing an effective drug delivery system for cancer therapy.
Keywords: drug delivery; hydrophilicity/hydrophobicity reversal; intracellular tracking; nanogels; stimuli-responsiveness.