Modulation of Glutathione Levels by Redox-Active Nanogel Carriers for the Synergistic Enhancement of Photodynamic Therapy

The therapeutic efficiency of commonly used photosensitizers in photodynamic therapy (PDT) remains far from satisfactory in clinical trials due to the redox regulation mechanisms of cancer cells, which eliminates the generated reactive oxygen species (ROS) prior to their antitumor activity. Herein, a novel pathway to greatly enhance the efficiency of PDT is proposed through an intracellular reaction that occurs in composite nanogels with Fe3O4 nanoclusters in their core and disulfide-crosslinked phosphorylcholines in their shell. These redox-active nanogels are able to downregulate the endogenous glutathione (GSH) levels via a thiol-disulfide exchange reaction, which results in the preferential accumulation of cytotoxic ROS generated by the encapsulated photosensitizer (Chlorine 6) for cell apoptosis and tumor-growth inhibition. In addition to disulfide-assisted PDT, the composite nanogel exhibits improved cellular uptake, circulation time, targeted distribution, intracellular degradation, and selective toxicity, which provides great promise for the use of these nanogels as a simple, safe, and effective cancer treatment.