Disulfide Containing Poly(?-Amino Ester) Hydrogels Inhibit Glutathione Reductase in Cancer Applications

Glutathione is a compound inside the cytosol that acts as the primary antioxidant in mammalian cells; it can be found in two forms- a reduced form (GSH) and an oxidized (GSSG). In its reduced form, it supports the reduction of reactive oxygen species (ROS), an excess of which results in a condition known as oxidative stress. Uncontrolled oxidative stress can result in damage to DNA, lipids, and proteins, leading to cell death. In the glutathione recycling reaction, GSH reduces hydrogen peroxide (H2O2), a common form of ROS, leaving it as an oxidized GSSG molecule. GSSG is then returned to its active form GSH through the enzyme, glutathione reductase. Under oxidative stress, a cell will have significantly more GSSG than GSH. The balance of the reduced and oxidized form is thus a critical part of establishing a cell’s ability to resist injury, as a higher ratio of GSH to GSSG indicates the cells preparedness to defend against ROS. In this work, we develop disulfide containing poly(β-amino ester) hydrogels, whose degradation products are structurally similar to GSSG. We demonstrate the ability of these hydrogels to inhibit glutathione reductase, suppressing GSH recycling. The ability to manipulate the ratio of the two forms creates opportunities for therapies in cancer, wound healing, and regenerative medicine.