ROS-Responsive 4D Printable Acrylic Thioether-Based Hydrogels for Smart Drug Release

Reactive oxygen species (ROS) play a key role in several biological functions like regulating cell survival and signaling; however, their effect can range from beneficial to nondesirable oxidative stress when they are overproduced causing inflammation or cancer diseases. Thus, the design of tailor-made ROS-responsive polymers offers the possibility of engineering hydrogels for target therapies. In this work, we developed thioether-based ROS-responsive difunctional monomers from ethylene glycol/thioether acrylate (EG n SA) with different lengths of the EG n chain (n = 1, 2, 3) by the thiol-Michael addition click reaction. The presence of acrylate groups allowed their photopolymerization by UV light, while the thioether groups conferred ROS-responsive properties. As a result, smart PEG n SA hydrogels were obtained, which could be processed by four-dimensional (4D) printing. The mechanical properties of the hydrogels were determined by rheology, pointing out a decrease of the elastic modulus (G′) with the length of the EG segment. To enhance the stability of the hydrogels after swelling, the EG n SA monomers were copolymerized with a polar monomer, 2-hydroxyethyl acrylate (HEA), leading to P­[(EG n SA) x -co-HEA y ] with improved compatibility in aqueous media, making it a less brittle material. Swelling properties of the hydrogels increased in the presence of hydrogen peroxide, a kind of ROS, reaching values of ≈130% for P­[(EG3SA)7-co-HEA93] which confirms the stimuli-responsive properties. Then, the P­[(EG3SA) x -co-HEA y ] hydrogels were employed as matrixes for the encapsulation of a chemotherapeutic drug, 5-fluorouracil (5FU), which showed sustained release over time modulated by the presence of H2O2. Finally, the effect of the 5-FU release from P­[(EG3SA) x -co-HEA y ] hydrogels was tested in vitro with melanoma cancer cells B16F10, pointing out B16F10 growth inhibition values in the range of 40–60% modulated by the EG3SA percentage and the presence or absence of ROS agents, thus confirming their excellent ROS-responsive properties for the treatment of localized pathologies.