ROS-Responsive 4D Printable Acrylic Thioether-Based Hydrogels for Smart Drug Release
Maria Regato-Herbella, Isabel Morhenn, Daniele Mantione, Giuseppe Pascuzzi, Antonela Gallastegui, Ana Beatriz Caribé dos Santos Valle, Sergio Moya, Miryam Criado‐Gonzalez, David Mecerreyes
Abstract
High Resolution Image Download MS PowerPoint Slide 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[(EG 3 SA) 7 - co -HEA 93 ] which confirms the stimuli-responsive properties. Then, the P[(EG 3 SA) 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 H 2 O 2 . Finally, the effect of the 5-FU release from P[(EG 3 SA) 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 EG 3 SA percentage and the presence or absence of ROS agents, thus confirming their excellent ROS-responsive properties for the treatment of localized pathologies.