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 E Moya; Miryam Criado-Gonzalez; David Mecerreyes

doi:10.1021/acs.chemmater.3c02264

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

Chem Mater. 2023 Dec 13;36(3):1262-1272. doi: 10.1021/acs.chemmater.3c02264. eCollection 2024 Feb 13.

Authors

Affiliations

¹ POLYMAT University of the Basque Country UPV/EHU, Joxe Mari Korta Center. Avda. Tolosa 72, 20018 Donostia-San Sebastián, Spain.
² Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Paseo de Miramón 194, 20014Donostia-San Sebastián, Spain.
³ Ikerbasque, Basque Foundation for Science, 48013 Bilbao, Spain.
⁴ Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano ,Italy.

Abstract

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_nSA) 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_nSA 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_nSA monomers were copolymerized with a polar monomer, 2-hydroxyethyl acrylate (HEA), leading to P[(EG_nSA)_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.