Hidrogeles magnéticos multifuncionales termosensibles reforzados con nanofibras de celulosa para la liberación controlada de doxorrubicina e hipertermia magnética/ Multifunctional Thermoresponsive Magnetic Hydrogels Reinforced with Cellulose Nanofibers for On-Demand Doxorubicin Release and Magnetic Hyperthermia

Abstract

Developing magnetic hydrogel composites that effectively combine drug loading, structural integrity, thermoresponsive behavior, and remote heat generation poses a significant challenge in localized cancer therapy. In this study, we designed thermoresponsive magnetic hydrogels (HMag) for synergistic chemotherapy and magnetic hyperthermia by incorporating superparamagnetic Fe3O4 nanoparticles coated with polyethylene glycol (PEG-8000) and TEMPO-oxidized cellulose nanofibers (TOCNF) into a crosslinked poly(N-isopropylacrylamide) (PNIPAM) matrix. We synthesized the magnetic nanoparticles via reverse co-precipitation in the presence of PEG-8000 to improve their colloidal stability and dispersion in water. We added TOCNF at a fixed content of 2.5 wt% to reinforce the hydrogel network while preserving responsiveness. HMag composites containing 2.5-10 wt% Fe3O4-PEG8000 were prepared by free-radical polymerization. FTIR, XRD, TGA, and SEM confirmed the formation of porous hybrid networks with a uniform magnetic phase. PEGylated magnetite and TOCNF cooperatively regulated water retention, pore architecture, and structural stability. Hydrated PEG domains and the interconnected, carboxylated TOCNF network created water-accessible microenvironments within the PNIPAM matrix, facilitating doxorubicin (DOX) loading and release. The hybrid hydrogels retained superparamagnetic behavior and showed efficient magnetothermal actuation under an alternating magnetic field (10.2 kA m-1, 354 kHz), reaching approximately 42-43 °C within 310 s. In vitro release experiments at 37 °C and physiological pH confirmed thermoresponsive delivery: HMag2.5 released 63% of its loaded DOX within 6 h, followed by sustained release. Exposure to a magnetic field triggered a rapid 18% release within 10 min, demonstrating on-demand delivery. DOX-loaded HMag significantly reduced the viability of MDA-MB-231 breast cancer cells, while the unloaded composites remained highly cytocompatible, confirming the biological activity of DOX released from the composite network. These results underscore HMag´s potential as a dual-action, localized, stimulus-responsive platform for cancer therapy, combining controlled drug delivery with magnetic hyperthermia.

Keywords: Magnetic hydrogels; Doxorubicin release; Magnetic hyperthermia