Development of a Multi-Stimuli-Responsive Magnetic Nanogel–Hydrogel Nanocomposite for Prolonged and Controlled Doxorubicin Release

The development of advanced drug delivery systems that offer precise, controlled, and sustained release of therapeutic agents remains a significant challenge, particularly for applications in oncology where effective targeting and prolonged drug exposure are essential. We synthesized and characterized a multistimuli-responsive magnetic nanogel-hydrogel nanocomposite (MNHNC) designed for controlled and extended drug release, with an emphasis on anticancer drug delivery. The MNHNC was developed by incorporating poly(<i>N</i>-isopropylacrylamide-<i>co</i>-acrylamide) (p(NIPAM-<i>co</i>-AAm)) nanogels (NGs) within a net-shaped salep-grafted poly(acrylic acid) (PAA) hydrogel matrix, coupled with in situ formation of Fe₃O₄ nanoparticles to introduce magnetic responsiveness and serve as a cross-linking agent. The nanocomposite exhibited notable swelling capabilities, achieving equilibrium values of 706 g/g at pH 9 (25 °C) and 603 g/g at physiological temperature (37 °C, pH 7.4). Additionally, MNHNC demonstrated responsiveness to pH, temperature, and magnetic fields, facilitating controlled drug release. Using doxorubicin (DOX) as a model drug, MNHNC exhibited dual pH sensitivity (NG at pH 5.4 and MNHNC at pH 7.4) and achieved a prolonged release profile of 400 h, significantly surpassing conventional systems, including our previous nanocomposite. Release kinetics followed a super case-II transport mechanism, where swelling primarily governed drug diffusion. Furthermore, the application of a magnetic field enabled fine-tuning of the release rate, offering an additional layer of control. The kinetic study indicated that the drug release from MNHNC followed zero-order kinetics under certain conditions, ensuring a consistent release rate over time, which is highly desirable for maintaining therapeutic efficacy. The Korsmeyer-Peppas model further confirmed the super case-II transport mechanism, highlighting the significant influence of polymer relaxation and swelling on the release process. The Hixson-Crowell model also demonstrated the role of matrix erosion in the drug release mechanism. The results showed a marked improvement in pH and temperature sensitivity compared to previous formulations, enhanced mechanical stability due to the integration of Fe₃O₄ nanoparticles, and the ability to modulate drug release through external magnetic fields. In vitro cytotoxicity assessment using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay demonstrated the biocompatibility of the MNHNC, with over 95% cell viability in the absence of DOX, confirming its nontoxic nature. Upon DOX loading, MNHNC exhibited a proper anticancer effect against cancer cell lines, showing a dose-dependent reduction in cell viability. The robust mechanical stability, biocompatibility, and multistimuli responsiveness of MNHNC position it as a promising candidate for advanced, targeted drug delivery systems.