Development of a Multi-Stimuli-Responsive Magnetic Nanogel–Hydrogel Nanocomposite for Prolonged and Controlled Doxorubicin Release
Ghasem Rezanejade Bardajee, Hossein Mahmoodian, Negin Shafiei, Bita Amiri
Abstract
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( N -isopropylacrylamide- co -acrylamide) (p(NIPAM- co -AAm)) nanogels (NGs) within a net-shaped salep-grafted poly(acrylic acid) (PAA) hydrogel matrix, coupled with in situ formation of Fe 3 O 4 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 Fe 3 O 4 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.