Dual-Responsive Hydrogel-Coated Nanoclusters for Combined Magnetic Hyperthermia and Drug Delivery: A Comprehensive In Vitro and In Vivo Toxicity Profiling.
Cancer therapy demands smarter, more targeted strategies that minimize healthy tissue damage while maximizing therapeutic efficacy. This study introduces Hy-Si-IONC, a dual heat- and pH-responsive hydrogel-coated magnetic nanocluster, engineered to deliver chemotherapeutic drug within the tumor microenvironment. When combined with magnetic hyperthermia, it offers targeted, localized drug release, outperforming conventional single-stimulus carriers. The encapsulation efficiency and drug loading capacity of the Hy-Si-IONC were 47.3% and 4.6%, respectively. Hy-Si-IONC exhibited a lower critical solution temperature (LCST) of 43 °C with drug-release potential of 41.89% under tumor-mimicking conditions. A combinational therapy of doxorubicin-loaded Hy-Si-IONC and magnetic hyperthermia reduced the cell viability to 18% in MDA-MB-231 cells, confirming a strong therapeutic effect between thermal and chemotherapy. The nanosystem displayed good compatibility with human lymphocytes, MCF-7 and MDA-MB-231 cell lines. Hemolysis remained below 1%, and no genotoxicity was detected. Long-term in vivo safety was confirmed in a 25-week mice study, the nanoclusters predominantly accumulated in the liver and spleen. Transient changes in antioxidant markers - superoxide dismutase (SOD), catalase, glutathione S-transferase (GST), and glutathione (GSH) normalized by end of the study. No major histopathological abnormalities were observed in vital organs. Collectively, Hy-Si-IONC presents a biocompatible and potential dual-modal cancer therapy.