Vitamin k3-Loaded Magnetic Nanoparticle-Mediated Synergistic Magnetothermodynamic Therapy Evokes Massive ROS and Immune Modulation for Augmented Antitumor Potential

Magneticnanoparticle (MNP)-mediated magnetic hyperthermia (MHT)under an alternating magnetic field (AMF) causes tumor regression via reactive oxygen species (ROS) generation. However, lesstherapeutic efficacy has been reported due to the generation of lowlevels of ROS in a hypoxic tumor microenvironment. Therefore, improvedtreatments are required to generate relatively high levels of ROSto promote irreversible oxidative damage to the tumor cells. Herein,we report a magnetothermodynamic (MTD) therapy, as a robust and versatileapproach for cancer treatment, by combining the magnetothermodynamic-relatedROS and heat-related immunological effect in order to overcome theaforementioned obstacle. The synergistic therapy was achieved by thedevelopment of vitamin k3 (Vk3)-loaded copper zinc ferrite nanoparticles(Vk3@Si@CuZnIONPs) as an efficient MTD agent. The in vitro results unveiled that enhanced ROS production under the influenceof AMF is a predominant aspect in yielding an assertive anticancerresponse. The in vivo antitumor response was assessedin an ectopic tumor model of A549 lung adenocarcinoma by MTD. Thetumor inhibition rate of 69% was achieved within 20 days of MTD treatment,exhibiting complete tumor eradication within 30 days. The validationof antitumor response was marked by severe apoptosis (TUNEL, Caspase-3)in the Vk3@Si@CuZnIONPs + AMF-treated group. The higher expressionlevel of heat shock proteins and proinflammatory cytokines (IL-6,TNF-alpha, IL-1 alpha, IL-1 beta) was speculated to play a rolein the activation of immune response for faster tumor regression inthe MTD-treated group. Therefore, by implementing a dual ROS and heat-mediatedimmunogenic effect, the antitumor efficiency of future cancer magnetotherapieswill be greatly enhanced.