Multifunctional l-arginine-based magnetic nanoparticles for multiple-synergistic tumor therapy

Tumor therapy is facing the big challenge of insufficient treatment. Here, we report high-intensity focused ultrasound (HIFU)-responsive magnetic nanoparticles based on superparamagnetic iron oxide (SPIO, Fe₃O₄ NPs) as the shell and l-arginine (LA) as the core entrapped by poly-lactide-co-glycolide (PLGA) nanoparticles (Fe₃O₄@PLGA/LA NPs) for synergistic breast cancer therapy. These NPs can significantly enhance therapeutic performance due to their enhanced accumulation and prolonged retention at the tumor site under magnetic guidance. The Fe₃O₄@PLGA/LA NPs exhibited synergistic therapeutic effects by the rational combination of HIFU-based tumor ablation and nitric oxide (NO) assisted antitumor gas therapy. Both Fe₃O₄ NPs and LA could be released rapidly under HIFU irradiation, where Fe₃O₄ NPs can promote HIFU-based tumor ablation by changing the acoustic properties of the tumor tissues and LA can spontaneously react with hydrogen peroxide (H₂O₂) in the tumor microenvironment to generate NO for gas therapy. Moreover, Fe₃O₄ NPs can react with H₂O₂ to produce highly reactive oxygen-containing species (ROS) to accelerate the oxidation of LA and the release of NO. This novel strategy showed synergistic tumor growth suppression as compared with individual HIFU therapy or gas therapy. This can be attributed to the rational design of multifunctional NPs with magnetic targeting and multi-modality imaging properties.