Altering the response of intracellular reactive oxygen to magnetic nanoparticles using ultrasound and microbubbles

Abstract

Engineered iron oxide magnetic nanoparticles (MNPs) are one of the most promising tools in nanomedicine-based diagnostics and therapy. However, increasing evidence suggests that their specific delivery efficiency and potential long-term cytotoxicity remain a great concern. In this study, using 12 nm γ-Fe2O3 MNPs, we investigated three types of uptake pathways for MNPs into HepG2 cells: (1) a conventional incubation endocytic pathway; (2) MNPs co-administrated with microbubbles under ultrasound exposure; and (3) ultrasound delivery of MNPs covalently coated on the surface of microbubbles. The delivery efficiency and intracellular distribution of MNPs were evaluated, and the cytotoxicity induced by reactive oxygen species (ROS) was studied in detail. The results show that MNPs can be delivered into the lysosomes via classical incubation endocytic internalization; however, microbubbles and ultrasound allow the MNPs to pass through the cell membrane and enter the cytosol via a non-internalizing uptake route much more evenly and efficiently. Further, these different delivery routes result in different ROS levels and antioxidant capacities, as well as intracellular glutathione peroxidase activity for HepG2 cells. Our data indicate that the microbubble–ultrasound treatment method can serve as an efficient cytosolic delivery strategy to minimize long-term cytotoxicity of MNPs.