Cellular Organelle-Dependent Cytotoxicity of Iron Oxide Nanoparticles and Its Implications for Cancer Diagnosis and Treatment: A Mechanistic Investigation

Iron oxide nanoparticles (IONPs) have been widely used in the diagnosis and treatment of cancer; however, analysis of the relevant literature yields contradictory results concerning their toxicity. In this work, a bubble-generating liposomal system that can be thermally triggered to liberate its loaded IONPs instantly and precisely in defined cellular organelles is utilized to elucidate the mechanism that is responsible for the contradictory observations concerning IONP toxicity. As-prepared liposomes are internalized by test cells via endocytosis, and these internalized particles follow the endocytotic pathway from the endosomes to the lysosomes. The degradation of IONPs and the consequent release of iron ions depend strongly on the pH of the environment in the cellular organelles from which they are liberated, to which they are exposed, during their intracellular transportation. Higher IONP toxicity is associated with stronger in situ degradation with the release of more iron ions, and the consequent generation of more reactive oxygen species (ROS) within cells. When the amount of ROS formed exceeds what can be scavenged by the intracellular antioxidant systems, the cells experience oxidative stress, which is responsible for the observed cellular organelle-dependent toxicity profiles. Understanding the mechanism that underlies the toxicity of IONPs is critical for designing IONP nanosystems that have a wide range of clinical applications.