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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. [ABSTRACT FROM AUTHOR]

In the absence of adequate oxygen, cancer cells that are grown in hypoxic solid tumors resist treatment using antitumor drugs (such as doxorubicin, DOX), owing to their attenuated intracellular production of reactive oxygen species (ROS). Hyperbaric oxygen (HBO) therapy favorably improves oxygen transport to the hypoxic tumor tissues, thereby increasing the sensitivity of tumor cells to DOX. However, the use of HBO with DOX potentiates the ROS-mediated cytotoxicity of the drug toward normal tissues. In this work, we hypothesize that regional oxygen treatment by an implanted oxygen-generating depot may enhance the cytotoxicity of DOX against malignant tissues in a highly site-specific manner, without raising systemic oxygen levels. Upon implantation close to the tumor, the oxygen-generating depot reacts with the interstitial medium to produce oxygen in situ, effectively shrinking the hypoxic regions in the tumor tissues. Increasing the local availability of oxygen causes the cytotoxicity of DOX that is accumulated in the tumors to be significantly enhanced by the elevated production of ROS, ultimately allaying the hypoxia-induced DOX resistance in solid malignancies. Importantly, this enhancement of cytotoxicity is limited to the site of the tumors, and this feature of the system that is proposed herein is unique. [ABSTRACT FROM AUTHOR]