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Immunological effects of iron oxide nanoparticles and iron-based complex drug formulations: Therapeutic benefits, toxicity, mechanistic insights, and translational considerations.
Shah, A, Dobrovolskaia, MA
Nanomedicine : nanotechnology, biology, and medicine. 2018;(3):977-990
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Abstract
Nanotechnology offers several advantages for drug delivery. However, there is the need for addressing potential safety concerns regarding the adverse health effects of these unique materials. Some such effects may occur due to undesirable interactions between nanoparticles and the immune system, and they may include hypersensitivity reactions, immunosuppression, and immunostimulation. While strategies, models, and approaches for studying the immunological safety of various engineered nanoparticles, including metal oxides, have been covered in the current literature, little attention has been given to the interactions between iron oxide-based nanomaterials and various components of the immune system. Here we provide a comprehensive review of studies investigating the effects of iron oxides and iron-based nanoparticles on various types of immune cells, highlight current gaps in the understanding of the structure-activity relationships of these materials, and propose a framework for capturing their immunotoxicity to streamline comparative studies between various types of iron-based formulations.
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Feraheme® suppresses immune function of human T lymphocytes through mitochondrial damage and mitoROS production.
Shah, A, Mankus, CI, Vermilya, AM, Soheilian, F, Clogston, JD, Dobrovolskaia, MA
Toxicology and applied pharmacology. 2018;:52-63
Abstract
Despite attractive properties for both therapeutic and diagnostic applications, the clinical use of iron oxide nanoparticles (IONPs) is limited to iron replacement in severely anemic patient populations. While several studies have reported about the immunotoxicity of IONPs, the mechanisms of this toxicity are mostly unknown. We conducted a mechanistic investigation using an injectable form of IONP, Feraheme®. In the cultures of primary human T cells, Feraheme induced miotochondrial oxidative stress and resulted in changes in mitochondrial dynamics, architecture, and membrane potential. These molecular events were responsible for the decrease in cytokine production and proliferation of mitogen-activated T cells. The induction of mitoROS by T cells in response to Feraheme was insufficient to induce total redox imbalance at the cellular level. Consequently, we resolved this toxicity by the addition of the mitochondria-specific antioxidant MitoTEMPO. We further used these findings to develop an experimental framework consisting of critical assays that can be used to estimate IONP immunotoxicity. We explored this framework using several immortalized T-cell lines and found that none of them recapitulate the toxicity observed in the primary cells. Next, we compared the immunotoxicity of Feraheme to that of other FDA-approved iron-containing complex drug formulations and found that the mitochondrial damage and the resulting suppression of T-cell function are specific to Feraheme. The framework, therefore, can be used for comparing the immunotoxicity of Feraheme with that of its generic versions, while other iron-based complex drugs require case-specific mechanistic investigation.