Immunological effects of iron oxide nanoparticles and iron-based complex drug formulations: Therapeutic benefits, toxicity, mechanistic insights, and translational considerations

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.

Keywords: Drug delivery; Imaging; Immunotherapy; Immunotoxicity; Nanoparticles.

Figure 1. Strategy for developing an experimental framework to assess the immunotoxicity of IONPs

This strategy starts with focusing on a specific formulation (e.g., Feraheme). The clinical experience is examined either to identify the immunological problem that was not detected during preclinical studies or to confirm the findings of preclinical studies. In vivo nonclinical data is used to identify the problem. However, in the cases when standard toxicology studies fail to detect the immunotoxicity and it is later experienced in the clinical setting, additional functional in vivo nonclinical studies are used to reproduce the immunotoxicity relevant to the patient population. In vitro experiments are then conducted to examine the toxicity; understand the molecular and cellular mechanism(s); and identify target cells and affected pathways to select biomarkers. This can be monitored in the future batches of the same material, or to compare the brand product with a generic counterpart. Additional in vitro work can be done to select the appropriate model (e.g., to decide whether to proceed with primary cells or use a particular cell line). This information is used to compile a network of bioassays that accurately, consistently, and reproducibly identify selected biomarkers in relevant cell models. The framework is applied for comparing brand and generic formulations, and it can also be implemented for other particles from the same family. The immunotoxicity may be unique to the given formulation; in such a case, the framework can only be used for comparison between batches or between the brand and generic versions of the particular nanomaterial. If, however, the immunotoxicity is shared by an entire class of iron oxides, the framework becomes applicable to screen for a broader range of IONPs. The information generated in this research should be used to design safer IONPs.