Mechanisms of immune response to inorganic nanoparticles and their degradation products
Graphical abstract
Introduction
The immune response is the reaction of the host to foreign substances which is regulated by the cells and molecules of the immune system. The act of the immune system is to eliminate unwanted foreign substances from the body and to maintain homeostasis [1]. >400 million years of evolution has resulted in the immune system to develop into the highly complex and adaptable defense mechanism that it is today [2]. There continues to be a need to modulate the immune system for better diagnostic or therapeutic outcomes. This modulation can be on activation of the immune system against new infections, or suppression of it to prepare the body to receive therapeutic interventions. Nanoparticles are one class of carriers for therapeutic agents. They can also act intrinsically as therapeutics or imaging systems. Understanding the in vitro and in vivo fate of nanoparticles and their related immunotoxicity is crucial to inform their choice for therapeutic and diagnostic applications.
The potential of inorganic nanoparticles in biomedical applications in general, and drug delivery in specific, is widely acknowledged [3], [4], [5], [6]. Inorganic nanoparticles ranging in size from 1 to 1000 nm can contain metals, metal oxides, metal alloys, and semiconductors [7], [8]. Some examples of inorganic nanoparticles include gold, iron oxide, silver, zinc oxide, silica and silicon dioxide, and titanium dioxide nanoparticles, as well as quantum dots [9]. Due to their unique physical, electronical, and optical properties, in many cases well-established synthetic methods, the ability to tune physicochemical properties, ease of scale-up, often low cost, and superparamagnetic and exhibition of quantum confinement effects, inorganic nanoparticles show promise in many biomedical applications. These include, but are not limited to, drug and gene delivery, as antibacterial agents, in cell and tissue imaging and labeling, and as diagnostics and/or theranostics [6], [10], [11]. Despite the fact that these particles have been investigated for decades, few of them have advanced to clinical applications in drug delivery. This is in contrast to some of the organic nanoparticles such as polymeric- or lipid-based systems where systematic evaluation of their biological fate has informed their translation to clinical use.
The relation between nanoparticles and immune cells is highly dynamic. The detailed life cycle of nanoparticles inside the immune cells and the cell reaction to them are still poorly understood. Administration of inorganic nanoparticles into the body, as a foreign substance, activates the host immune response which may lead to desirable (e.g., activation of the immune response as a vaccine adjuvant) or undesirable (e.g., autoimmunity or allergic reaction) immune reactions [12]. The interaction of inorganic nanoparticles with the immune system and the alteration of normal immune function raises concerns about the safety of these materials. Such interaction can result from the intact nanoparticles, as well as their degradation and dissolution products. Once administered, the physicochemical properties of nanoparticles start to change. They may interact with proteins and macromolecules, aggregate or agglomerate, and potentially biodegrade and dissolve. The biological milieu will then encounter different particulate products than the original nanoparticle formulation, with different physical and chemical properties than the parent particles. This change will pose simple and very important questions: What would happen when the immune system encounters these modified products? What would be the fate and function of the immune cells and the ensuing molecular events in response to these modified inorganic nanoparticles and their degradation or dissolution products? Finding the answers to these questions is instrumental for the design of safe and effective inorganic nanoparticles with minimal immunotoxicity.
Extensive research has been conducted to study the interaction of inorganic nanoparticles with the immune system. In the present review, we aim to provide a summary of the key cellular mechanisms of immune responses observed to various inorganic nanoparticles with focus on delivery applications. We describe the degradation profile of selected inorganic nanoparticles and the current knowledge regarding their fate in vitro and in vivo. The importance of the understanding of immunological properties of these nanoparticles and their degradation products, and the different factors that influence their immune response will be discussed. We then discuss the challenges, critical gaps, and future directions for better understanding of the immunological properties of inorganic nanoparticles and their degradation products.
Section snippets
Immunogenicity of inorganic nanoparticles and cellular mechanisms of their immune response
The ability of nanoparticles serving as immunogen to stimulate the immune response in particular species is called immunogenicity [12]. The immunogenicity of nanoparticles depends on their physicochemical properties and the genetic capacity of the host defense [13], [14]. Numerous reports have reviewed the immunogenicity of gold [15], silica [16], silver [17], [18], [19], titanium dioxide [20], zinc oxide [21], and iron oxide nanoparticles [22]. Altogether, these reports have demonstrated that
Clinical application of inorganic nanoparticles and their immunotoxicity
Inorganic nanoparticles have been used for different applications in the clinic. Gold, iron oxide, and silica nanoparticles received the U.S. Food and Drug Administration (FDA) approval for thermal ablation of tumors, chronic kidney disease, cancer imaging, imaging probe for magnetic resonance imaging (MRI) and computed tomography (CT), and for treatment of anemia [10], [147], [148]. For example, Ferumoxytol has been approved by the FDA as a contrast agent for gastrointestinal imaging upon oral
Degradation mechanisms of inorganic nanoparticles
Much research has been done about the degradation and dissolution of various inorganic nanoparticles. Different terminologies are used to describe the inorganic nanoparticles’ susceptibility to degradation, disintegration, and dissolution including bio-persistent, durable, stable, labile, nondegradable or degradable. Inorganic nanoparticles can degrade into smaller fragments, or to their precursors, e.g., metal ions or metal oxides in air, in solution, in vitro, or in vivo. Here, we first
The influence of degradation products on the immune system
The degradation and dissolution of silver, iron, zinc oxide nanoparticles, and quantum dots, as well as their biological fate have been reviewed [162], [184]. The released metal ions from the etched nanoparticles may be toxic even at low concentrations (e.g. Ag+, Au+, and Cd+), or may participate in different cellular pathways (e.g. Zn+2, Fe+2), or induce ROS and changes in metal homeostasis of the cells [162]. For example, the released ions from metal nanoparticles, trapped inside endosomes or
Fate of inorganic nanoparticles inside the immune cells
Low degradation rate of many inorganic nanoparticles, along with their rapid clearance by the reticuloendothelial system (RES) continues to pose a major problem for use of these systems in delivery applications. For example it has been reported that a very low percentage of intravenously injected nanoparticles reach the target solid tumors [189], [190]. This limitation coupled with a low loading capacity of many of inorganic nanoparticles may result in a high dose or frequency of administration
Conclusion, challenges, and future directions
In summary, various cellular mechanisms are involved in immune responses to inorganic nanoparticles. These responses may be to the intact nanoparticles, and/or to their degradation fragments and dissolution products. The degradation products of inorganic nanoparticles may be a biologically relevant compound which cells already have (such as iron), or it might be a non-relevant compound (such as degradation fragments). The biologically relevant compound might be involved in the existing cellular
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
Financial support was provided by the National Institute of Environmental Health Sciences of the NIH (R01ES024681) and the ALSAM Foundation. We would like to acknowledge Dr. Marina A. Dobrovolskaia from NCI Nano Characterization Laboratory for her valuable suggestions for this manuscript. Biorender.com (Toronto, Ontario) tool was used to create the graphical abstract and Fig. 1.
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