Handbook of Immunological Properties of Engineered Nanomaterials

The following sections are included:

• Preface
• Contents
• List of Contributors

Nanoparticle (NP) uptake by the mononuclear phagocytic system (MPS) has been described through several in vitro and in vivo studies, and is a field of research that is constantly evolving and continuing to grow. While many NP agents contain traditional small molecules that have been used therapeutically for decades, the unique delivery system of NPs allows for greater exposure and efficacy of the active chemical entity in the body. Once an NP enters the body, they encounter a much different host response than that observed with small molecule administration. The network of opsonins and circulating and tissue phagocytes is very complex, and their interaction with NPs often depends on the biological atmosphere as well as the physicochemical properties of the NP. Moreover, these factors, and MPS function in general, appear to be highly variable across animal models and in patients. This chapter will discuss NP uptake by the MPS and the resulting clinical manifestations. More specifically, key concepts will include differences in NP physicochemical properties, cell lines and/or animal models used, and the bidirectional interaction between the MPS and NPs in patients.

The ability of nanoparticles to evade the immune system, cross biological barriers, and localize at the target tissue ultimately determines their therapeutic potential. Leukocytes naturally encompass all of these features and, therefore, provide great inspiration in biomimetic vectors. Herein, we present a hybrid drug delivery system, termed leukolike vectors, composed of a synthetic nanoporous silicon core cloaked with cellular membranes derived from circulating white blood cells. These particles possess the ability to avoid clearance by the mononuclear phagocyte system, interact with endothelial cells through receptor–ligand interaction, and efficiently deliver a therapeutic payload to inflamed endothelia. Furthermore, in vivo studies revealed an ability to retain the leukocyte membrane's biological function following systemic administration, demonstrating prolonged circulation and improved tumor targeting abilities.

Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that induce the primary immune response and are responsible for the activation of T and B cells. The main function of DCs is to serve as a link between the innate and adaptive immunity. Understanding the role of DCs in controlling the immune system can provide powerful tools for the successful manipulation of immune cells to optimize vaccine delivery and to expand possibilities of immunotherapeutic approaches. Nanoparticle (NP) applications for targeted delivery of antigens to the DCs is a promising strategy for vaccine development. Herein, I present an overview of different NPs and approaches of their delivery to DCs, review the interaction between NPs and DCs, NP effects on the maturation, activation, and function of DCs, and outline future directions for NP-enhanced immune control to further foster the development of successful vaccination strategies and cancer immunotherapies.

This chapter reviews the observations made during the last decade in the area of nanoparticle effects on bone marrow cells such as nanoparticle biodistribution in the host including the bone marrow, nanoparticle-assisted imaging of the bone marrow, immunomodulatory effects, toxicity to bone marrow cells, and the use of nanoparticles for the radioprotection of the bone marrow. Depending on the nature of nanoparticles and their surface modifications, their biodistribution can be controlled to some extent, allowing the increase or decrease of their uptake into the bone marrow for the intended application. Magnetic resonance imaging with magnetic iron oxide nanoparticles has been gaining momentum with studies being conducted both in patients and animal models. Nanoparticles have proven to be useful in helping to induce the suppression or stimulation of the bone marrow as well as avoid the immunomodulatory effects of certain drugs altogether. The delivery of radioprotectors to the bone marrow by nanoparticles helps to enhance their radioprotective effect. Since the application of nanomaterials in biomedical research and medicine is a relatively new field, the most thorough evaluation of their potential toxicity, especially to the bone marrow, is paramount. While biodegradable nanoparticles in general lack bone marrow toxicity, metal and metal oxide nanoparticles vary in their effects on the bone marrow depending on the dose and route of administration, with TiO₂ particles having the highest cause for concern. Hence, research in this area should continue for any newly introduced nanomaterial.

Interest in nanoparticles and their use as vaccine carriers and adjuvants has greatly increased in recent times. However, despite current intense research in this field, the ways in which the immune system responds to nanoscale particulates are still being defined. This chapter will review the physical and chemical characteristics of nanoparticles 1–1000 nm in diameter, considering size, shape, surface charge and chemistry, and their effects on the immune system, including drainage to the lymph nodes (LNs), uptake by antigen-presenting cells (APCs) and the triggering of intracellular signalling pathways. We examine how particle size affects nanoparticle uptake by the key innate stimulators of the immune system, i.e., dendritic cells (DCs), and how nanoparticles modulate DCs and the induction of multiple arms of the immune response, including antibody production and CD4 and CD8 T cell responses via conventional and cross-priming pathways. We further discuss how inert nanoparticles, which by themselves may not necessarily promote the significant inflammation usually associated with adjuvants, can nevertheless induce powerful immunity, suggesting nanotechnology has outstanding potential to deliver safe synthetic vaccines against today's major diseases such as cancer and malaria. Biodegradable or biocompatible nanoparticles, such as polymeric particles, chitosan, polystyrene, gold/silver particles and magnetic/metallic particles, are discussed in relation to the induction of immune responses and vaccine formulations. An in-depth understanding of how nanoparticles physicochemically modulate the immune system supports the rational development of nanoparticle-based vaccines, as well as safe nanoparticulate drug delivery systems.

Although the adverse direct health effects of nanoparticles/materials have been proposed and are being clarified widely, their facilitating effects on preexisting pathological conditions have not been fully examined. In this review, I provide insights into the immunotoxicity of nanoparticles/materials as an aggravating factor in hypersusceptible subjects, especially those with immune-related respiratory disorders using our in vivo experimental model. I first exhibit the effects of nanoparticles/materials on lung inflammation induced by bacterial endotoxin (lipopolysaccharide: LPS) in vivo as a disease model in innate immunity, and demonstrated that nanoparticles instilled through both an intratracheal tube and an inhalation system can exacerbate the lung inflammation. Secondly, I introduce the effects of nanoparticles/materials on allergic asthma in vivo as a disease model in adaptive immunity, and showed that repetitive pulmonary exposure to nanoparticles has aggravating effects on allergic airway inflammation, including adjuvant effects on Th2-milieu. Taken together, nanoparticle/ material exposure may synergistically facilitate pathological inflammatory conditions via both innate and adaptive immunological abnormalities.

Nanoparticle interactions with various components of the immune system are determined by their physicochemical properties such as size, charge, hydrophobicity and shape. Nanoparticles can be engineered to either specifically target the immune system or to avoid immune recognition. Nevertheless, identifying their unintended impacts on the immune system and understanding the mechanisms of such accidental effects are essential for establishing a nanoparticle's safety profile. While immunostimulatory properties have been reviewed before, little attention in the literature has been given to immunosuppressive and anti-inflammatory properties. The purpose of this chapter is to fill this gap. We will discuss intended immunosuppression achieved by either nanoparticle engineering, or the use of nanoparticles to carry immunosuppressive or anti-inflammatory drugs. We will also review unintended immunosuppressive properties of nanoparticles per se and consider how such properties could be either beneficial or adverse.

The ever-exploding scientific advancements in the field of nanotechnology have enabled its integration into biosciences and medicine. Such interdisciplinary approaches allow researchers to engineer novel tools for diagnosis, therapy, and prognosis of different clinical complications. One of the most successful nano-tools that have emerged in recent years are nano-drug delivery devices. The use of such nano-sized carriers to load therapeutic agents (drugs, vaccines, biomolecules, and enzymes) aid in overcoming their pharmacological and toxicological hurdles through site-specific and controlled drug delivery. This chapter is a comprehensive account on the recent developments in the delivery of anti-inflammatory drugs using nanocarriers. Here, various kinds and types of nanocarriers and their countless inherent and engineered properties which make them ideal for delivering anti-inflammatory drugs, and the special characteristics of inflammation and inflammatory cells and tissues, which make them vulnerable to these nano-tools, will be discussed. The potential active and passive targeting approaches using drug-loaded nanocarriers for various inflammatory disorders are also elaborated.

The introduction of modern antiretroviral chemotherapy has significantly improved the morbidity and mortality associated with HIV infection. However, there are many factors that can contribute to the success of antiretroviral therapy including, but not limited to; patient adherence, genetic variability in drug disposition and pharmacokinetic pathways, the natural history of HIV itself, adverse drug reactions, and drug–drug interactions. Nanoformulation offers opportunities to overcome some of these limitations by simplifying dosing, improving pharmacokinetics and/or mitigating off-target toxicities through improving penetration of antiretrovirals into anatomical and cellular sanctuary sites. However, nanomaterials exhibit the potential to interact with the immune system raising the possibility of unwanted side effects. In the context of HIV-infected individuals, such side-effects may be influenced by dysregulation in the immune system as a consequence of the disease. The aim of this chapter is to provide an overview of current progress in nanotechnology-enabled drug delivery in HIV. Current knowledge of the impact of HIV-infection on the immune system is also summarized, in the context of how this may be expected to influence known immunological safety concerns with specific nanotechnologies.

Nanostructures can interact with biological systems, e.g., the immune system, inducing a response to these foreign elements in different ways, including the induction of phagocytosis and activation or inhibition of the immune cells. However, it can also respond by triggering hypersensitivity or allergy reactions. The process of allergy to nanostructures is still relatively unknown, but the process of pseudoallergy (which involves complement activation and inflammatory responses) is the one most described. This chapter summarizes the types of hypersensitivity reactions, the most frequent symptoms, several examples of allergy induced by nanomaterials, and the most common methods of diagnosis.

The immune system is highly versatile at recognizing foreign substances and mounting a multi-stage response against them. Antigenicity is a subtype of the immunogenic response characterized by the formation of an antibody specific to the given type of foreign substance, called an antigen. Due to their small size, nanoparticles are not antigenic themselves. However, some of them act as haptens and become antigenic when conjugated to a protein carrier. Antibodies against several types of engineered nanomaterials have been produced by the conjugation of the nanomaterial to a protein carrier and immunization in the presence of strong adjuvants. Conversely, engineered nanomaterials not conjugated to a protein, and those specifically designed to carry therapeutics proteins, were shown to be non-antigenic and moreover, helped to reduce the antigenicity of therapeutic proteins attached to them. However, accidental non-engineered nanomaterials which contaminate clinical formulations of therapeutic proteins are believed to contribute to their antigenicity. This chapter will review the scientific literature regarding the antigenic response to engineered nanomaterials, describe nanoparticle physicochemical properties contributing to antigenicity, with focus on the role of nanoparticle surface coating in antibody generation, and discuss the role of accidental nanoparticles in the antigenicity of therapeutic proteins.

Combinatorial use of iron oxide nanoparticles (IONPs) and an alternating magnetic field (AMF) can induce local hyperthermia in tumors in a controlled and uniform manner. Heating B16 primary tumors at 43°C for 30 min activated dendritic cells (DCs) and subsequently CD8⁺ T cells in the draining lymph node (dLN) and conferred resistance against rechallenge with B16 (but not unrelated Lewis Lung carcinoma) given seven days post hyperthermia on both the primary tumor side and the contralateral side in a CD8⁺ T cell-dependent manner. Mice with heated primary tumors also resisted rechallenge given 30 days post hyperthermia. Mice with larger heated primary tumors had greater resistance to secondary tumors. No rechallenge resistance occurred when tumors were heated at 45°C. Our results demonstrate the promising potential of local hyperthermia treatment applied to identify tumors in inducing anti-tumor immune responses that reduce the risk of recurrence and metastasis.

The following sections is included:

• Index