Professor Neill Liptrott BSc (Hons), MSc, PhD, FHEA, FRSB

Nanomaterial behaviour has been demonstrated to differ considerably from that of larger bulk materials. The production and use of engineered nanomaterials is constantly expanding, but there remain uncertainties surrounding the potential risks posed to human health and the environment. The size of nanomaterials influences their toxicity, and this has been consistently demonstrated for nanomaterials encountered in workplace environments (e.g. carbon black, polystyrene, titanium dioxide, and silver). Nanomaterials vary considerably with respect to their composition, charge, surface area, solubility, crystal structure, surface chemistry, and shape.

Many nanomaterials have been shown to interact with the immune system by either stimulating or suppressing various responses through their interaction with proteins found within the blood. Many nanomaterials interact with serum proteins such as opsonins (e.g. antibodies, complement) and are rapidly taken up into cells of the mononuclear phagocyte system (e.g. macrophages). Interactions with serum proteins may render nanomaterials antigenic and it has been suggested that functionalisation (e.g., with growth factors or receptors) may induce neutralising antibodies that also recognise the body’s own molecules, with implications similar to those for biotechnology-derived therapeutics. We are utilising a number of approaches to understand how nanomaterials interact with biological systems. Identification of these mechanisms may allow rational design of future materials and reduction of unwanted effects, particularly how complex systems can interact, to bring about clinical events, and how inflammation is key to the definition of Adverse Outcome Pathways (AOP)

Interaction of nanomaterials with the human immunological & haematological systems, pathways of cellular uptake of nanoparticles (both receptor and non-receptor mediated), nanotoxicity of nanomaterials, and interaction of nanoparticles with plasma proteins (biomolecular corona). immune modulation, hypersensitivity, and pseudo-allergies related to advanced materials such as liposomes and lipidic nanoparticles, liposomes, polymeric materials, inorganic nanoparticles, virosomes and exosomes, and nanobiomaterials.

Keywords: advanced therapies and therapeutics, liposomes, lipidic nanoparticles (LNP), CARPA, pseudoallergy, hypersensitivity, complex medicines, extracellular vesicles, nanomedicines, nanotherapeutics, biocompatibility, immunology, immunotoxicology, intracellular drug delivery (ICD)

Sub-project;

- Development of techniques and technologies for the characterisation of nanomaterials.
The field of nanoimmunotoxicology is constantly evolving as new materials are developed. In order to meet these challenges it is necessary to ensure that current techniques and methodologies are sufficient to identify nanomaterial interactions with biological systems that may be undesirable. New characterisation techniques are studied for their utility and introduced into our assay cascade as appropriate. Interaction with agencies such as EMA and FDA are also key in order to stay ahead of what is required from a regulatory perspective.

Dysregulation of the immune system is a hallmark of a number of diseases, such as HIV. The mechanisms by which the immune system can influence drug disposition are relatively understudied, but recent work has highlighted the necessity of examining its impact on pharmacokinetics and pharmacodynamics. A more comprehensive approach in clinical studies will allow better determination of the impact of cytokines on drug disposition. In addition, determining the mechanisms that underpin the differential effects of cytokines across different cell types will clarify the responses reported in these studies. This in turn relates to the biocompatibility of nanomaterials in patients with dysregulated immune systems as in HIV infection, specifically when comparing the response of uninfected vs infected cells.

Cytokines etc. are integral to the successful resolution of many diseases. Data are emerging on a role for regulation of the expression and activity of drug transporters and drug metabolising enzymes.. Investigation of the interaction between pharmacological and immunological responses is key to understanding the complex relationships involved in patient responses to therapy as well as how they may respond to nanoformulated therapies.

Keywords: immune response, drug disposition, human immune cells

Activation of immune cells results in alteration of energy and nutrient requirements in order to provide sufficient energy resources for the cells and biomass for replication and protein synthesis. Upon activation, immune cells increase their uptake of glucose in order to power cellular processes by glycolysis. Glucose uptake is, primarily, accomplished by the glucose uptake transporters GLUT1 and GLUT4. We have shown that the antiretroviral drugs Efavirenz and Lopinavir can inhibit the activation of primary immune cells (T cells and monocyte-derivd macrophages); nanoformulations of these drugs appear to mitigate some of these processes. Work from the group has demonstrated that Efavirenz and Lopinavir can inhibit glucose uptake, altering bioenergetic profiles in immune cells.. We are determining the activity of metabolite transporters in the metabolic responses to immunological challenges and assessing the long-term implications of exposure to xenobiotics on metabolic profiles.

Additionally, other factors within the local environment may influence immune cell behaviour. Exosomes are nano-sized, extracellular vesicles that are involved in intercellular communication and are generally thought to be involved in immune homeostasis. Their presence in, multiple, biological fluids suggests their importance in controlling the immune response. We have shown that the presence of so-called “tolerosomes” in the plasma may dampen the immunological response of human immune cells to pro-inflammatory stimuli. The aim of this work is to ascertain further the impact of tolerosomes on immunological responses to stimuli, as well as engineered nanobiomaterials, to further our understanding of interindividual responses to treatments.

Keywords: immune metabolism, microenvironment, transporters