Adverse effects of nanoparticles. Promoters of allergic diseases

The existence of numerous applications of different nanomaterials in biomedicine has arisen the need of evaluating the possible adverse effects, either toxicity or hypersensitivity responses.
One of the main concerns about nanostructures is their toxicity, which made nanotoxicology discipline emerge.72 In general, physico-chemical properties including size, surface charge or area, solubility, morphology or reactivity, redox-active properties, and aggregation capacity will contribute to the toxicity of the compounds.73,74In vitro studies have shown a correlation between lower size and higher toxicity, probably because small nanostructures are better uptaken by cells.75 Nanostructures can also generate reactive oxygen species and oxidative stress inducing DNA damage or apoptosis, as observed in keratinocytes, fibroblasts, and macrophages.76 The route of administration can also affect their toxicity, being it higher intravenously administered, since body distribution increases. Nevertheless, although there are no definitive rules, toxicity can be modified by changing nanostructures properties as reducing surface charges or including low cytotoxic groups such as zwitterionic segments.77
Nanostructures can be recognised as foreign compounds by immune cells inducing dual effects as an allergen or sensitiser, or as booster or adjuvants even acting as immunomodulators.78,79 The mechanism by which nanomaterials can immunomodulate is related to their ability to interact with antigen presenting cells (APCs) as dendritic cells (DCs), modifying their activation and maturation, and thereby leading to T-lymphocytes activation.78 The physico-chemical properties of NPs have demonstrated to strongly affect DCs responses.80Small nanomaterials (<200nm) favour the uptake and migration of DCs and macrophages towards draining lymph nodes,81,82 improving the induction of immune response. Moreover, the type of response, Th1 or Th2 could depend on the nanostructure redox potential, with oxidant titanium dioxide NPs (TiO2NPs)83 inducing a Th1 response, whereas antioxidant cerium oxide NPs inducing a Th2 phenotype with IL-10 production.84
Nanomaterials have been developed to interact with DCs through C-type lectins and Toll-like receptors (TLRs) for modulating immune responses.85 Different nanostructures have been applied as vaccines in cancer and viral and bacterial infections, etc.86 In allergy, the application of nanotechnology is especially interesting for immunotherapy since NPs can present a dual action, being an adjuvant and protecting allergen from degradation.31,87 At the same time, they could be used as co-delivering immunostimulatory agents. In this sense, dendrimers, functionalised with sugars (glycodendrimers) have been used for targeting DCs through the DC-SIGN or mannose receptors88 influencing the internalisation process and presentation through major histocompatibility complexes to T-cells. This has been applied to develop compounds than can be used in Flu viral infection immunotherapy89 and as adjuvants to treat allergic diseases. In fact, NPs have shown efficacy in oral immunotherapy for FA.90-92 See structures in Table 1.
Nanostructures can be internalised in cells by phagocytosis, macropinocytosis, as well as clathrin-, caveolae-, and scavenger receptor-mediated endocytosis, which will deeply depend on nanomaterial properties, again dependent on the NP size.93 Several studies support evidences of active mechanisms such as endocytosis, with NPs present in both endosomes and lysosomes of DCs.80,93 The functionalisation with multivalent mannose ligands that interact with C-lectin receptors can facilitate the internalisation on DCs and major histocompatibility complexes class presentation to T-cells inducing preferentially a Th1 response.89,93 Other chemical groups decorating the NPs have also showed to impact the modulation: oxidised or hydrocarbonised porous silicon induce immunoactivation, whereas zwitterionic-stabilised gold nanoclusters strongly immunosuppress the response.94

Allergic responses.

Nanomaterials can produce adverse effects on respiratory systems, producing asthma exacerbation and also altering the response to allergens.78 Moreover, they can enhance the sensitisation to an allergen by a depot capacity that increases the local antigen level, persistence, and prolonged release as demonstrated with TiO2NPs.95 This effect has been observed even though the allergen–nanomaterial compounds do not penetrate the epidermis.96
CNTs, TiO2NPs, gold (AuNPs), silver (AgNPs), silica (SiNPs), and zinc oxide (ZnONPs) NPs have demonstrated exacerbation of Th2 allergic models.97 The pulmonary exposure to NPs can induce the lung expression of inflammatory mediators, TARC, MIP-1a, GM-CSF even in the absence of allergen, although with an increase of this effect in its presence.98,99 Although these results suggest that small NPs could potentiate allergic lung inflammation,100 others indicate that they can attenuate these responses,101,102 indicating the complexity of the NPs interaction with the immune system and the need for further research.
In general, nanomaterials can induce hypersensitivity reactions by interacting with both innate and adaptive immune systems at different levels: antigen presenting cells, mainly DCs affecting their antigen processing and presentation to T-cells inducing effector cells, as mast cells, basophils, and eosinophils; or complement system activation and pattern recognition receptors and/or release of alarmin molecules producing inflammasome activation.97
Metal-based nanomaterials can present an additional concern in allergy because they include metals known to cause allergic contact dermatitis, asthma, and allergy adjuvancy.72,96TiO2NP and ZnONP have been extensively incorporated in sunscreens and cosmetics for their ultraviolet radiation protective effects, AgNP due to their antimicrobial properties, and SiNP in cosmetics and to alter the properties of other materials. For these extensive uses and their potential capacity to penetrate the skin, they could induce sensitisation.72 Small size has shown to cause greater inflammatory response mainly because they can deeply penetrate the tissues and have a larger surface area.96,98 In cases of skin barrier dysfunction, TiO2NP can exacerbate atopic dermatitis symptoms103 and polystyrene NPs are able to stimulate skin inflammation even without the allergen by overexpressing CC-chemokines.103
Pseudoallergy or idiosyncratic reactions that are non-IgE-mediated hypersensitivity have been associated to a wide range of NPs such as AuNPs, AgNPs, copper oxide, SiO2NPs, TiO2NPs, and CNT.97 One possible mechanism could be the complement activation leading to anaphylatoxin (C5a and C3a) secretion and subsequent activation of mast cells, basophils, and possibly other inflammatory cells in blood.104,105 Moreover some reports demonstrated that NPs activate the NLRP3 inflammasome,106 which is one of the pattern recognition receptors expressed intracellularly promoting IL-1𝛽 and IL-18 production.107
Besides the immunological mechanisms described above, NPs can also produce allergy and asthma by damaging the epithelial barriers (pulmonary and intestinal mucosa, skin, etc.), inducing not only an innate immune response but also promoting the entrance of allergenic proteins.97,108
The identification of possible side effects should be done to assess the safety and efficacy of these nanomaterials before product commercialisation. These effects cannot be generalised, since the immune effects are highly dependent on the physico-chemical structure and properties of each type of nanomaterial and, even with the same material, on the administration conditions. Thus their potential risks should be identified in each particular case by preclinical studies.109,110