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