2. How nanostructures can improve the treatment approaches
Nanomaterials can interact directly with the immune system triggering
immune responses, consequently they have been considered as potential
adjuvants.97 Their functionalisation with ligands
produces a particular effect in a more controlled way. NPs have been
considered as adequate platforms to conjugate ligands that can tune the
physico-chemical properties of these nanostructures, but also to
facilitate the interaction with target cells for a selective drug
delivery. In addition, they can encapsulate allergens to be delivered
selectively in cells of the immune system.131
CpG oligodeoxynucleotides (CpG-ODNs), a conserved sequence present in
bacteria and viruses, are recognised by TLR9 receptors, inducing a Th1
response. CpG-ODNs have been used as potent and efficient adjuvants in
allergic models. Mesoporous silica NPs, boron nitride particles, AuNPs,
liposomes, CNTs, polymers, among other platforms have been extensively
used to deliver CpG-ODNs into cells. The NPs not only prevent the
degradation of the ODNs but also increase the cell uptake, facilitating
the internalisation, and inducing the enhancement of the
immunostimulation, and the release of pro-inflammatory
cytokines.132
NPs have been also used for topical administration of drugs such as
betamethasone, hydrocortisone, hydroxytyrosol, tacrolimus,
anti-histamine drugs, etc. with the aim to treat atopic dermatitis. NPs
improve the solubility of these drugs, their stability against
degradation and facilitate the skin penetration capabilities, reducing
side-effects.133
The use of nanomaterials has been also extensively applied to the
treatment of asthma.134 Different types, as PAMAM and
Polyethyleneimine dendrimers, polyethylenglycol (PEG) NPs, and liposomes
have been used as carriers of CpG, DNA plasmids, beclomethasone
dipropionate, dexamethasone, salbutamol, etc.
NPs based on chitosane, poly(D,L-lactic-co-glycolic) acid (PLGA),
ceramic, plygammaglutamic acid, etc. have been used as mucosa adjuvants
encapsulating antigens for oral vaccination. The properties of the
polymers are fundamental for an adequate allergen release. PEG
functionalisation can retain the NPs in the mucosa, reducing the
treatment dose. Microbial adhesins functionalisation enhances NPs
bioadhesive properties to colonise the gut.135Besides, a water soluble self-assembled micellar formulation, using
PEG400, propylene glycerol and ethanol, has been used to encapsulate
Cannflavin A, a flavone derivative with anti-inflammatory activity and
poorly soluble in water. This composition was tested in an experimental
asthma/chronic obstructive pulmonary disease in rats enhancing the
anti-inflammatory effects in vivo .136
Protein-cage NPs using ferritin of 12 nm of diameter have been
functionalised on their surface with 24 units of a small peptide (AP-1),
a ligand for the receptor IL-R4 which abolishes the IgE response and has
been tested in a murine model of allergic asthma. The treatment clearly
decreased the severity of the symptoms.137
NPs combined with allergens have been applied for treating allergy. PLGA
nanospheres particles loaded with Bet v 1, the major allergen of birch
pollen, prevent the production of IgE and modify the Th2 response
producing IFN-γ and IL-10.138 This can be considered
the first example of that an allergen entrapped in PLGA polymer for
allergy treatment reduces the predominance of the Th2
response.92 Poly(anhydride) NPs containing cashew nut
proteins can induce a strong Th1 and Treg immune response after oral
administration.92,139 This can be considered the first
example of how an allergen entrapped in PLGA polymer for allergy
treatment reduces the predominance of the Th2 response.
As result of the previous research 87,90, the first
peanut oral immunotherapy clinical trial has started. It is a
multicentre, double-blind, randomised, placebo-controlled phase I/II
study (ClinicalTrials.gov Identifier: NCT04163562).
A copolymer based on poly(hydroxyethyl)aspartamide (PHEA) functionalised
in the side chains with butyryl and succinyl moieties has been used to
form nanoaggregates of 90 nm of diameter with the allergen lipid
transfer protein Par j 1 and 2 (from Parietaria judaica
pollen).140
After that, several examples demonstrate the use of NPs for allergy
treatment in animal models. PLGA NPs have been used to load rChe a 3
(the most abundant allergen in Chenopodium album pollen) with the aim to
modulate a Th2 immune responses by sublingual immunotherapy in a mouse
model of allergic rhinitis.141 The Polyethyleneimine
polymer loaded with Bet v 1 plasmid has demonstrated to induce a
reduction of IgE and an increase of Th1 response in mice against birch
pollen.142 Der f 1 plasmid complexed with a copolymer
of propylene oxide and ethylene oxide has been used to reduce
inflammation in asthmatic mice.143 Ara h 2 (peanut
allergen) together with the adjuvant CpG was combined with protamine
(arginine rich protein) NPs to induce a Th1
response.144 Natural polysaccharides have also been
used as adjuvant together with allergens to decrease allergic responses.
Alginate, extracted from algae, in combination with grass pollen
extracts, induces a reduction of IgE in mice.145Studies using chitin as adjuvant produce a reduction of IgE and Th2
cytokines in allergic mice.146 Many other examples
using biodegradable and non-biodegradable NPs have been revised
recently,31 indicating that these platforms provide
interesting approaches for the treatment of allergy.
Dendrosomes (hyperbranched dendritic spheroidal particles) have been
used as adjuvants with plasmid for Bet v 1 in DNA vaccination in birch
pollen allergy. In mice, footpath administration of these dendrosomes
produces the inhibition of the allergic reaction, inhibiting the
production of IgE, and maintaining the Th1/Th2
balance.142
Small CdSe/ZnS core/shell QDs NPs with a negative surface (using
glutathione) show immunosuppressive effects when tested in skin allergy
and used topically in combination with the allergen
1-fluoro-2,4-dinitrobenzene. The NPs penetrate the skin, facilitating
their effect.147
Besides NPs, dendrimers have also been used to treat allergic diseases
(Figure 3). Glycodendrimers containing mannoses (Table 1) have been
conjugated with a peptide corresponding with a T-cell epitope of the
major allergen of olive tree pollen (Ole e 1). This compound has
demonstrated to induce Treg proliferation in vitro , in particular
in cells from allergic donors.148 The same
glycodendrimer conjugated with an epitope for the Pru p 3 lipid transfer
protein induces long-term tolerance in a peach anaphylactic mice model
when administered sublingually.149 These promising
results indicate that glycodendrimers can be considered as promising
adjuvants to be applied in allergy.