Immune Repertoire and Advancements in Nanotherapeutics for the Impediment of Severe Steroid Resistant Asthma (SSR)

Figures & data

Figure 1 The pathophysiology of asthma and the SSR asthma: Altered genomic mechanisms induced by the repeated intake of glucocorticoids in asthma conditions: Dissociation of glucocorticoid receptor (GR) and the chaperone protein dissociation can induce translocation of GRs into the nucleus. Thus, activation of GRE elements by the translocation of GR activity (when glucocorticoids taken) through specific and nonspecific interactions can provoke the modulation in the activity of HDCS (left panel), and the genome wide changes upon P38MAPK activity (Middle panel). Activation of SSR asthma (right panel) by the intake of allergens or due to infections through the formation of NLRP inflammasome; the administration of MCC950, YVA, and α-IL-1β to impair the pathophysiology induced through NLRP inflammasome and release of intracellular content that cause airway inflammation.

Abbreviations: MCC950, selective NLRP3 inhibitor; Ac-YVAD-cho, specific caspase-1 inhibitor; α-IL-1β, neutralizing anti-IL-1β antibody; ASC, apoptosis-associated speck-like protein.

Figure 2 Mitigation in the SSR asthma by modulating the miR-21/PTEN/PI3K/HDAC2 signaling suggesting the significant role of miR-21. Ant-21 and a pan-PI3K inhibitor LY294002 treatment mitigated the activity of PI3K and retrieved HDAC2 levels subsequently impaired the airway hyperresponsiveness and enhanced the steroid sensitivity to allergic airway disease.

Figure 3 The pathophysiology and various antiasthmatic therapeutic modalities in the form of nanoformulations in treating asthma: Anti-IL-4Ra (ex. dupilumab), Anti-IgE (omalizumab), CRTH2 antagonist (Fevipiprant), antiIL-5R (benralizumab), Anti-IL-5 (meprolizumab), anti-TSLP (tezepelumab), chemokine receptors blockers, CCR5 modulators, specific kinase blockers, corticosteroids, chemokine receptor blockers, antiallergy blockers, cytokine agonists are prominent therapeutic strategies to target asthma pathophysiology; the nanoformulations (liposomes, nanoparticles, microparticles) by inducing surface modifications can enable responsive drug release against disease-specific enzymes. The therapeutic formulation loaded with antiasthmatic drugs can minimize the underlying pathophysiology of asthma or SSR (severe steroid resistant) asthma.

Table 1 Various Nanocarrier Compositions (Liposome-Based Formulations) and the Method of Preparations and Their Mode of Actions in Targeting AADs Including Allergic Asthma: Possible Future Implications Against SSR Asthma

Nanocarrier Composition	Drug	Method of Preparation	Size	Route of Administration, and Mode of Study (in vitro/in vivo/Clinical Trials)	Mode of Action	Ref
L-a-dipalmitoylphosphatidylcholine, cholesterol and stearylamine	Catalase and superoxide dismutase	Reverse-phase evaporation	–	Intravenous; Sprague Dawley rat models,	Scavenge either subcellular organelle-derived reactive oxygen species or partially reduced reactive oxygen species generated by phagocytic cells infiltrating into or residing in oxygen-damaged lungs	[^Citation70]
Dipalmitoylphosphatidylcholine	a-Tocopherol	Reverse-phase evaporation	320 ± 40 nm	Intratracheal; rodent models	Reduced allergen-induced interleukin 3 and interleukin levels, and augmented levels of interleukin 12 in bronchoalveolar lavage fluid. Natural-source d-α-tocopheryl acetate improved airway responsiveness	[^Citation71]
Dipalmitoylphosphatidylcholine and cholesterol	Copper, ZincCatalase and superoxide dismutase	Reverse-phase evaporation	200 nm	Intratracheal instillation; rabbit models	Increase in lung antioxidant enzyme levels which protects the pulmonary microvasculature from free radical-initiated injury.	[^Citation72]
PEG-4-Acrylate and trypsin sensitive peptide sequence	Mesalamine	Encapsulation of liposomes with microgels	200nm	Raw 264.7 cell line	NF-kB inhibitor and the nanoformulation could effectively mitigate the inflammation-induced pathophysiology	[^Citation73]
Stealth liposomes(long circulating liposome formulation)	Budesonide	Aerosol		C57/Black 6 mice	Reducing markers of lung inflammation in experimental asthma	[^Citation74]
Stealth liposomes (long circulating liposome formulation)	Salbutamol sulfate	Thin film hydration technique	167.2 ± 0.170 nm	Aerosol	Ameliorates the asthma-induced chronic alveolar obstruction	[^Citation75]
Dilauroylphosphatidylcholine	Formoterol		Possibilities of formoterol to enhance the peripheral lung deposition of the inhaled liposome corticosteroids	● Nebulizer	Bronchodilating effect	[^Citation76]
Freeze-dried soya phosphatidylcholine: cholesterol (1:1)	Salbutamol sulphate (SS) and beclometasonedipropionate		73.80 + 1.70 nm	–	–	[^Citation77]
Encapsulated allergen	CpG-ODN, a synthetic TLR9 agonist		C57BL/6 mice (WT)	● Intranasal	Anti-allergic effect, provided long-term protection	[^Citation79]
Dilauroylphosphatidylcholine (DLPC)	Budesonide		1.2 pm ± 1.9 nm	● Pressurized metered dose inhaler (pMDI), sheep models	–	[^Citation80]

Table 2 Various Nanocarrier Compositions (Nanoparticles) Formulated for Several Therapeutic Molecules and the Method of Preparations and Their Mode of Actions in Targeting AADs Including Allergic Asthma: Possible Future Implications Against SSR Asthma

Nanocarrier Composition	Drug	Preparation Technique	Size	Mode of Administration	Mode of Action	Reference
Chitosan (CS) and hyaluronic acid (HA)	Macromolecular drug heparin	Ionotropic gelation technique	162 and 217 nm	Pulmonary administration	Heparin is released during the degranulation of mast cells and inhibits the proliferation of smooth muscle cells	[^Citation94]
Poly PLA homopolymers and polyethylene glycol (PEG)- block-PLA copolymers	Betamethasone disodium phosphate	Oil-in-water solvent diffusion method	116 ± 10 nm	Intravenous	Induces anti-inflammatory effects	[^Citation95]
Stearic acid, lecithin and chloroform	Curcumin	Solvent injection method	190.4 ± 10.6 nm			[^Citation96]
PEGYlated bilirubin	Bilirubin	A carboxylic acid in bilirubin was activated by carbodiimide and reacted with amine-modified polyethylene glycol, yielding mono-PEGylated bilirubin	94 ± 12 nm	Intravenous	Induces antioxidant, and anti-inflammatory effects during allergic reactions	[^Citation97]
Chitosan, Tween-80, methanol	Prednisolone	Ionotropic external gelation technique	130–450 nm	Oral dispersible tablets	Induces anti-inflammatory effects	[^Citation98]
PEG5000-PLGA	Bavachinin, Psoralea corylifolia	Emulsion-solvent evaporation technique	196 nm	Oral delivery	Selective inhibition of Th2 cytokine production	[^Citation99]
Monoolein (MO) and celastrol	Celastrol Tripterygium wilfordii	Ultrasonication method	194.1 ± 9.78 nm		Celastrol-loaded LCNPs attenuate the inflammation via IL-1b.	[^Citation100]
Monoolein, Distilled water	Quercetin	Ultrasonication method	210.0 to 268.7 nm		Induces anti-inflammatory effects in allergic conditions	[^Citation101]
Dimethyl sulfoxide, PLGA, l- dichloromethane, acetone	Andrographolide	Multiple-emulsion solvent evaporation technique	205 nm	Oral/pulmonary administration	Mitigates the allergic asthma by impairing NF-kappaB signaling pathway	[^Citation102]
Chitosan, Thioglycolic acid, sodium tripolyphosphate	Theophylline		220 ± 23 nm	Intranasal delivery	Induces anti-inflammatory effects in allergic asthma	[^Citation103]
Chitosan, acetic acid, cinnamaldehyde	Baicalein		285 ± 25 nm	Inhalation	Anti-asthma effects induced by impairing the NF-κB and inhibiting CCR7/CCL19/CCL21.	[^Citation104]
PEG-20000, dichloromethane, - poly (lactic-co-glycolic acid) (PLGA), Tween 80	Atropine	Multiple emulsification solvent evaporation	88.30 ± 7.54 nm	Inhalation route	Muscarinic acetylcholine receptor (mAChR) blockers	[^Citation105]

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