Researchers report physical barrier to SARS-CoV-2 infection based on respirable bioadhesive hydrogel

In a recent study published in Natural materialsresearchers developed a spherical hydrogel inhaler for enhanced lung defense (SHIELD) to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Background

The constant emergence of highly contagious SARS-CoV-2 variants poses a threat. efficacy of Vaccines for the novel coronavirus disease 2019 (COVID-19) and therapeutics such as antiviral drugs and monoclonal antibodies, ensuring the development of new treatments. Airway mucosa provides an initial level of protection against SARS-CoV-2 by trapping and removing pathogens and foreign bodies. Impaired mucociliary clearance may facilitate SARS-CoV-2 infection. Therefore, mucosal bioadhesive polymer molecules may expand the therapeutic landscape for COVID-19.

About research

In the current study, researchers used the SHIELD approach for protection against SARS-CoV-2.

SHIELD’s particle-mucus interactions facilitate particle diffusion and reduce SARS-CoV-2 penetration. Inhalation of the particles is followed by swelling and adhesion. The particles were prepared by a water-in-oil emulsion method and consisted of a gelatin-crosslinked N-hydroxysuccinimide ester (PAAc-NHS ester) with robust mechanical and mucoadhesive properties.

scanning electron microscopy (SEM), immunohistochemistry (IHC), live Imaging system (IVIS), and confocal microscopy analysis were performed to assess the dynamics of expansion and changes in volume. Particles were tracked by labeling with Cyanine7 dye to assess particle stability. Additionally, Fourier transform infrared (FTIR) spectroscopy was performed. We collected mucus from the pig stomach and investigated whether the SHIELD method could be used to enhance mucosal barrier protection.

Using a tertiary airway model, particle-mucin interactions were further evaluated by wheat germ agglutinin staining. Polystyrene beads similar in size to SARS-CoV-2 were generated using a nebulizer and used to simulate penetration of SARS-CoV-2 into mucous membranes.

The protection conferred by SHIELD was tested in mice challenged with SARS-CoV-2 pseudovirus containing the D614G, N501Y, K417N, and E484K mutations at 4, 8, and 24 hours after 3.0 mg/kg SHIELD inhalation. it was done. In addition, protection by SHIELD was evaluated against her H1N1 influenza virus and murine pneumonia virus in mice, as well as scenarios following SARS-CoV-2 infection.

The biocompatibility of SHIELD was evaluated in cell culture experiments. To determine the effect of His SHIELD on mucociliary function, mouse animals received acute (2 h) or chronic (14 days of regular inhalation) SHIELD therapy. A pilot study was conducted using non-human primates challenged with the ancestral his SARS-CoV-2 Wuhan-Hu-1 strain and his SARS-CoV-2 Delta variant. Nasal swabs and bronchoalveolar lavage samples were collected on days 1.0, 2.0, 4.0, and 7.0.

An enzyme-linked immunosorbent assay (ELISA) was performed to measure secretory immunoglobulin A (sIgA) levels in bronchoalveolar lavage (BAL) fluid. viral load determined using reverse transcription PCR (RE-PCR) specific for subgenomic ribonucleic acid (sgRNA). Lung SARS-CoV-2 RNA levels were on site Ribonucleic acid hybridization.

result

SHIELD inhalable particles are delivered as a dry powder (powder size <5.0 μm, particle diameter 0.5–5.0 μm) inhaler and consist of dense hydrogel crosslinked structures formed by the particles after hydroswelling, coated bronchi and bronchioles, Enhanced particle diffusion and limited penetration of SARS-CoV-2. SHIELD therapy protected mice challenged with a SARS-CoV-2 pseudovirus containing a mutated spike (S) protein.

Strikingly, among African green monkeys, protection from a single inhalation of SHIELD lasted up to 8.0 hours against the Wuhan-Hu-1 strain and the Delta mutant. His SHIELD containing food grade substances did not alter his respiratory function. Particle size favored particle deposition in deep lung tissue. After swelling, the particle volume increased 10-fold at 10.0 min and a similar swelling was observed in the BAL samples. Particle fluorescence was stable for up to 3.0 days.

This finding indicated that mucoadhesion occurs upon particle contact with moist mucosal surfaces. Particle swelling began at the onset of mucoadhesion and was facilitated by the anionic carboxylic acid molecule of the N-hydroxysuccinimide ester. Ester groups may attach to surfaces by coupling with mucosal primary amines. SHIELD particles increased the elastic modulus and viscosity of mucus and decreased the Brownian motion of polystyrene beads.

SHIELD protected mice from H1N1 influenza virus and mouse pneumonia virus. However, his SHIELD had minimal efficacy in post-SARS-CoV-2 infection scenarios. 95% cell viability was observed even at a concentration of 10.0mg/ml^–1). Tracheal and bronchial tissue obtained from mice showed a regular morphology indicating the safety of SHIELD.

SHIELD particles had minimal effects on pulmonary mucociliary ablation, formed short-term bridges with mucus, and induced transient mucosal changes. SHIELD did not affect mucosal immunity levels. SHIELD-treated animals exhibited 50.0- to 300.0-fold less viral load than controls and were protected from Wuhan-Hu-1 and Delta. SHIELD reduces pulmonary fibrosis, SARS-CoV-2 nucleocapsid (N) protein levels, SARS-CoV-2 replication, and SARS-CoV-2 infection, and clusters of differentiated 206+ macrophage numbers in a non-toxic manner. lowered it.

Conclusion

Overall, the study results demonstrate that the SHIELD approach can protect against respiratory pathogens such as SARS-CoV-2 without altering lung function by enhancing mucosal spreading properties to physically protect against COVID-19. We have shown that it can be effectively and safely protected.

This approach is easy to use and suitable for regular dosing using a cost-effective inhaler device. SHIELD can be seen as an adjunct to face masks, providing protection when the mask is not on (such as when eating or drinking) and can be very beneficial for children who are hesitant to wear a mask. .