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. 2019 Jul 8;5(7):3409-3418.
doi: 10.1021/acsbiomaterials.9b00482. Epub 2019 May 24.

Nitric oxide-releasing alginates as mucolytic agents

Mona Jasmine R Ahonen  1 , David B Hill  2 , Mark H Schoenfisch  1
Affiliations

Nitric oxide-releasing alginates as mucolytic agents

Mona Jasmine R Ahonen et al. ACS Biomater Sci Eng. .

Abstract

The excessive production of thick, viscous mucus in severe respiratory diseases leads to obstruction of the airways and provides a suitable environment for the colonization of pathogenic bacteria. The effect of nitric oxide (NO)-releasing alginates with varying NO release kinetics on the viscoelastic properties of human bronchial epithelial (HBE) mucus was evaluated as a function of the NO-release kinetics using parallel plate rheology. Low molecular weight (~5 kDa) alginates with high NO flux (~4000 ppb/mg) and sustained release (half-life ~0.3 h) proved to be most effective in reducing both mucus elasticity and viscosity (≥60% reduction for both). The efficacy of the NO-releasing alginates was shown to be dose-dependent, with high concentrations of NO-releasing alginates (~80 mg•mL-1) resulting in greater reduction of the viscosity and elasticity of the mucus samples. Greater reduction in mucus rheology was also achieved with NO-releasing alginates at lower concentrations when compared to both NO-releasing chitosan, a similarly biocompatible cationic polymer, and N-acetyl cysteine (NAC), a conventional mucolytic agent.

Keywords: alginates; mucolytic agent; mucus; nitric oxide.

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Conflict of interest statement

The authors declare the following competing financial interest(s): Mark Schoenfisch is a cofounder, a member of the board of directors, and maintains financial interest in Novan therapeutics Inc. and Vast Therapeutics, Inc. Both companies commercialize macromolecular nitric oxide storage and release vehicles for multiple clinical indications.

Figures

Figure 1.
Figure 1.
Elastic and viscous moduli of 3 wt% human bronchial epithelial (HBE) mucus following treatment with 20 mg/mL Alg300 (black solid), Alg10 (black diagonal), Alg5 (gray solid), and Alg1 (gray diagonal). Single asterisks (*) indicate significant differences (p < 0.05) relative to untreated sample (hollow).
Figure 2.
Figure 2.
Elastic and viscous moduli of 3 wt% human bronchial epithelial (HBE) mucus following treatment with 20 mg/mL unmodified (solid), modified (horizontal stripe), and NO-releasing (diagonal stripe) (A) Alg5-DETA, (B) Alg5-DPTA, (C) Alg5-PAPA, (D) Alg5-SPER, (E) Alg5-PAPA-DPTA, and (F) COS-EA. Values presented as the mean standard error of the mean for n = 3 experiments. Asterisks (*) indicate significant differences (p < 0.05) relative to untreated sample (hollow).
Figure 3.
Figure 3.
Elastic and viscous moduli of 3 wt% HBE mucus following treatment with (A) COS-EA/NO, (B) Alg5-DPTA/NO, (C) Alg5-PAPA/NO, and (D) Alg5-PAPA-DPTA/NO after 1 hour (black solid), 3 hours (black diagonal), 5 hours (gray solid), and 24 hours (gray diagonal) exposure. Asterisks (*) indicate significant differences (p < 0.05) relative to untreated sample (hollow).
Figure 4.
Figure 4.
Elastic (circle) and viscous (square) moduli of 3 wt% HBE mucus following treatment with 20, 40, 60, and 80 mg/mL concentrations of control (hollow) and NO-releasing (solid) (A) Alg5-PAPA-DPTA and (B) COS-EA.
Figure 5.
Figure 5.
Elastic and viscous moduli of 3 wt% HBE mucus following treatment with NAC at 0.1 wt% (black solid), 0.2 wt % (black diagonal), 10 wt % (gray solid), and 20 wt% (gray diagonal). Values presented as the mean standard error of the mean for n = 3 experiments. Asterisks (*) indicate significant differences (p < 0.05) relative to untreated sample (hollow).
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