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. 2018 Apr 9;19(4):1189-1197.
doi: 10.1021/acs.biomac.8b00063. Epub 2018 Mar 26.

Nitric Oxide-Releasing Alginates

Mona Jasmine R Ahonen  1 , Dakota J Suchyta  1 , Huanyu Zhu  1 , Mark H Schoenfisch  1
Affiliations

Nitric Oxide-Releasing Alginates

Mona Jasmine R Ahonen et al. Biomacromolecules. .

Abstract

Low and high molecular weight alginate biopolymers were chemically modified to store and release potentially therapeutic levels of nitric oxide (NO). Carbodiimide chemistry was first used to modify carboxylic acid functional groups with a series of small molecule alkyl amines. The resulting secondary amines were subsequently converted to N-diazeniumdiolate NO donors via reaction with NO gas under basic conditions. NO donor-modified alginates stored between 0.4-0.6 μmol NO·mg-1. In aqueous solution, the NO-release kinetics were diverse (0.3-13 h half-lives), dependent on the precursor amine structure. The liberated NO showed bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus with pathogen eradication efficiency dependent on both molecular weight and NO-release kinetics. The combination of lower molecular weight (∼5 kDa) alginates with moderate NO-release durations (half-life of ∼4 h) resulted in enhanced killing of both planktonic and biofilm-based bacteria. Toxicity against human respiratory epithelial (A549) cells proved negligible at NO-releasing alginate concentrations required to achieve a 5-log reduction in viability in the biofilm eradication assay.

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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 Novoclem Therapeutics, Inc. Both companies commercialize macromolecular nitric oxide storage and release vehicles for clinical indications.

Figures

Figure 1.
Figure 1.
(A) Real time NO-release profiles for the first 1 h and (B) plot of total NO release vs. time for Alg300-DETA/NO (solid), Alg300-DPTA/NO (dash), Alg300-SPER/NO (dash-dot), and Alg300-PAPA/NO (dot) measured via chemiluminescence in pH 7.4 PBS.
Figure 2.
Figure 2.
Time-based bactericidal efficacy of Alg300-DETA/NO (square), Alg300-DPTA/NO (circle), Alg300-SPER/NO (triangle), and Alg300-PAPA/NO (diamond). Comparison of all high molecular weight NO-releasing alginates at equivalent concentrations of 8 mg/mL is presented in (A), and the time-based killing of the fast NO-releasing systems (Alg300-SPER/NO and Alg300-PAPA/NO) at their respective MBEC24h is presented in (B). Studies consisted of at least three experiments with error bars representing the standard deviation.
Figure 3.
Figure 3.
Viability of A549 human respiratory epithelial cells exposed to control and NO-releasing (white) and control (dash) alginates at the MBEC24h against (A) P. aeruginosa and (B) S. aureus. Studies consisted of at least three experiments with error bars representing the standard deviation.
Scheme 1.
Scheme 1.
Synthesis of amine-functionalized alginate.
Scheme 2.
Scheme 2.
Synthesis of N-diazeniumdiolate-modified alginates.
See this image and copyright information in PMC

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