S -Nitrosothiol-modified nitric oxide-releasing chitosan oligosaccharides as antibacterial agents

Abstract

S-nitrosothiol-modified chitosan oligosaccharides were synthesized by reaction with 2-iminothiolane hydrochloride and 3-acetamido-4,4-dimethylthietan-2-one, followed by the thiol nitrosation. The resulting nitric oxide (NO)-releasing chitosan oligosaccharides stored ~0.3 μmol NO/mg chitosan. Both the chemical structure of the nitrosothiol (i.e., primary and tertiary) and the use of ascorbic acid as a trigger for NO donor decomposition were used to control the NO-release kinetics. With ascorbic acid, the S-nitrosothiol-modified chitosan oligosaccharides elicited a 4-log reduction in Pseudomonas aeruginosa (P. aeruginosa) viability. Confocal microscopy indicated that the primary S-nitrosothiol-modified chitosan oligosaccharides associated more with the bacteria relative to the tertiary S-nitrosothiol system. The primary S-nitrosothiol-modified chitosan oligosaccharides elicited minimal toxicity towards L929 mouse fibroblast cells at the concentration necessary for a 4-log reduction in bacterial viability, further demonstrating the potential of S-nitrosothiol-modified chitosan oligosaccharides as NO-release therapeutics.

Co-delivery of nitric oxide and antibiotic using polymeric nanoparticles

“… 42 – 45 In previous studies, we and others have developed polymeric and organic/inorganic nanoparticles for the delivery of NO, facilitating its application in dispersion or eradication of biofilms. 28 , 46 – 48 For instance, we made core cross-linked star polymers containing N -diazeniumdiolate (NONOate) compounds that were capable of releasing NO in a controlled manner for several days, and these polymeric materials were able to prevent and disperse biofilms. 48 In addition, NO at high concentration (typically mM) can have a killing effect on several types of bacteria as demonstrated by Schoenfisch and co-workers.…”

“… 48 In addition, NO at high concentration (typically mM) can have a killing effect on several types of bacteria as demonstrated by Schoenfisch and co-workers. 46 , 49 – 54 The authors have investigated a range of nano-scaled objects with various shapes, and studied their efficacy as bactericidal agents. 53 Very recently, the combination of cationic polymers presenting antimicrobial activity with NO for the treatment of biofilms was reported in recent papers by Schoenfisch, 55 , 56 significantly enhanced the killing ability of the antibacterial polymers.…”

Functionalized Mesoporous Silica via an Aminosilane Surfactant Ion Exchange Reaction: Controlled Scaffold Design and Nitric Oxide Release

“… 10 , 11 Unfortunately, limited NO capacity and duration generally preclude the use of these small molecule NO donors for therapeutic applications. For enhancement of NO storage and for exerting additional control over NO release, much work has focused on the synthesis of N -diazeniumdiolate-modified macromolecular NO delivery scaffolds, including chitosan oligosaccharides, 12 dendrimers, 13 − 15 gold clusters, 16 , 17 and silica nanoparticles. 18 − 25 With respect to silica, surface grafting, 21 , 26 co-condensation, 20 , 27 and water-in-oil microemulsion 19 methods have been used to prepare N -diazeniumdiolate-functionalized particles.…”

Nitric oxide diffusion through cystic fibrosis-relevant media and lung tissue

“…[34][35][36] We have previously described NO-releasing biopolymers to reduce cytotoxicity and potentially enable natural biodegradation pathways to clear the drug, while also providing large NO payloads, extended release, and targeted therapy. [37][38][39] The diffusion of NO released from a biopolymeric scaffold through simple and complex media (PBS and ASM, respectively) was examined using a diffusion cell methodology. Differences in the rate of NO diffusion through PBS and ASM provided insight into NO's potential interactions with these uids.…”