Nitric Oxide-Release Vehicles as Oral Disease Therapeutics Public Deposited

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  • March 19, 2019
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  • Backlund, Christopher
    • Affiliation: College of Arts and Sciences, Department of Chemistry
Abstract
  • Oral diseases (e.g., dental caries and periodontal disease) are caused by dental plaque biofilms. Due to the central role of nitric oxide (NO) in the immune response to bacterial infection, the delivery of exogenous NO as an antibacterial to combat dental biofilms is of interest. Herein, the synthesis of NO-release vehicles, followed by the evaluation of their chemical and physical properties in relation to their in vitro microbiological performance is described. Hybrid silica nanoparticles exhibiting a range of NO-release totals and kinetics were synthesized by varying the aminosilane precursor identity and composition. The greatest NO storage obtained was ~1 µmol/mg silica nanoparticle. To study the effects of NO-release kinetics on bacterial killing, NO-release half-lives were also tuned (~30 and ~120 min), independent of both particle size (~150 nm) and NO-release totals (~0.2 µmol/mg). Macromolecular nitric oxide-release vehicles (i.e., silica and dendrimers) proved more efficient than a small molecule NO donor (i.e., PROLI/NO) at delivering NO to oral pathogens, requiring lower NO doses to kill bacteria. Periodontopathogens were significantly more susceptible to NO treatment than cariogenic bacteria, suggesting a differential sensitivity to NO. At the concentrations required to kill periodontopathogens, NO-releasing silica and dendrimers were mildly toxic (>60% cell viabilities) to human gingival fibroblasts (HGF-1), and were significantly less toxic than clinical concentrations of chlorhexidine (0.12 and 0.20% w/w). The kinetic-dependent killing of cariogenic and periodontopathogenic bacteria with NO-releasing silica nanoparticles was evaluated. Particles with slower NO-release kinetics (half-life ~120 min) demonstrated the greatest efficacy against periodontopathogens at pH 7.4. They were also least cytotoxic to HGF-1 cells, supporting the use of extended NO-release from silica-based materials for killing periodontopathogens. In contrast, cariogenic Streptococcus mutans was more susceptible to rapid NO release at lower pH (6.4). The anti-biofilm activity of NO-releasing alkyl chain-modified poly(amidoamine) dendrimers was evaluated against S. mutans as a function of alkyl chain length, pH, and NO-release kinetics. Longer alkyl chains (i.e., hexyl, octyl, and dodecyl) were more bactericidal than shorter alkyl chains (i.e., propyl and butyl) at pH 7.4 due to greater membrane disruption. At lower pH, bactericidal efficacy was enhanced due to greater dendrimer-bacteria association, increased membrane damage (longer chains), and faster NO-release kinetics (shorter chains). The long alkyl chain dendrimers were toxic to mammalian cells, but less toxic with NO release. The efficient anti-biofilm activity and reduced cytotoxicity for NO-releasing long alkyl chain-modified dendrimers supports their future development as dental caries therapeutics.
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  • In Copyright
Advisor
  • Schoenfisch, Mark H.
  • Offenbacher, Steven
  • Lockett, Matthew
  • Jorgenson, James
  • Miller, Alexander
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2014
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  • Chapel Hill, NC
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