title: Sustained release nitric oxide from long-lived circulating nanoparticles.
abstract: The current limitations of nitric oxide (NO) delivery systems have stimulated an extraordinary interest in the development of compounds that generate NO in a controlled and sustained manner with a heavy emphasis on the treatment of cardiovascular disease states. This work describes the positive physiological response to the infusion of NO-releasing nanoparticles prepared using a new platform based on hydrogel/glass hybrid nanoparticles. When exposed to moisture, these nanoparticles slowly release therapeutic levels of NO, previously generated through thermal reduction of nitrite to NO trapped within the dry particles. The controlled and sustained release of NO observed from these nanoparticles (NO-np) is regulated by its hydration over extended periods of time. In a dose-dependent manner, circulating NO-np both decreased mean arterial blood pressure and increased exhaled concentrations of NO over a period of several hours. Circulating NO-np induced vasodilatation and increased microvascular perfusion during their several hour circulation lifetime. Control nanoparticles (control-np; without nitrite) did not induce changes in arterial pressure, although a decrease in the number of capillaries perfused and an increase in leukocyte rolling and immobilization in the microcirculation were observed. The NO released by the NO-np prevents the inflammatory response observed after infusion of control-np. These data suggest that NO release from NO-np is advantageous relative to other NO-releasing compounds, because it does not depend on chemical decomposition or enzymatic catalysis; it is only determined by the rate of hydration. Based on the observed physiological properties, NO-np has clear potential as a therapeutic agent and as a research tool to increase our understanding of NO signaling mechanisms within the vasculature.
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA. pcabrales@ucsd.edu
authors.forename: Pedro
authors.initials: P
authors.lastname: Cabrales
authors.forename: George
authors.initials: G
authors.lastname: Han
authors.forename: Camille
authors.initials: C
authors.lastname: Roche
authors.forename: Parimala
authors.initials: P
authors.lastname: Nacharaju
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Friedman
authors.forename: Joel M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000818:Animals; D006224:Cricetinae; D003692:Delayed-Action Preparations; D016503:Drug Delivery Systems; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000295:instrumentation / Q000379:methods; D009569:Nitric Oxide / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D010316:Particle Size; D015398:Signal Transduction
chemical_list: D003692:Delayed-Action Preparations; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D009569:Nitric Oxide
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