Localization of HydrophobicN-Diazeniumdiolates in Aqueous Micellar Solution

Abstract

The interaction of phenyl-substituted zwitterionic N-diazeniumdiolates PhCH(2)N[N(O)NO](-)(CH(2))(2)NH(3)(+) (1) and PhCH(2)N[N(O)NO](-)(CH(2))(2)NH(2)(+)CH(2)Ph (2) with aqueous micellar solutions of prototypal surfactants was investigated by means of UV/vis and (1)H NMR spectroscopy in order to establish the localization of hydrophobic N-diazeniumdiolates in micelles as a model for the binding of the NO donors in biological membranes. In the presence of sodium dodecyl sulfate (SDS), significant shifts of the apparent pK(a) values of 1 and 2 were observed, suggesting strong electrostatic interaction between the diazeniumdiolates and the negatively charged SDS micelles. No effect on both pK(a) and rate of NO release was found in the presence of Triton X-100. The solubilization site of micellar bound N-diazeniumdiolates was established by (1)H NMR spectroscopic studies, taking advantage of the spectroscopic effects induced by CH-pi interactions. The spectra indicate that in alkaline solutions of SDS 1 resides preferably at the micellar surface within the interfacial region, whereas the more hydrophobic NO donor 2 penetrates into the apolar region of the micelle. This suggests hydrophobic interaction as the main driving force for micellar binding of 2 in alkaline solution. Similar studies in presence of Triton X-100 indicate that 1 and 2 are adsorbed within the poly(oxyethylene) layer of the micellar surface rather than penetrating the palisade layer of the micelles. In alkaline solutions of hexadecyltrimethylammonium bromide (CTAB), 1 and 2 bind to the cationic micellar aggregates, whereby the solubilization site strongly depends on the hydrophobicity of the substrate. Up to a moderate pH of 8, the hydrophobic NO donor 2 penetrates the hydrocarbon region of the micelles. As a result, the rate of NO release from 2 is noticeably inhibited by the micellar aggregates due to the higher local concentration of hydroxide ions along the micelle-water interface. From solubilization studies, guidelines for the development and application of future NONOates can be derived. The rate of NO release from micellar bound diazeniumdiolates is determined by the surface charge of the micelles. This ability to tune stability is significant for the design and selection of potential NO delivery systems (drug formulations).