Synthesis and characterization of nitric oxide-releasing agents/polymers for biomedical applications.

Abstract

Nitric oxide (NO) has been shown to have significant anti-platelet activity. Polymers capable of releasing NO may also show enhanced blood compatibility. To this end, <italic>N,N</italic><super>'</super>-dialkylhexamethylenediamine diazeniumdiolates (zwitterionic) and their bis dizeniumdiolate analogues were synthesized and characterized. It was determined that the side chain length had little affect on the apparent half-lives of the zwitterionic diazeniumdiolates. The bis-diazeniumdiolates were found to have shorter apparent half-lives than their zwitterionic analogues. Both the zwiterionic and bis-diazeniumdiolates were incorporated into hydrophobic polymer matrixes and their NO-release profiles determined using chemiluminescence. For polymer matrixes prepared with the more lipophilic diazeniumdiolate species, NO-release was enhanced by the addition of a lipophilic borate salt. It was determined that the borate salt serves to buffer the polymer film during the NO-release process. NO-releasing polymers were prepared using this approach that exhibited NO surfaces fluxes of at least 4 x 10<super>-10</super> mol&middot;cm<super>-2</super>&middot;min<super> -1</super>. The more lipophilic zwitterionic diazeniumdiolate, <italic> N,N</italic><super>'</super>-dibutylhexamethylenediamine diazeniumdiolate, was embedded into polymer coatings and used to prepared coatings fro vascular access grafts and electrochemical oxygen sensors. When these NO-releasing polymers were used as coatings for medical devices, significant reduction of thrombus formation on their surfaces was observed compared to control surfaces (without NO release). Secondly, synthetic methods were explored to covalently attach diazeniumdiolates to polyurethane backbones. The first method involved preparing polyurethanes that contained diamine chain extenders. These diamine-containing polyurethanes were then reacted with NO. The resulting polymers were found to release mostly nitrite. However, when these diamine-containing polyurethanes are reacted with NO in the presence of exogenous salts, an increase in the amount of NO compared to nitrite was achieved. The second method involved incorporation of protected pre-formed diazeniumdiolate moieties directly onto chain extender diols incorporated into the polyurethane backbone. More control over the NO-loading was demonstrated using this approach.