Nitric Oxide Generating Polymers (NOGPs).

[摘要] Several functional polymers that can catalytically generate nitric oxide (NO) from naturally occurring substrates (S-nitrosothiols; RSNOs) in blood by means of immobilized catalytic sites within the polymers were synthesized and investigated.Such polymers are termed NO generating polymers (NOGPs) and they have the potential to be used as more biocompatible polymeric coatings for biomedical devices (e.g., catheters, vascular grafts, indwelling sensors, etc.) owing to NO’s ability to inhibit platelet activation/adhesion and reduce smooth muscle cell proliferation. In this thesis, two distinctive catalysts were employed to develop the NOGPs: a) Cu(II)-cyclen (cyclen; 1,4,7,10-tetraazacyclododecane) complex, already recognized as an NO generating catalyst via reductive decomposition of RSNOs; and b) 5,5’-ditelluro-2,2’-dithiophenecarboxylic acid (DTDTCA), a newly synthesized organoditelluride (RTeTeR) species that was discovered, in this thesis work, to exhibit catalytic RSNO denitrosation to NO in the presence of thiol reducing agents (RSHs) at physiological pH.To optimize the catalytic function of the immobilized RTeTeR species, its catalytic mechanism toward RSNO was investigated.Both NO generating catalysts were covalently linked to a variety of polymers including poly(2-hydroxyethyl methacrylate), thermoplastic polyurethane (PU), and poly(allylamine hydrochloride) using standard synthetic methodologies.Loading of catalytic sites on such polymers ranged from 0.04 – 7.5 wt % (Cu or Te content). In addition, some of these catalytic polymers were also employed to create interpenetrating polymer networks using a cellulose membrane or PU base.In all cases, NO generation from RSNOs by the new NOGPs, as measured by chemiluminescence, was found to be proportional to the amount of Cu(II)-cyclen or RTeTeR species linked to the polymeric backbone.Further, it was found that all polymers retained significant catalytic function for at least two weeks, with < 10 -30 % loss of catalytic sites when bathed in buffer containing RSH/RSNO.The ability of each new NOGP to generate NO when in contact with fresh animal blood was also investigated and confirmed by employing the polymers as outer coatings at the distal end of an amperometric NO sensor.Finally, such a measurement configuration was shown to function as a useful RSNO sensor for direct detection of total RSNO species in whole blood samples.

[发布机构] University of Michigan

[效力级别] S-Nitrosothiols

[关键词] Nitric Oxide Generating Polymers;S-Nitrosothiols;Hemocompatible Polymers;Cu(II)-Cyclen Complex;Amperometric RSNO Sensor;Organoditelluride;Chemistry;Science;Chemistry