| Novel polymeric, exogenous NO donors were synthesized by reacting compounds containing secondary amines with nitric oxide gas to produce polymeric NONOates that spontaneously release NO under physiological conditions. Polyethyleneimine was cross-linked with 1,4-butanediol diglycidyl ether (PEIX) and reacted with NO to form a rubber material that was coated onto prosthetic vascular grafts, stents and central venous catheters. Expanded polytetrafluoroethylene (PTFE) vascular grafts coated with PEIX-NO were found to inhibit platelet aggregation and adhesion in vivo in the baboon model and inhibited the proliferation of vascular smooth muscle cell in vitro. Microspheres of PEIX-NO were also synthesized and incorporated into the pores of a PTFE graft for delivery of NO as an alternative to coating vascular grafts.; Stent and catheter coatings were also developed that involved immobilizing soluble triamine-based NO donors, diethylenetriamine NONOate (DETA-NO) and dipropylenetriamine NONOate (DPTA-NO), in a polymeric matrix such as polyurethane or silicone rubber. The resulting composite increased the half life of DETA-NO from 20 hrs at physiological pH to over 4 days which indicated that entrapment of soluble NO-donors in a polymeric matrix provided sustained NO release under physiological conditions.; L-{dollar}alpha{dollar}-phosphatidylethanolamine dipalmitoyl (PMMED) was also reacted with 5 atm of NO to give a phospholipid NONOate. Liposomes of this material were found to release NO spontaneously in buffer at physiological pH with a half life of 74 hrs for application in pulmonary conditions such as respiratory distress syndrome and viral infections.; Another particle form of a polymeric NONOate was synthesized by reacting polyethyleneimine cellulose (PEIC) with 5 atm NO gas. PEIC-NO provided extended nitric oxide release with a half life of over 16 hrs. Topical application of this material to wounds resulted in a two to four fold excess of urinary nitrates, an indirect measurement of NO, providing evidence of exogenous NO delivery in vivo while significantly accelerating wound healing without prolonged hypotensive effects.; These results suggest that polymeric NO-donating compounds provide site specific, controlled release of NO under physiological conditions and could be used for a variety of clinical applications in place of systemic nitrovasodilating compounds. |
