Nitric oxide releasing polyurethanes with covalently linked diazeniumdiolated secondary amines.
Two novel strategies for synthesizing stable polyurethanes (PUs) capable of generating bioactive nitric oxide (NO) are described. The methods rely on covalently attaching diazeniumdiolate (N(2)O(2)(-)) groups onto secondary amine nitrogens at various positions within the polymer chain such that, when in contact with water or physiological fluids, only the two molecules of NO available from each diazeniumdiolate moiety are released into the surrounding medium, with potential byproducts remaining covalently bound to the matrix. Extensive analysis of the NO(x)() products released from the polymers was employed to develop appropriate strategies to better stabilize the diazeniumdiolate-based polymer structures. In one approach, diazeniumdiolate groups are attached to secondary amino nitrogens of alkane diamines inserted within the diol chain extender of a PU material. Oxidative loss of NO was minimized by blending the polymer with a biocompatible, relatively nonnucleophilic salt before exposing solutions of the polymer to NO during the diazeniumdiolation step. Fluxes of molecular NO from such materials during immersion in physiological buffer reached levels as high as 19 pmol x cm(-2) x s(-1) with a total recovery of 21 nmol of NO/mg of PU. A second general synthetic strategy involved omega-haloalkylating the urethane nitrogens and then displacing the halide from the resulting polymer with a nucleophilic polyamine to form a PU with pendent amino groups suitable for diazeniumdiolation. Commercially available Pellethane 2363-80AE that was bromobutylated and then reacted with diethylenetriamine and further exposed to gaseous NO proved stable in solid form for several months, but released NO with a total recovery of 17 nmol/mg upon immersion in physiological buffer. This material showed an initial NO flux of 14 pmol x cm(-2) x s(-1) when immersed in pH 7.4 buffer at 37 degrees C, with gradually decreasing but still observable fluxes for up to 6 days.
Reynolds
Melissa M
MM
Department of Chemistry, University of Michigan, Ann Arbor, 48109-1055, USA.
Hrabie
Joseph A
JA
Oh
Bong K
BK
Politis
Jeffrey K
JK
Citro
Michael L
ML
Keefer
Larry K
LK
Meyerhoff
Mark E
ME
D000588:Amines / Q000737:chemistry; D001391:Azo Compounds / Q000737:chemistry*; D003671:DEET / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008956:Models, Chemical; D009569:Nitric Oxide / Q000737:chemistry*; D009573:Nitrites; D010100:Oxygen / Q000378:metabolism; D011108:Polymers / Q000737:chemistry; D011140:Polyurethanes / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors
D000588:Amines; D001391:Azo Compounds; D009573:Nitrites; D011108:Polymers; D011140:Polyurethanes; C452539:diazeniumdiolate; D003671:DEET; D009569:Nitric Oxide; D010100:Oxygen