Reynolds Melissa M, Hrabie Joseph A, Oh Bong K, Politis Jeffrey K, Citro Michael L, Keefer Larry K, Meyerhoff Mark E
Department of Chemistry, University of Michigan, Ann Arbor, 48109-1055, USA.
Biomacromolecules. 2006 Mar;7(3):987-94. doi: 10.1021/bm060028o.
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.
本文描述了两种合成能够产生生物活性一氧化氮（NO）的稳定聚氨酯（PU）的新策略。这些方法依赖于将二醇二氮烯醇盐（N₂O₂⁻）基团共价连接到聚合物链内不同位置的仲胺氮上，使得当与水或生理流体接触时，每个二醇二氮烯醇盐部分仅释放出两个NO分子到周围介质中，潜在的副产物仍共价结合在基质上。对聚合物释放的NOₓ产物进行了广泛分析，以制定适当策略来更好地稳定基于二醇二氮烯醇盐的聚合物结构。在一种方法中，二醇二氮烯醇盐基团连接到插入PU材料二醇扩链剂中的烷二胺的仲氨基氮上。在二醇二氮烯醇化步骤中将聚合物溶液暴露于NO之前，通过将聚合物与生物相容性、相对非亲核的盐混合，可使NO的氧化损失最小化。在生理缓冲液中浸泡期间，此类材料的分子NO通量高达19 pmol·cm⁻²·s⁻¹，NO的总回收率为21 nmol/mg的PU。第二种通用合成策略涉及对聚氨酯氮进行ω-卤代烷基化，然后用亲核多胺从所得聚合物中取代卤化物，以形成具有适合二醇二氮烯醇化的侧链氨基的PU。市售的Pellethane 2363-80AE经溴丁基化，然后与二亚乙基三胺反应，并进一步暴露于气态NO中，结果表明其固体形式可稳定数月，但浸入生理缓冲液后释放的NO总回收率为17 nmol/mg。当在37℃下浸入pH 7.4缓冲液中时，该材料的初始NO通量为14 pmol·cm⁻²·s⁻¹，在长达6天的时间内通量逐渐降低但仍可观察到。
