Thromboresistant Polymers via Catalytic Generation of NO

描述（由申请人提供）：拟定了旨在制备和测试新型聚合物材料的体内抗血栓性/生物相容性的研究，该新型聚合物材料能够从血液中的内源性亚硝基硫醇物质生物降解产生一氧化氮（NO）。最近在这些实验室中已经发现，掺杂有某些亲脂性Cu（II）-配体络合物的有机聚合物通过催化反应在其界面处产生生理相关水平的NO，当浸泡在含有亚硝酸盐和/或各种亚硝基硫醇的溶液中时。已知一氧化氮是血小板粘附和活化以及平滑肌细胞增殖的有效的天然存在的抑制剂。Pi实验室正在进行的研究已经证明了合成聚合物的抗血栓性大大增强，该聚合物从新型NO加合物（二醇二氮烯鎓）中释放NO，通量=正常内皮细胞（1 × 10-10 mol/cm 2 min）。然而，使用现有的NO释放聚合物用于长期生物医学植入物（例如，作为分流器、移植物、支架等上的涂层）受到可以装载在薄的聚合物涂层内的NO加合物的相对小的储存器的限制。与此相反，正常血液已经拥有大量的NO前体以亚硝基硫醇的形式，形成从氧化的内源性NO产生的一氧化氮合酶（NOS）的水库。据信，这些物质可用于在体内在具有掺杂在某些生物医学级聚氨酯（PU）聚合物内或共价连接到某些生物医学级聚氨酯（PU）聚合物的Cu（II）络合物（环戊二烯衍生物）的聚合物的界面处产生局部增强的NO水平持续延长的时间段。络合的铜（II）可以容易地通过硫醇盐（例如，谷胱甘肽、半胱氨酸等）和抗坏血酸该计划的主要目标是制备和检查各种Cu（II/I）-配体/聚氨酯材料，这些材料可以进行这种新的氧化还原化学反应，并进一步测试所得材料在小动物中的毒性/致热原性/炎症反应，以及辛辛那提大学医学中心的合作研究者在动静脉分流（猪）的长期（28天）植入模型中的抗血栓性/生物相容性。如果用含有Cu（II）络合物的PU聚合物进行的所提出的体内研究产生由于局部NO生成而减少血栓形成（与对照涂层相比）的预期证据，则预期这些新的仿生材料将立即应用于制备/涂覆许多生物医学植入物。

DESCRIPTION (provided by applicant): Studies aimed at preparing and testing the in vivo thromboresistivity/biocompatibility of novel polymeric materials capable of biomimetically generating nitric oxide (NO) from endogenous nitrosothiol species in blood are proposed. It has been discovered recently in these laboratories that organic polymers doped with certain lipophilic Cu(II)-ligand complexes generate, via a catalytic reaction, physiologically relevant levels of NO at their interface, when bathed in solutions containing nitrite and/or various nitrosothiols. Nitric oxide is known to be a potent, naturally occurring inhibitor of platelet adhesion and activation as well as smooth muscle cell proliferation. Ongoing studies in the Pi's laboratories have already demonstrated the greatly enhanced thromboresisitivity of synthetic polymers that liberate NO from novel NO adducts (diazeniumdiolates) with fluxes = to normal endothelial cells (1 x 10-10 mol/cm2min). However, use of existing NO release polymers for long-term biomedical implants (e.g., as coatings on shunts, grafts, stents, etc.) is limited by the relatively small reservoir of NO adduct that can be loaded within thin polymeric coatings. In contrast, normal blood already possesses a substantial reservoir of NO precursors in the form of nitrosothiols; formed from the oxidation of endogenous NO produced by nitric oxide synthase (NOS). It is believed that these species can be used to generate locally enhanced NO levels for extended time periods in vivo at the interface of polymers possessing Cu(II) complexes (cyclen derivatives) either doped within or covalently linked to certain biomedical grade polyurethane (PU) polymers. Complexed copper(II) can be readily reduced to Cu(I) by thiolates (e.g., glutathione, cysteine, etc.) and ascorbate in blood. The Cu(I) is then capable of reducing nitrosothiols back to NO. The principal objectives of this program will be to prepare and examine a variety of Cu(II/I)-ligand/polyurethane materials that can carry out this novel redox chemistry and further test the resulting materials for toxicity/pyrogenicity/inflammatory response in small animals, as well as thromboresistivity/biocompatibility in a longer term (28 d) implant model for arteriovenous shunts (in pigs) by co-investigators at the University of Cincinnati Medical Center. If the proposed in vivo studies with PU polymers containing Cu(II) complexes yield the expected evidence of reduced thrombosis (vs. control coatings) due to local NO generation, it is anticipated that these new biomimetic materials would have immediate applications for preparing/coating a host of biomedical implants.