Thromboresistant Polymers via Catalytic Generation of NO

描述(申请人提供)：提出了一项旨在制备和测试新型聚合物材料的体内血栓抗性/生物相容性的研究，该材料能够从血液中的内源性亚硝硫醇物种仿生地产生一氧化氮(NO)。最近在这些实验室中发现，掺入某些亲脂性铜(II)配体络合物的有机聚合物，当沐浴在含有亚硝酸盐和/或各种亚硝硫醇的溶液中时，通过催化反应在其界面产生生理水平的NO。众所周知，一氧化氮是一种有效的、自然产生的抑制血小板黏附和激活以及平滑肌细胞增殖的药物。PI实验室正在进行的研究已经证明，合成聚合物的血栓抗性大大增强，这些聚合物从新型NO加合物(重氮二醇酸盐)中释放出NO，并与正常内皮细胞(1 x 10-10mol/cm2min)形成助熔剂。然而，现有的NO释放聚合物用于长期生物医学植入物(例如，作为分流管、移植物、支架等的涂层)。受限于可在薄聚合物涂层中负载的相对较小的无加成物储存库。相比之下，正常血液已经拥有大量亚硝硫醇形式的NO前体，亚硝硫醇是由一氧化氮合酶(NOS)产生的内源性NO氧化形成的。人们认为，这些物种可以用于在体内产生局部增强的NO水平，在体内的聚合物界面上，具有掺入或共价连接到某些生物医用级聚氨酯(PU)聚合物中的铜(II)络合物(环烯衍生物)。络合铜(II)很容易被硫酸盐(如谷胱甘肽、半胱氨酸等)还原为铜(I)。并在血液中产生抗坏血剂。然后，铜(I)能够将亚硝硫醇还原为NO。该计划的主要目标将是由辛辛那提大学医学中心的合作研究人员制备和检测各种可以进行这种新型氧化还原化学的铜(II/I)配体/聚氨酯材料，并进一步测试所产生的材料在小动物中的毒性/致热性/炎症反应，以及在较长期(28天)的动静脉分流植入模型(猪)中的血栓抵抗力/生物相容性。如果用含铜(II)络合物的PU聚合物进行的体内研究能够得到局部NO生成减少血栓形成(与对照涂层相比)的预期证据，预计这些新的仿生材料将立即应用于制备/涂层一系列生物医学植入物。

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.