Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):12938-43. doi: 10.1073/pnas.1204928109. Epub 2012 Jul 25.
Development of effective, yet safe, antithrombotic agents has been challenging because such agents increase the propensity of patients to bleed. Recently, naturally occurring polyphosphates such as extracellular DNA, RNA, and inorganic polyphosphates have been shown to activate blood coagulation. In this report, we evaluate the anticoagulant and antithrombotic activity of nucleic acid-binding polymers in vitro and in vivo. Such polymers bind to DNA, RNA, and inorganic polyphosphate molecules with high affinity and inhibit RNA- and polyphosphate-induced clotting and the activation of the intrinsic pathway of coagulation in vitro. Moreover, [NH(2)(CH(2))(2)NH(2)](G = 3);dendri PAMAM(NH(2))(32) (PAMAM G-3) prevents thrombosis following carotid artery injury and pulmonary thromboembolism in mice without significantly increasing blood loss from surgically challenged animals. These studies indicate that nucleic acid-binding polymers are able to scavenge effectively prothrombotic nucleic acids and other polyphosphates in vivo and represent a new and potentially safer class of antithrombotic agents.
开发有效且安全的抗血栓形成药物一直具有挑战性，因为这类药物会增加患者出血的倾向。最近，已发现细胞外 DNA、RNA 和无机多磷酸盐等天然存在的多磷酸盐可激活血液凝固。在本报告中，我们评估了核酸结合聚合物在体外和体内的抗凝和抗血栓形成活性。这些聚合物与 DNA、RNA 和无机多磷酸盐分子具有高亲和力，可抑制 RNA 和多磷酸盐诱导的凝固以及体外凝血固有途径的激活。此外，[NH(2)(CH(2))(2)NH(2)](G = 3);dendri PAMAM(NH(2))(32) (PAMAM G-3) 可防止颈动脉损伤和小鼠肺血栓栓塞后的血栓形成，而不会显著增加手术挑战动物的失血。这些研究表明，核酸结合聚合物能够有效地清除体内促血栓形成的核酸和其他多磷酸盐，代表了一类新的、潜在更安全的抗血栓形成药物。
