Evaluation of anticoagulant behavior of thrombin-inhibiting polymer with fibrinolytic factor-binding sites and application for biomaterials

本研究制备了以两性离子型l-丝氨酸或l-赖氨酸为侧链修饰的新型聚合物，聚（o -甲基丙烯酰-l -丝氨酸）[poly(SerMA)]、聚（α-甲基丙烯酰胺-l -赖氨酸）[poly(α-LysMA)]和聚（ε-甲基丙烯酰胺-l -赖氨酸）[poly(ε-LysMA)]作为血液相容性生物材料（如导管、透析器等）的表面改性剂。从两性离子聚合物对血清蛋白或血小板变性的影响，对凝血过程中起中心作用的凝血酶的抑制作用，对纤溶途径中主要酶原纤溶酶原的选择性结合作用，以及对纤溶酶或纤溶酶原/组织型纤溶酶原激活剂（t-PA）纤溶活性的增强作用等方面对其血液相容性的评价进行了研究。Poly（SerMA）、Poly（α-LysMA）和Poly（ε-LysMA）与白蛋白、γ-球蛋白、纤维蛋白原的相互作用较弱，可防止蛋白质变性。聚α-LysMA非竞争性抑制凝血酶活性。与纤溶酶原特异性结合的poly（α-LysMA）存在时，纤溶酶和纤溶酶原/t-PA的纤溶活性增强，而poly（SerMA）或poly（ε-LysMA）存在时，纤溶酶活性未见增强。根据测量结果，认为具有氨基酸片段的两性离子聚合物，特别是聚α-LysMA作为血液相容材料适用于生物医学设备。

Novel polymers modified with zwitterionic L-serine or L-lysine in the side chain, poly-(O-methacryloyl-L-serine)[poly(SerMA)], poly(α-methacrylamide-L-lysine)[poly(α-LysMA)], and poly(ε-methacrylamide-L-lysine) [poly(ε-LysMA)] were prepared as a surface modifier for blood compatible biomaterials such as catheter, dialyzer and so forth, Tn this research, the evaluation of their blood compatibility has been investigated from the point of view of effects of zwitterionic polymers on the denaturation of serum proteins or platelets, on the inhibition of thrombin which plays a central role in the bloodclotting process, on the selective binding of plasminogen which is the primary zymogen in the fibrinolytic pathway, and on the enhancement of fibrinolytic activity of plasmin or plasminogen/tissue type plasminogen activator(t-PA). Poly(SerMA), poly(α-LysMA), and poly(ε-LysMA) showed the low interaction with albumin, γ-globulin, fibrinogen to prevent protein denaturation. Poly(α-LysMA) uncompetitively inhibits thrombin activity. The fibrinolytic activity by plasmin and plasminogen/t-PA, was enhanced in the presence of poly(α-LysMA) showing specific binding to plasminogen, no enhancement of their fibrinolytic activity was observed in the case of poly(SerMA) or poly(ε-LysMA). As a result ofmeasurements, it is considered that zwitterionic polymers having amino acid moiety, especially poly(α-LysMA) as a blood compatible material are applicable for use in the biomedical devices.