Abstract

Polyamidoamine (PAMAM) dendrimers are used in medicine for systemic drug delivery. The safety assessment of biomaterials, which come into contact with blood components and tissues is especially important. For example, PAMAM-NH₂ dendrimers G4–G7 cause platelet and fibrinogen aggregation. We have studied the effect of the PAMAM-COOH dendrimers G1.5–G3.5 on key components of the fibrinolysis system. The dendrimers have not affected the plasmin activity. However, the amidolytic activities of tissue activators of plasminogen (tPA) and urokinase (uPA) have decreased markedly with increasing the dendrimer concentration and generation. The peak intensity at 340 nm of Glu-plasminogen fluorescence in the absence and presence of 0.15 M NaCl has decreased with increasing the dendrimer concentration, thus indicating the change in the microenvironment of the Trp residues and molecular conformation of the open and closed Glu-plasminogen forms. A comparison of the fluorescence quenching constants suggests that the anionic dendrimer and chloride ion simultaneously bind to Glu-plasminogen and each of these ligands exerts its independent effects through the separate binding sites. With increasing the dendrimer concentration, the rate of the tPA- and uPA-induced activation of Glu-plasminogen has dramatically decreased due probably to the formation of dendrimer*plasminogen complexes with the increasing dendrimer content, which makes the plasminogen bond increasingly unavailable for the cleavage by the activators. The rate of tPA- and uPA-induced lysis of the plasma clot in plasma has moderately decreased with increasing the dendrimer concentration due probably to the reduced effect of the dendrimer on the fibrin-bound plasminogen. Thus, the nature of the inhibitory action of the anionic PAMAM dendrimers on the Glu-plasminogen activation and tPA- and uPA-induced thrombolysis consists of a noticeable inactivation of the activators and a significant change in plasminogen conformation. The PAMAM-COOH dendrimers in circulation can affect other physiological and pathological processes, which are associated with an important role of the plasminogen/plasmin system.

中文翻译：

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1.5-3.5代阴离子聚酰胺型胺树枝状大分子对纤溶系统活性的抑制作用性质

摘要

聚酰胺胺（PAMAM）树状大分子在药物中用于全身性药物输送。与血液成分和组织接触的生物材料的安全性评估尤为重要。例如，PAMAM-NH ₂树状大分子G4-G7导致血小板和纤维蛋白原聚集。我们已经研究了PAMAM-COOH树状大分子G1.5-G3.5对纤溶系统关键成分的影响。树状聚合物没有影响纤溶酶的活性。然而，纤溶酶原（tPA）和尿激酶（uPA）的组织激活剂的酰胺分解活性随着树枝状聚合物浓度和生成的增加而显着降低。在不存在和存在0.15 M NaCl的情况下，Glu-纤溶酶原荧光在340 nm处的峰值强度随着树枝状聚合物浓度的增加而降低，从而表明Trp残基的微环境以及开闭Glu-纤溶酶原的分子构象的变化形式。荧光猝灭常数的比较表明，阴离子树状聚合物和氯离子同时与Glu-纤溶酶原结合，并且这些配体中的每一个都通过单独的结合位点发挥其独立的作用。随着树枝状聚合物浓度的增加，tPA和uPA诱导的Glu-纤溶酶原激活的速率已显着降低，这可能是由于树枝状聚合物含量增加而形成的树枝状聚合物*纤溶酶原复合物，这使得纤溶酶原键越来越不可用于裂解。由激活者。tPA和uPA诱导的血浆中血浆凝块的溶解速率随着树枝状聚合物浓度的增加而有所降低，这可能是由于树枝状聚合物对血纤蛋白结合的纤溶酶原的作用减弱所致。从而，阴离子PAMAM树状聚合物对Glu-纤溶酶原激活以及tPA和uPA诱导的溶栓的抑制作用的性质包括激活剂的显着失活和纤溶酶原构象的显着变化。循环中的PAMAM-COOH树状聚合物可影响其他生理和病理过程，这些过程与纤溶酶原/纤溶酶系统的重要作用有关。