Mina Natasha, Guido Vinicius S, Prezoto Benedito C, Oliva Maria Luiza V, Sousa Alioscka A
Department of Biochemistry, Federal University of São Paulo, São Paulo, SP 04044-020, Brazil.
Laboratory of Pharmacology, Butantan Institute, São Paulo, SP 05503-900, Brazil.
ACS Omega. 2024 Dec 18;9(52):51306-51319. doi: 10.1021/acsomega.4c08120. eCollection 2024 Dec 31.
Polyamidoamine (PAMAM) dendrimers, with their unique structural versatility and tunable surface functionalities, have emerged as promising nanomaterials for a wide range of biomedical applications. However, their in vivo use raises concerns, as unintended interactions between dendrimers and blood components could disrupt the delicate hemostatic balance and lead to serious complications like bleeding or thrombosis. In this study, we explored the impact of low-generation PAMAM dendrimers on the kinetics of fibrin clot formation, along with their influence on the structure, properties, and resistance to lysis of the resulting clots. For this purpose, we employed a multilevel characterization approach using purified fibrinogen, human plasma, and whole blood to assess the effects of four dendrimer types: G2-NH, G4-NH, G3.5-COOH, and G4-OH. Among the main findings, both G2-NH and G4-NH significantly impaired thrombin generation and delayed clot formation, with G4-NH also promoting fibrin aggregation, increasing clot permeability, and accelerating clot lysis. When present at high concentrations, G4-OH also affected critical clotting parameters, delaying thrombin generation and prolonging clotting time. Notably, the prolongation of clotting time by G4-OH was evident in both human plasma and whole blood. Interestingly, G3.5-COOH showed potential as a safer option since it induced minimal alterations across most tested metrics. These results will be important for guiding the rational design of dendrimers and identifying safe concentrations for future clinical applications.
聚酰胺-胺（PAMAM）树枝状大分子凭借其独特的结构多样性和可调节的表面功能，已成为用于广泛生物医学应用的有前途的纳米材料。然而，它们在体内的使用引发了担忧，因为树枝状大分子与血液成分之间的意外相互作用可能会破坏微妙的止血平衡，并导致出血或血栓形成等严重并发症。在本研究中，我们探讨了低代PAMAM树枝状大分子对纤维蛋白凝块形成动力学的影响，以及它们对所得凝块的结构、性质和抗溶解能力的影响。为此，我们采用了一种多级表征方法，使用纯化的纤维蛋白原、人血浆和全血来评估四种树枝状大分子类型的影响：G2-NH、G4-NH、G3.5-COOH和G4-OH。主要研究结果包括，G2-NH和G4-NH均显著损害凝血酶生成并延迟凝块形成，G4-NH还促进纤维蛋白聚集、增加凝块通透性并加速凝块溶解。当高浓度存在时，G4-OH也会影响关键的凝血参数，延迟凝血酶生成并延长凝血时间。值得注意的是，G4-OH对凝血时间的延长在人血浆和全血中均很明显。有趣的是，G3.5-COOH显示出作为更安全选择的潜力，因为它在大多数测试指标上引起的变化最小。这些结果对于指导树枝状大分子的合理设计以及确定未来临床应用的安全浓度将具有重要意义。
