BACKGROUND: Polyamidoamine (PAMAM) dendrimers are a new class of monodisperse polymers that are used for drug delivery in systemic administrations. The influence of PAMAM dendrimers on components of the blood coagulation system has been extensively studied, but their effect on the activity of the fibrinolysis system has not been studied to date. METHODS: The effect of cationic (G1-G3) and anionic (G1.5-G3.5) PAMAM dendrimers on the conformation and function of the main components of the coagulation and fibrinolysis systems was comparatively studied. Changes in overall plasma hemostatic potential, thrombin generation, prothrombin time, thrombin and tPA activities, the fluorescence of fibrinogen and plasminogen, zeta potential, polymerization of fibrinogen, and activation of plasminogen were analyzed to assess coagulofibrinolytic mechanisms of influence of the charge of the dendrimers. RESULTS: Cationic dendrimers increased prothrombin time, suppressed thrombin generation in plasma, and changed the conformation and coagulability of fibrinogen, while anionic dendrimers did not have such effects. Anionic dendrimers slightly reduced tPA activity and altered plasminogen conformation much more strongly than the cationic dendrimers. Plasminogen activation by tPA was strongly inhibited by anionic dendrimers and weakly stimulated by cationic dendrimers. All these effects were enhanced with increasing generation and concentration of the dendrimers. CONCLUSIONS: PAMAM-NH2 dendrimers inhibit the extrinsic activation pathway of the coagulation system and alter the conformation and function of fibrinogen. PAMAM-COOH dendrimers change the conformation of plasminogen and inhibit its activation by tPA. This study gives new insight into the effect of anionic PAMAM dendrimers on the activity of the fibrinolytic system. For intravenous applications, the antifibrinolytic effect of anionic PAMAM dendrimers of generation ≥G2.5 should be considered.
BACKGROUND:Polyamidoamine (PAMAM) dendrimers are a new class of monodisperse polymers that are used for drug delivery in systemic administrations. The influence of PAMAM dendrimers on components of the blood coagulation system has been extensively studied, but their effect on the activity of the fibrinolysis system has not been studied to date. METHODS: The effect of cationic (G1-G3) and anionic (G1.5-G3.5) PAMAM dendrimers on the conformation and function of the main components of the coagulation and fibrinolysis systems was comparatively studied. Changes in overall plasma hemostatic potential, thrombin generation, prothrombin time, thrombin and tPA activities, the fluorescence of fibrinogen and plasminogen, zeta potential, polymerization of fibrinogen, and activation of plasminogen were analyzed to assess coagulofibrinolytic mechanisms of influence of the charge of the dendrimers. RESULTS: Cationic dendrimers increased prothrombin time, suppressed thrombin generation in plasma, and changed the conformation and coagulability of fibrinogen, while anionic dendrimers did not have such effects. Anionic dendrimers slightly reduced tPA activity and altered plasminogen conformation much more strongly than the cationic dendrimers. Plasminogen activation by tPA was strongly inhibited by anionic dendrimers and weakly stimulated by cationic dendrimers. All these effects were enhanced with increasing generation and concentration of the dendrimers. CONCLUSIONS:PAMAM-NH2 dendrimers inhibit the extrinsic activation pathway of the coagulation system and alter the conformation and function of fibrinogen. PAMAM-COOH dendrimers change the conformation of plasminogen and inhibit its activation by tPA. This study gives new insight into the effect of anionic PAMAM dendrimers on the activity of the fibrinolytic system. For intravenous applications, the antifibrinolytic effect of anionic PAMAM dendrimers of generation ≥G2.5 should be considered.
Authors: Kamila Białkowska; Katarzyna Miłowska; Sylwia Michlewska; Paulina Sokołowska; Piotr Komorowski; Tania Lozano-Cruz; Rafael Gomez-Ramirez; Francisco Javier de la Mata; Maria Bryszewska Journal: Int J Mol Sci Date: 2021-07-01 Impact factor: 5.923
Authors: Magdalena Szota; Katarzyna Reczyńska-Kolman; Elżbieta Pamuła; Olga Michel; Julita Kulbacka; Barbara Jachimska Journal: Int J Mol Sci Date: 2021-10-16 Impact factor: 5.923