The effect of the liposomal form of alteplase on the effectiveness of thrombolysis in coronary arteries in acute myocardial infarction

Abstract

A liposomal (Lip) formulation of tissue plasminogen activator, alteplase (AlT), has been developed. The quantitative and qualitative composition of the liposomes, as well as their physicochemical properties and proteolytic activity, have been studied in relation to the thrombolytic liposomal form. It was determined that a formulation consisting of liposomes with a phosphatidylcholine/cholesterol ratio of 1.5 : 1, and lipids/alteplase ratio of 1 : 1, is optimal for treating acute myocardial infarction (AMI) in experimental models. At different component ratios, liposomes had a negative zeta potential value greater than 30 mV, indicating their aggregative stability, even after storage for two days at 20 degrees Celsius. Liposomes derived from soy phosphatidylcholine showed greater colloidal stability with a zeta potential of approximately –57 mV and a lower hydrodynamic diameter of approximately 140 nanometers, compared to liposomes derived from egg phosphatidylcholine, which had a zeta potential around –35.4 mV and a hydrodynamic diameter around 220 nanometers. The initial content of free AlT in the liposome supernatant from egg phosphatidylcholine (Lipeg) was 15.0 ± 4.0 %. During the incubation period of 4 days, the concentration of free AlT decreased to 9.0 ± 4.5 %. In contrast, in liposomes derived from soy phosphatidylcholine (LipS), the content of free AlT increased from 11.0 ± 4.5 % to 32.5 ± 6.0 % over the same incubation period. The value of the proteolytic activity of tissue plasminogen activator (tPA) in the compositions of Lipeg(AlT) and Lips (AlT) depends on the type of phosphatidylcholine. The initial tPA activity in Lipeg (AlT) was 36.0 %, and after 1 day, it increased to 45 %. In Lips (AlT), the initial activity was 61.0 % and increased to 66 % after 1 day. When using the liposomal form of alteplase for delivery into the coronary arteries of rats with acute myocardial infarction (AMI), a more complete fibrin lysis is noted compared to animals receiving the native form of the drug. The developed system of targeted delivery of alteplase using soy liposomes has been shown to significantly improve the degree of coronary artery lumen restoration by more than 15 %, compared to the use of a conventional drug (p < 0.05).