The use of PEGylated liposomes to prolong circulation lifetimes of tissue plasminogen activator
The use of PEGylated liposomes to prolong circulation lifetimes of tissue plasminogen activator
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DOI：
10.1016/j.biomaterials.2009.07.021
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发表时间：
2009-10-01
期刊：
影响因子：
14
通讯作者：
Kim, Chong-Kook
中科院分区：
文献类型：
--
作者：
Kim, Ji-Young;Kim, Jin-Ki;Kim, Chong-Kook
组织型纤溶酶原激活剂（tPA）是一种广泛应用的溶栓药物，但由于半衰期短而限制了其应用。为了延长tPA的半衰期，采用脂质膜法制备了由卵磷脂（EPC）、胆固醇（CHOL）和胆固醇-3-硫酸钠（CS）组成的脂质体。此外，包括二硬脂酰磷脂酰乙醇胺-N-聚（乙二醇）2000（DSPE-PEG 2000），以提供脂质体的空间屏障。考察了其粒径、Zeta电位、包封率和4 ℃长期贮存稳定性等理化特性。通过纤维蛋白凝块溶解试验证实脂质体中负载的tPA的纤维蛋白溶解活性。还评价了tPA的体内药代动力学特性和PEG对载tPA的脂质体在循环中的血液循环的影响。常规脂质体（EPCL）和聚乙二醇化脂质体（EPC-PEGL）均适合作为具有小粒径的可注射制剂。将tPA负载到脂质体中的过程不改变完整tPA的纤溶活性。与游离tPA相比，将tPA封装到EPCL和EPC-PEGL中分别使tPA的半衰期延长16倍和21倍。因此，脂质体的使用可以延长循环寿命，并且PEG增加了脂质体对tPA的寿命效应。(C)2009爱思唯尔有限公司保留所有权利。
Tissue plasminogen activator (tPA), a widely used thrombolytic agent, has an application limit due to short half-life. To prolong the half-life of tPA, liposomes composed of egg phosphatidylcholine (EPC), cholesterol (CHOL) and sodium cholesterol-3-sulfate (CS) were prepared by lipid film method. In addition, distearolyphosphatidyl ethanolamine-N-poly(ethylene glycol) 2000 (DSPE-PEG 2000) was included to give steric barrier to liposomes. Physicochemical characteristics such as particle size, zeta potential, entrapment efficiency and long-term storage stability at 4 degrees C were investigated. The fibrinolytic activity of tPA-loaded in liposomes was confirmed by fibrin clot lysis assay. In vivo pharmacokinetic properties of tPA and the effect of PEG on the blood circulation of tPA-loaded in liposomes in circulation were also evaluated. Both conventional liposomes (EPCL) and PEGylated liposomes (EPC-PEGL) were proper as an injectable formulation with small particle size. Loading process of tPA into liposomes did not alter fibrinolytic activity of intact tPA. Encapsulation of tPA into EPCL and EPC-PEGL prolonged half-life of tPA by 16 and 21 folds compared with free tPA, respectively. Therefore, the use of liposomes could prolong the circulation lifetimes and longevity effect of liposomes on tPA was increased by PEG. (C) 2009 Elsevier Ltd. All rights reserved.