Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes
Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes
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DOI：
10.1016/s0168-3659(99)00166-2
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发表时间：
2000-01-03
影响因子：
10.8
通讯作者：
Cattel, L
中科院分区：
文献类型：
--
作者：
Crosasso, P;Ceruti, M;Cattel, L
紫杉醇(Taxol)是从短叶红豆杉中分离出来的一种二萜类化合物，经FDA批准用于治疗卵巢癌和乳腺癌。由于其在水中的溶解度较低，临床上常溶于乳油、聚乙氧基蓖麻油和乙醇，副作用严重。在脂质体中加入紫杉醇已被证明是消除这种载体和提高药物抗肿瘤疗效的一种很好的方法。我们制备了不同的紫杉醇常规脂质体和聚乙二醇化脂质体，并测定了包封率、物理稳定性和药物在人体内的渗漏。以EPC/PG 9：1为最佳常规脂质体处方，以EPC/PG/Chol/PEG(5000)-DPPE 9：1：2：0.7为最佳配方。在37℃下，聚乙二醇化脂质体的稳定性比相应的常规脂质体差，药物在人血浆中的释放量也较低。体外细胞毒活性测定对人结肠腺癌和MeWo黑色素瘤细胞系的细胞毒作用。2、48h后，常规脂质体与游离紫杉醇具有相同的细胞毒性，而聚乙二醇化脂质体仅在48h后才具有与游离药物相同的细胞毒性。注射紫杉醇，无论是在Cremvoor EL中，还是在常规脂质体或聚乙二醇化脂质体中，紫杉醇在常规脂质体中的包封率与游离药物的药代动力学有显著差异。聚乙二醇化脂质体为长循环脂质体，其t(1/2)β为48.6h，而常规脂质体的t(1/2)为9.27h。生物分布研究表明，注射聚乙二醇化聚乙二醇酯后0.5h和3h，含MPS的器官(肝和脾)的药物摄取量与常规脂质体相比显著降低。(C)2000 Elsevier Science B.V.保留所有权利。
Paclitaxel (Taxol) is a diterpenoid isolated from Taxus brevifolia, approved by the FDA for the treatment of ovarian and breast cancers. Due to its low solubility in water, it is clinically administered dissolved in Cremophor EL, (polyethoxylated castor oil) and ethanol, which cause serious side effects. Inclusion of paclitaxel in liposomal formulations has proved to be a good approach to eliminating this vehicle and improving the drug's antitumor efficacy. We prepared different conventional and PEGylated liposomes containing paclitaxel and determined encapsulation efficiency, physical stability and drug leakage in human plasma. The best conventional liposome formulation was composed of ePC/PG 9:1, while for PEGylated liposomes the best composition was ePC/PG/CHOL/PEG(5000)-DPPE 9:1:2:0.7. PEGylated liposomes were found to be less stable during storage than the corresponding conventional liposomes and to have lower drug release in human plasma at 37 degrees C. in vitro cytotoxic activities were evaluated on HT-29 human colon adenocarcinoma and MeWo melanoma cell Lines. After 2 and 48 h, conventional liposomes had the same cytotoxicity as free paclitaxel, while PEGylated liposomes were as active as free drug, only after 48 h. Pharmacokinetics and biodistribution were evaluated in Balb/c mice after i.v. injection of paclitaxel, formulated in Cremophor EL or in conventional or in PEGylated liposomes, Encapsulation of paclitaxel in conventional liposomes produced marked differences over the free drug pharmacokinetics. PEGylated liposomes were long-circulating liposomes, with an increased t(1/2) beta 48.6 h, against t(1/2) beta 9.27 h of conventional liposomes. Biodistribution studies showed a considerable decrease in drug uptake in MPS-containing organs (liver and spleen) at 0.5 and 3 h after injection with PEGylated compared to conventional liposomes. (C) 2000 Elsevier Science B.V. All rights reserved.