Targeted delivery and triggered release of liposomal doxorubicin enhances cytotoxicity against human B lymphoma cells
Targeted delivery and triggered release of liposomal doxorubicin enhances cytotoxicity against human B lymphoma cells
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DOI：
10.1016/s0005-2736(01)00409-6
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发表时间：
2001-12-01
影响因子：
3.4
通讯作者：
Allen, TM
中科院分区：
文献类型：
--
作者：
Ishida, T;Kirchmeier, MJ;Allen, TM
含有二油酰磷脂酰乙醇胺（DOPE）且其内容物呈现pH依赖性释放的脂质体，通过添加一种可裂解的聚乙二醇（PEG）脂质衍生物而稳定在双层结构形式。在该衍生物中，PEG通过二硫键连接到脂质锚定物上（mPEG - S - S - DSPE）。用不可裂解的PEG（mPEG - DSPE）或mPEG - S - S - DSPE稳定的脂质体在pH 5.5时能保留包封的染料，但是用二硫苏糖醇或无细胞提取物在pH 5.5处理用mPEG - S - S - DSPE稳定的脂质体时，由于PEG链的裂解以及伴随的DOPE脂质体不稳定，会导致内容物释放。虽然载有阿霉素（DXR）的制剂在培养基中是稳定的，但DXR在人血浆中会迅速释放。靶向B淋巴瘤细胞上CD19表位的pH敏感脂质体，与非pH敏感脂质体相比，显示出向靶细胞细胞核内的DXR递送增强以及细胞毒性增加。药代动力学研究表明，mPEG - S - S - DSPE在循环中会迅速裂解。在B细胞淋巴瘤的小鼠模型中，尽管pH敏感制剂的药物释放和清除更快，但抗CD19靶向的pH敏感制剂的治疗效果优于稳定的长循环靶向脂质体制剂。这些结果表明，药物的靶向pH敏感制剂可能能够提高所包封药物的治疗效果。（C）2001 Elsevier Science B.V.保留所有权利。
Dioleoylphosphatidylethanolamine (DOPE)-containing liposomes that demonstrated pH-dependent release of their contents were stabilized in the bilayer form through the addition of a cleavable lipid derivative of polyethylene glycol (PEG) in which the PEG was attached to a lipid anchor via a disulfide linkage (mPEG-S-S-DSPE). Liposomes stabilized with either a non-cleavable PEG (mPEG-DSPE) or mPEG-S-S-DSPE retained an encapsulated dye at pH 5.5, but treatment at pH 5.5 of liposomes stabilized with mPEG-S-S-DSPE with either dithiothreitol or cell-free extracts caused contents release due to cleavage of the PEG chains and concomitant destabilization of the DOPE liposomes. While formulations loaded with doxorubicin (DXR) were stable in culture media, DXR was rapidly released in human plasma. pH-Sensitive liposomes, targeted to the CD19 epitope on B-lymphoma cells, showed enhanced DXR delivery into the nuclei of the target cells and increased cytotoxicity compared to non-pH-sensitive liposomes. Pharmacokinetic studies suggested that mPEG-S-S-DSPE was rapidly cleaved in circulation. In a murine model of B-cell lymphoma, the therapeutic efficacy of an anti-CD19-targeted pH-sensitive formulation was superior to that of a stable long-circulating formulation of targeted liposomes despite the more rapid drug release and clearance of the pH-sensitive formulation. These results suggest that targeted pH-sensitive formulations of drugs may be able to increase the therapeutic efficacy of entrapped drugs. (C) 2001 Elsevier Science B.V. All rights reserved.