文献：Targeted delivery and triggered release of liposomal doxorubicin enhances cytotoxicity against human B lymphoma cells

作者：TIshida a 1, M.J Kirchmeier a 2, E.H Moase a, S Zalipsky b, T.M Allen 

文献链接：https://www.sciencedirect.com/science/article/pii/S0005273601004096

摘要：

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.

通过添加聚乙二醇（PEG）的可切割脂质衍生物，其中PEG通过二硫键（mPEG-S-S-DSPE）连接到脂质锚定物上，含二油酰磷脂酰乙醇胺（DOPE）的脂质体以双层形式稳定其内容物的pH依赖性释放。

用不可切割的PEG（mPEG-DSPE）或mPEG-S-S-DSPE稳定的脂质体在pH 5.5时保留了包封的染料，但用二硫苏糖醇或无细胞提取物在pH 5.5下处理用mPEG-S-S-S-DSPE固定的脂质体，由于PEG链的切割和DOPE脂质体的伴随失稳，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在人血浆中迅速释放。pH敏感脂质体靶向B淋巴瘤细胞上的CD19表位，与非pH敏感脂质体制备的脂质体相比，显示出增强的DXR向靶细胞核的递送，并增加了细胞毒性。

药代动力学研究表明，mPEG-S-S-DSPE在循环中迅速裂解。在B细胞淋巴瘤的小鼠模型中，尽管抗CD19靶向pH敏感制剂的药物释放和清除速度更快，但其治疗效果优于稳定的靶向脂质体长循环制剂。

这些结果表明，靶向pH敏感的药物制剂可能能够提高包埋药物的治疗效果。

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