文献：A folate receptor-targeted liposomal formulation for paclitaxel

作者：Jun Wu, Qing Liu, Robert J. Lee

文献链接：https://www.sciencedirect.com/science/article/abs/pii/S0378517306001505

摘要：

A novel liposomal formulation of paclitaxel targeting the folate receptor (FR) was synthesized and characterized. This formulation was designed to overcome vehicle toxicity associated with the traditional Cremophor EL-based formulation and to provide the added advantages of prolonged systemic circulation time and selective targeting of the FR, which is frequently overexpressed on epithelial cancer cells. The formulation had the composition of dipalmitoyl phosphatidylcholine/dimyristoyl phosphatidylglycerol/monomethoxy-polyethylene glycol (PEG)2000-distearoyl phosphatidylethanolamine/folate-PEG3350-distearoyl phosphatidylethanolamine (DPPC/DMPG/mPEG-DSPE/folate-PEG-DSPE) at molar ratios of (85.5:9.5:4.5:0.5) and a drug-to-lipid molar ratio of 1:33. The liposomes were prepared by polycarbonate membrane extrusion. The mean particle size of the liposomes was 97.1 nm and remained stable for at least 72 h at 4 °C. FR-targeted liposomes of the same lipid composition entrapping calcein were shown to be efficiently taken up by KB oral carcinoma cells, which are highly FR+. FR-targeted liposomes containing paclitaxel showed 3.8-fold greater cytotoxicity compared to non-targeted control liposomes in KB cells. Plasma clearance profiles of paclitaxel in the liposomal formulations were then compared to paclitaxel in Cremophor EL formulation. The liposomal formulations showed much longer terminal half-lives (12.33 and 14.23 h for FR-targeted and non-targeted liposomes, respectively) than paclitaxel in Cremophor EL (1.78 h). In conclusion, the paclitaxel formulation described in this study has substantial stability and favorable pharmacokinetic properties. The FR-targeted paclitaxel formulation is potentially useful for treatment of FR+ tumors and warrants further investigation.

合成并表征了一种靶向叶酸受体（FR）的紫杉醇脂质体制剂。该制剂旨在克服与传统的基于Cremophor EL的制剂相关的载体毒性，并提供延长全身循环时间和选择性靶向FR的额外优势，FR在皮细胞上经常过表达。

该制剂的组成为二棕榈酰磷脂酰胆碱/二肉豆蔻酰磷脂酰甘油/单甲氧基聚乙二醇（PEG）2000二硬脂酰磷脂酰乙醇胺/叶酸-PEG3350-二硬脂酰膦酰乙醇胺（DPPC/DMPG/mPEG-DSPE/叶酸-PEG-DSPE），摩尔比为（85.5:9.5:4.5:0.5），药物与脂质摩尔比为1:33。脂质体通过聚碳酸酯膜挤出制备。

脂质体的平均粒径为97.1 nm，在4°C下保持稳定至少72小时。包埋钙黄绿素的相同脂质组成的FR靶向脂质体被高度FR+的KB细胞有效吸收。

在KB细胞中，含有紫杉醇的FR靶向脂质体的细胞毒性是非靶向对照脂质体的3.8倍。然后将脂质体制剂中紫杉醇的血浆清除率与Cremophor EL制剂中的紫杉醇进行比较。

脂质体制剂的终末半衰期（FR靶向和非靶向脂质体分别为12.33和14.23小时）比Cremophor EL中的紫杉醇（1.78小时）长得多。总之，本研究中描述的紫杉醇制剂具有相当的稳定性和良好的药代动力学特性。

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