文獻：A folate receptor-targeted liposomal formulation for paclitaxel

作者：Jun Wu, Qing Liu, Robert J. Lee

文獻鏈接：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.

合成并表征了一種靶向葉酸受體（FR）的紫杉醇脂質體制劑。該制劑旨在克服與傳統的基于Cremophor EL的制劑相關的載體毒性，并提供延長全身循環時間和選擇性靶向FR的額外優勢，FR在皮細胞上經常過表達。

該制劑的組成為二棕櫚酰磷脂酰膽堿/二肉豆蔻酰磷脂酰甘油/單甲氧基聚乙二醇（PEG）2000二硬脂酰磷脂酰乙醇胺/葉酸-PEG3350-二硬脂酰膦酰乙醇胺（DPPC/DMPG/mPEG-DSPE/葉酸-PEG-DSPE），摩爾比為（85.5:9.5:4.5:0.5），藥物與脂質摩爾比為1:33。脂質體通過聚碳酸酯膜擠出制備。

脂質體的平均粒徑為97.1 nm，在4°C下保持穩定至少72小時。包埋鈣黃綠素的相同脂質組成的FR靶向脂質體被高度FR+的KB細胞有效吸收。

在KB細胞中，含有紫杉醇的FR靶向脂質體的細胞毒性是非靶向對照脂質體的3.8倍。然后將脂質體制劑中紫杉醇的血漿清除率與Cremophor EL制劑中的紫杉醇進行比較。

脂質體制劑的終末半衰期（FR靶向和非靶向脂質體分別為12.33和14.23小時）比Cremophor EL中的紫杉醇（1.78小時）長得多。總之，本研究中描述的紫杉醇制劑具有相當的穩定性和良好的藥代動力學特性。

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