Synthesis and evaluation of a novel lipophilic folate receptor targeting ligand.
Synthesis and evaluation of a novel lipophilic folate receptor targeting ligand.
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发表时间：
2011-05
影响因子：
2
通讯作者：
Y. Liu;Songlin Xu;Lesheng Teng;Bryant C Yung;Jing Zhu;Hong Ding;Robert J. Lee
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作者：
Y. Liu;Songlin Xu;Lesheng Teng;Bryant C Yung;Jing Zhu;Hong Ding;Robert J. Lee
背景技术靶向叶酸受体(FR)的脂质体已被研究作为抗癌药物的递送载体。合成了一种新型亲脂性 FR 配体叶酸-谷胱甘肽-聚乙二醇-二硬脂酰磷脂酰乙醇胺 (F-GSH-PEG-DSPE)，将其掺入脂质体中并评估 FR 靶向效率。然后将这些脂质体作为化疗药物长春新碱（VIN）的载体进行评估。材料和方法合成了F-GSH-PEG-DSPE，并通过薄膜水合，然后聚碳酸酯膜挤出，以及在VIN的情况下通过远程加载，制备了负载钙黄绿素（F-L-Calcein）或VIN（F-L-VIN）的FR靶向脂质体。为了评估脂质体稳定性，在 4°C 下储存 3 个月后测量 KB (FR+) 癌细胞中 F-L-VIN 的摄取。使用 F-L-VIN 和 L-VIN（非靶向对照脂质体）进行比较药代动力学研究。结果 与非靶向脂质体相比，F-L-钙黄绿素在 KB 细胞中显示出明显更高的细胞摄取。此外，与对照脂质体相比，F-L-VIN 在体外对 KB 细胞显示出增强的细胞毒性。药代动力学参数表明，F-L-VIN和对照脂质体均比游离VIN具有更高的曲线下面积（AUC）、平均停留时间（MRT）、消除半衰期（t1/2-β）和更低的全身清除率（CL），而这些脂质体制剂之间没有显着差异。结论 F-GSH-PEG-DSPE 作为合成 FR 靶向脂质体的新型配体是有效的。
BACKGROUND Folate receptor (FR)-targeted liposomes have been investigated as delivery vehicles for anticancer drugs. A novel lipophilic FR ligand, folate-glutathione-polyethyleneglycol-distearoyl phosphatidylethanolamine (F-GSH-PEG-DSPE), was synthesized, incorporated into liposomes and evaluated for FR targeting efficiency. These liposomes were then evaluated as carriers of the chemotherapy agent vincristine (VIN). MATERIALS AND METHODS F-GSH-PEG-DSPE was synthesized and FR-targeted liposomes loaded with either calcein (F-L-Calcein) or VIN (F-L-VIN) were prepared by thin film hydration followed by polycarbonate membrane extrusion and, in the case of VIN, by remote loading. To assess liposome stability, the uptake of F-L-VIN in KB (FR+) cancer cells was measured after storage under 4°C for 3 months. Comparative pharmacokinetic studies were carried out with F-L-VIN and L-VIN (non-targeted control liposomes). RESULTS F-L-Calcein showed significantly higher cellular uptake in KB cells compared to non-targeted liposomes. In addition, F-L-VIN showed enhanced cytotoxicity in KB cells in vitro compared to control liposomes. Pharmacokinetic parameters indicated that both F-L-VIN and control liposomes had higher area under the curve (AUC), mean residence time (MRT), elimination half life (t1/2-β) and lower total body clearance (CL) than those of free VIN, while there were no significant differences between these liposomal formulations. CONCLUSION F-GSH-PEG-DSPE is effective as a novel ligand for the synthesis of FR-targeted liposomes.