School of Pharmacy, The University of Auckland, Auckland, New Zealand.
J Drug Target. 2010 Feb;18(2):125-33. doi: 10.3109/10611860903244199.
Chlorambucil was incorporated into a nanoemulsion modified with poly(ethylene glycol) to improve its pharmacokinetics and tissue distribution, and thus enhance its therapeutic efficacy. A long-circulating nanoemulsion (LNE) was prepared using soybean oil, egg lecithin, cholesterol and PEG(2000)DSPE. The LNE had an oil droplet size <200 nm with a surface charge of -32.2 to -35.6 mV. Approximately, 97% of the chlorambucil was encapsulated in the LNE. Intravenous (i.v.) administration of the chlorambucil LNE to C57 B/6 mice showed improved pharmacokinetic parameters with 1.4-fold higher area under the plasma concentration-time curve (AUC) and 1.3-fold longer half-life compared to a non-PEG-modified nanoemulsion, and 2.7-fold higher AUC and 7.6-fold longer half-life compared to chlorambucil solution. Tissue distribution studies after i.v. administration with LNE showed a considerable decrease in drug uptake in the reticulo-endothelial system containing organs compared to non-PEG-modified nanoemulsion. Additionally, the chlorambucil delivered in LNE significantly enhanced therapeutic efficacy in the subcutaneous colon-38 adenocarcinoma tumor mouse model with no apparent increase in toxicity. This study suggests that LNE could produce remarkably improved pharmacokinetic profile and therapeutic efficacy of chlorambucil compared to non-PEG-modified nanoemulsion and solution.
氯丁二烯与聚乙二醇（PEG）修饰的纳米乳液结合，以改善其药代动力学和组织分布，从而提高其治疗效果。使用大豆油、蛋黄卵磷脂、胆固醇和 PEG（2000）DSPE 制备长循环纳米乳液（LNE）。LNE 的油滴大小<200nm，表面电荷为-32.2 至-35.6mV。大约 97%的氯丁二烯被包裹在 LNE 中。将氯丁二烯 LNE 静脉注射（i.v.）给予 C57 B/6 小鼠，与非 PEG 修饰的纳米乳液相比，其药代动力学参数得到改善，表现为血浆浓度-时间曲线下面积（AUC）增加 1.4 倍，半衰期延长 1.3 倍；与氯丁二烯溶液相比，AUC 增加 2.7 倍，半衰期延长 7.6 倍。静脉注射 LNE 后的组织分布研究表明，与非 PEG 修饰的纳米乳液相比，药物在含网状内皮系统的器官中的摄取量明显减少。此外，LNE 递送的氯丁二烯在皮下结肠-38 腺癌肿瘤小鼠模型中显著提高了治疗效果，而毒性没有明显增加。本研究表明，与非 PEG 修饰的纳米乳液和溶液相比，LNE 可显著改善氯丁二烯的药代动力学特征和治疗效果。
