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Influence of Drug-to-Lipid Ratio on Drug Release Properties and Liposome Integrity in Liposomal Doxorubicin Formulations
Journal of Liposome Research ( IF 3.6 ) Pub Date : 2008-01-01 , DOI: 10.1080/08982100802129372
Michael J W Johnston 1 , Katarina Edwards , Goran Karlsson , Pieter R Cullis
Affiliation  

Recent studies have shown that the release properties of vincristine encapsulated in large unilamellar vesicles (LUV) can be regulated by varying the drug-to-lipid (D/L) ratio. In this work it is shown that the drug-to-lipid ratio technique for regulating drug release also applies to doxorubicin encapsulated in LUV. In particular it is shown that the half-times (T1/2) for doxorubicin release from distearoylphosphatidylcholine (DSPC)/cholesterol LUV in vitro can be increased more than six-fold by increasing the D/L ratio from 0.05 (wt/wt) to 0.39 (wt/wt). This behavior is consistent with the behavior expected for drugs that precipitate following accumulation into liposomes. It is shown that the release properties of ciprofloxacin—a drug that does not precipitate following accumulation into LUV—are not affected by the D/L ratio. It is also shown that the crystalline intravesicular doxorubicin precipitates observed as the D/L ratio is raised from 0.05 to 0.46 adopt increasingly unusual morphologies. Linear crystals are observed at lower D/L values, however triangular and rectangular variations are observed as the D/L ratio is increased, and induce considerable distortion in vesicle morphology. It is noted that trapping efficiency following uptake of external doxorubicin into LUV is reduced from nearly 100% at a D/L ratio of 0.05 (wt/wt) to less than 70% at an (initial) D/L ratio of 0.8 (wt/wt). It is suggested that this arises, at least in part, from membrane-disrupting effects of internal drug crystals as they increase in size.

中文翻译:

药物与脂质比对阿霉素脂质体制剂中药物释放特性和脂质体完整性的影响

最近的研究表明,包裹在大单层囊泡 (LUV) 中的长春新碱的释放特性可以通过改变药物与脂质 (D/L) 的比率来调节。在这项工作中表明,用于调节药物释放的药物与脂质比技术也适用于封装在 LUV 中的阿霉素。特别是表明,通过将 D/L 比从 0.05 (wt/wt) 增加,阿霉素在体外从二硬脂酰磷脂酰胆碱 (DSPC)/胆固醇 LUV 释放的半衰期 (T1/2) 可以增加六倍以上到 0.39(重量/重量)。这种行为与药物在脂质体中积累后沉淀的预期行为一致。结果表明,环丙沙星(一种在积累到 LUV 后不会沉淀的药物)的释放特性不受 D/L 比的影响。还表明,随着 D/L 比从 0.05 增加到 0.46,观察到的结晶囊内阿霉素沉淀采用越来越不寻常的形态。在较低的 D/L 值下观察到线性晶体,但是随着 D/L 比的增加,观察到三角形和矩形的变化,并引起囊泡形态的相当大的变形。值得注意的是,将外部多柔比星吸收到 LUV 后的捕获效率从 D/L 比为 0.05 (wt/wt) 时的近 100% 降低到 (初始) D/L 比为 0.8 (wt/wt) 时的小于 70% /wt)。有人认为,这至少部分是由于内部药物晶体随着尺寸增加而产生的膜破坏作用。46 采用越来越不寻常的形态。在较低的 D/L 值下观察到线性晶体,但是随着 D/L 比的增加,观察到三角形和矩形的变化,并引起囊泡形态的相当大的变形。值得注意的是,将外部多柔比星吸收到 LUV 后的捕获效率从 D/L 比为 0.05 (wt/wt) 时的近 100% 降低到 (初始) D/L 比为 0.8 (wt/wt) 时的小于 70% /wt)。有人认为,这至少部分是由于内部药物晶体随着尺寸增加而产生的膜破坏作用。46 采用越来越不寻常的形态。在较低的 D/L 值下观察到线性晶体,但是随着 D/L 比的增加,观察到三角形和矩形的变化,并引起囊泡形态的相当大的变形。值得注意的是,将外部多柔比星吸收到 LUV 后的捕获效率从 D/L 比为 0.05 (wt/wt) 时的近 100% 降低到 (初始) D/L 比为 0.8 (wt/wt) 时的小于 70% /wt)。有人认为,这至少部分是由于内部药物晶体随着尺寸增加而产生的膜破坏作用。值得注意的是,将外部多柔比星吸收到 LUV 后的捕获效率从 D/L 比为 0.05 (wt/wt) 时的近 100% 降低到 (初始) D/L 比为 0.8 (wt/wt) 时的小于 70% /wt)。有人认为,这至少部分是由于内部药物晶体随着尺寸增加而产生的膜破坏作用。值得注意的是,将外部多柔比星吸收到 LUV 后的捕获效率从 D/L 比为 0.05 (wt/wt) 时的近 100% 降低到 (初始) D/L 比为 0.8 (wt/wt) 时的小于 70% /wt)。有人认为,这至少部分是由于内部药物晶体随着尺寸增加而产生的膜破坏作用。
更新日期:2008-01-01
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