State Key Laboratory of Virology, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Wuhan University School of Pharmaceutical Sciences, Wuhan, PR China.
Anticancer Res. 2012 Jul;32(7):2919-23.
Gefitinib is a promising agent for the treatment of non-small cell lung cancer. The purpose of this study was to develop a novel liposomal formulation for gefitinib (L-GEF) to improve its therapeutic index.
Several L-GEF formulations were prepared and characterized for their physical chemical properties and cytotoxicity. The pharmacokinetic parameters of the liposomes were determined in mice. The effect of lipid composition, transmembrane pH gradient, and incorporation of hydroxypropyl-β-cyclodextrin (HPβCD) on drug-loading efficiency, liposomal stability, and the rate of drug release were investigated.
The L-GEF formulation composed of hydrogenated soy phosphatidylcholine (HSPC)/cholesterol (Chol)/monomethoxy polyethylene glycol 2000-distearoyl phosphatidyl-ethanolamine (mPEG-DSPE) encapsulating 0.3 M (NH4)2SO4 and 0.1 M HPβCD (L-GEF-HSPC), had a drug-loading efficiency (DLE) of 85.5%. In vitro release studies showed that gefitinib release from L-GEF-HSPC in the presence of human plasma was slow and exhibited non-Fickian kinetics. Pharmacokinetic study in mice after i.v. bolus administration of L-GEF-HSPC showed that the area under the plasma concentration time curve (AUC) for gefitinib was 32.41 μg·h /ml and six times that of free gefitinib. The elimination half life (t(1/2β)) of L-GEF-HSPC was 7.29 h, while that of free gefitinib was 2.26 h.
It was shown that gefitinib can be efficiently loaded into L-GEF-HSPC composed of HSPC/Chol/mPEG-DSPE (55/40/5 mol/mol) with 0.3 M (NH(4))(2)SO(4) and 0.1 M HPβCD as trapping agents. Compared with the free drug, L-GEF-HSPC had high drug loading, good stability, and long-circulating properties.
吉非替尼是一种有前途的非小细胞肺癌治疗药物。本研究旨在开发一种新的吉非替尼脂质体（L-GEF）制剂，以提高其治疗指数。
制备了几种 L-GEF 制剂，并对其理化性质和细胞毒性进行了表征。在小鼠中测定了脂质体的药代动力学参数。考察了脂质组成、跨膜 pH 梯度和羟丙基-β-环糊精（HPβCD）的加入对载药量、脂质体稳定性和药物释放速率的影响。
由氢化大豆磷脂酰胆碱（HSPC）/胆固醇（Chol）/单甲氧基聚乙二醇 2000-二硬脂酰基磷脂酰乙醇胺（mPEG-DSPE）组成的 L-GEF 制剂（HSPC/Chol/mPEG-DSPE 摩尔比为 55/40/5），包封 0.3 M（NH4）2SO4和 0.1 M HPβCD（L-GEF-HSPC），载药量（DLE）为 85.5%。体外释放研究表明，在人血浆存在的情况下，L-GEF-HSPC 中吉非替尼的释放缓慢，呈非菲克动力学。小鼠静脉推注 L-GEF-HSPC 后的药代动力学研究表明，吉非替尼的血浆浓度时间曲线下面积（AUC）为 32.41 μg·h/ml，是游离吉非替尼的 6 倍。L-GEF-HSPC 的消除半衰期（t1/2β）为 7.29 h，而游离吉非替尼为 2.26 h。
结果表明，吉非替尼可有效包封于由 HSPC/Chol/mPEG-DSPE（55/40/5mol/mol）组成的 L-GEF-HSPC 中，以 0.3 M（NH4）2SO4和 0.1 M HPβCD 作为捕获剂。与游离药物相比，L-GEF-HSPC 具有较高的载药量、良好的稳定性和长循环特性。
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