Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation.
Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation.
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DOI：
10.2147/ijn.s38221
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发表时间：
2013
影响因子：
8
通讯作者：
Fang X
中科院分区：
文献类型：
--
作者：
Chen L;Sha X;Jiang X;Chen Y;Ren Q;Fang X
这项工作的目的是建立一种新型聚合物混合胶束，由 Pluronic P105 和 F127 共聚物组成，负载有难溶性抗肿瘤药物多西他赛 (DTX)，可对抗紫杉醇耐药的非小细胞肺癌。采用中心复合设计优化制备工艺，有助于提高药物增溶效率和胶束稳定性。采用薄膜水合法制备，优化后的混合胶束平均尺寸为23 nm，包封率为92.40%，载药率为1.81%。优化后的制剂在冻干形式下表现出较高的储存稳定性，4℃储存6个月后药物含量仍保持在95.7%。体外细胞毒性试验表明，泰索帝®和混合胶束对A549的IC50值相似，而在A549/紫杉醇细胞系上，负载DTX的P105/F127混合胶束表现出优异的超敏作用；与泰素帝注射液（0.593 μg/mL）相比，其IC50值（0.059 μg/mL）大大降低。体内药代动力学研究表明，与泰索帝相比，混合胶束制剂的循环平均停留时间长1.85倍，血浆浓度-时间曲线下面积大3.82倍。此外，混合胶束在体内针对 A549/紫杉醇的治疗效果也得到改善。胶束的抑瘤率为69.05%，而泰素帝为34.43%（P < 0.01）。因此，从结果可以得出结论，负载DTX的P105/F127混合胶束可能作为一种潜在的抗肿瘤药物递送系统来克服肺癌的多药耐药性。
The aim of this work was to establish a novel polymeric mixed micelle composed of Pluronic P105 and F127 copolymers loaded with the poorly soluble antitumor drug docetaxel (DTX) against Taxol-resistant non-small cell lung cancer. A central composite design was utilized to optimize the preparation process, helping to improve drug solubilization efficiency and micelle stability. Prepared by a thin-film hydration method, the average size of the optimized mixed micelle was 23 nm, with a 92.40% encapsulation ratio and a 1.81% drug-loading efficiency. The optimized formulation showed high storage stability in lyophilized form, with 95.7% of the drug content remaining after 6 months’ storage at 4°C. The in vitro cytotoxicity assay showed that the IC50 values for Taxotere® and mixed micelles were similar for A549, while on A549/Taxol cell lines, DTX-loaded P105/F127 mixed micelles showed a superior hypersensitizing effect; their IC50 value (0.059 μg/mL) was greatly reduced compared to those of Taxotere injections (0.593 μg/mL). The in vivo pharmacokinetic study showed that the mixed-micelle formulation achieved a 1.85-fold longer mean residence time in circulation and a 3.82-fold larger area under the plasma concentration-time curve than Taxotere. In addition, therapeutic improvement of mixed micelles in vivo against A549/Taxol was obtained. The tumor inhibition rate of the micelles was 69.05%, versus 34.43% for Taxotere (P < 0.01). Therefore, it could be concluded from the results that DTX-loaded P105/F127 mixed micelles might serve as a potential antitumor drug delivery system to overcome multidrug resistance in lung cancer.