Enhanced antitumor efficacy by paclitaxel-loaded pluronic P123/F127 mixed micelles against non-small cell lung cancer based on passive tumor targeting and modulation of drug resistance.

摘要

The aim of this work was to demonstrate the advantage of using paclitaxel (PTX)-loaded Pluronic P123/F127 mixed micelles (PF-PTX) against non-small cell lung cancer (NSCLC) compared to Taxol. Modulation of multidrug resistance (MDR) by Pluronic mixed micelles was evaluated in lung resistance protein (LRP)-overexpressing human lung adenocarcinoma A-549 cell line. Influence of PF-PTX on in vitro cytotoxicity was determined by MTT assay, while cellular apoptosis was detected by cell nuclei staining and Annexin V-FITC apoptosis detection kit. Cell cycle arrest was also confirmed by flow cytometry. Additionally, in vivo fate and antitumor efficacy of PF-PTX were extensively evaluated in comparison with Taxol. It was demonstrated that PF-PTX had superior anti-proliferation activity against A-549 cells compared with Taxol as measured by IC(50). The enhanced anti-cancer efficacy of PF-PTX was associated with PTX-induced apoptosis and cell arrest in the G(2)/M phase. Intracellular ATP depletion and decreased mitochondrial potential caused by Pluronic copolymers were found to be related to modulation of MDR. PF-PTX also exhibited significant advantages in pharmacokinetics and A-549 xenograft tumor model versus Taxol. The PF-PTX formulation achieved 3.0-fold longer mean residence time in circulation, 2.2-fold larger area under the plasma concentration-time curve than Taxol. At 28days, tumor volume in PF-PTX group was only 31.8% that of the Taxol. Therefore, PF-PTX significantly enhanced the anti-cancer activity of PTX and might be considered a promising drug delivery system to overcome MDR in lung cancer.