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.
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.
Zhang
Wei
W
School of Pharmacy, Fudan University, Shanghai, China.
Shi
Yuan
Y
Chen
Yanzuo
Y
Yu
Shuangyin
S
Hao
Junguo
J
Luo
Jieqi
J
Sha
Xianyi
X
Fang
Xiaoling
X
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage*; D011060:Poloxalene / Q000737:chemistry*
D000972:Antineoplastic Agents, Phytogenic; D008823:Micelles; C464484:pluronic block copolymer P123; D011060:Poloxalene; D017239:Paclitaxel