title: Mechanism of inhibition of P-glycoprotein mediated efflux by Pluronic P123/F127 block copolymers: relationship between copolymer concentration and inhibitory activity.
abstract: The aim of this study was to clarify the relationship between the concentration of Pluronic P123/F127 block copolymers and P-glycoprotein (P-gp) inhibitory potency. Modulation of multidrug resistance (MDR) by Pluronic P123/F127 was evaluated in P-gp over-expressing human breast cancer cell line MCF-7/ADR and its non-P-gp over-expressing counterpart MCF-7 cells. Four different probes (known as P-gp substrates) including rhodamine 123 (R-123), rhodamine 6G (R-6G), doxorubicin (DOX), and paclitaxel (PTX) were applied to investigate the impact of Pluronic P123/F127 copolymers with different concentrations on the intracellular accumulation of these probes. Additionally, the intracellular ATP and mitochondrial transmembrane potential in MCF-7/ADR cells were determined over a wide concentration range of Pluronic P123/F127. Furthermore, the endocytic mechanisms of Pluronic micelles were performed. It was suggested that P-gp substrate hydrophobicity and the concentration of P123/F127 copolymers had little impact on P-gp inhibitory activity of Pluronic P123/F127 itself. Intracellular ATP depletion was the main mechanism of Pluronic P123/F127 for P-gp inhibition. In vitro cytotoxicity study was also conducted in order to compare cytotoxic effect among different PTX formulations. It indicated that the IC50 of PTX-loaded Pluronic P123/F127 mixed micelles was 6.3-fold lower than free PTX and 2.3-fold lower than Taxol, respectively. Therefore, Pluronic P123/F127 polymeric micelles could be considered a promising drug delivery system to overcome MDR in cancer therapy.
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, China; Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Shanghai, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Shanghai Hengrui Pharmaceuticals Co. Ltd., Shanghai, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Yuan
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, China; Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Shanghai, China.
authors.forename: Junguo
authors.initials: J
authors.lastname: Hao
authors.affiliation: School of Pharmacy, Fudan University, Shanghai, China; Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Shanghai, China. Electronic address: xlfang@shmu.edu.cn.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Fang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000255:Adenosine Triphosphate / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage; D011060:Poloxalene / Q000008:administration & dosage*; D011095:Polyethylenes / Q000008:administration & dosage*; D011108:Polymers / Q000008:administration & dosage*; D011126:Polypropylenes / Q000008:administration & dosage*; D020112:Rhodamine 123 / Q000008:administration & dosage; D012235:Rhodamines / Q000008:administration & dosage
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008823:Micelles; D011095:Polyethylenes; D011108:Polymers; D011126:Polypropylenes; D012235:Rhodamines; C026188:rhodamine 6G; D020112:Rhodamine 123; C464484:pluronic block copolymer P123; D004317:Doxorubicin; D000255:Adenosine Triphosphate; D011060:Poloxalene; C078661:UCON 50-HB-5100; D017239:Paclitaxel
keywords: Cellular uptake; Multidrug resistance; P-gp; Pluronic block copolymer; Polymeric micelles