title: Mixed Micelles of Doxorubicin Overcome Multidrug Resistance by Inhibiting the Expression of P-Glycoprotein.
abstract: With the goal of overcoming multidrug resistance, DSPE-PEG (polyethylene glycol 2000 grafted with distearoyl phosphatidylethanolamine) and TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) were combined, each with a different inhibiting mechanism for P-glycoprotein (P-gp) expression, to create mixed micelles with the purpose of encapsulating the water-soluble drug, doxorubicin (Dox). As the molar ratio of Dox/DSPE-PEG/TPGS was 1:1:0.2, the encapsulation efficiency and particle size of the micelles were 98.2% and 12.8 nm respectively. Compared to Dox/DSPE-PEG micelles, Dox/DSPE-PEG/TPGS mixed micelles demonstrated enhanced in vitro cytotoxicity, drug uptake, and apoptosis for drug resistant H460/TaxR cancer cells. Western blot results showed that the expression level of P-gp significantly decreased as H460/TaxR cells were incubated with Dox/DSPE-PEG/TPGS mixed micelles. The anti-tumor efficacy in vivo was evaluated using H460/TaxR-bearing mice and showed that Dox/DSPE-PEG/TPGS mixed micelles were more effective at inhibiting tumor growth than Dox/DSPE-PEG micelles and free Dox solution. It was also found that the high efficacy of mixed micelles was associated with the ability to induce dramatic apoptosis of the tumor cells. In summary, through combining different P-gp inhibiting mechanisms, mixed micelles could be a promising nanocarrier for anti-cancer drugs in overcoming multidrug resistance.
authors: Yan
authors: Y
authors: Jin
authors: Zhijie
authors: Z
authors: Zhang
authors: Tie
authors: T
authors: Zhao
authors: Xiaodong
authors: X
authors: Liu
authors: Lingyan
authors: L
authors: Jian
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008823:Micelles; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010714:Phosphatidylethanolamines / Q000008:administration & dosage / Q000737:chemistry; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D016896:Treatment Outcome; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008823:Micelles; D053769:Nanocapsules; D010714:Phosphatidylethanolamines; D014810:Vitamin E; D011092:Polyethylene Glycols; D004317:Doxorubicin; C014225:tocophersolan